Quantification of primary mitral regurgitation by echocardiography: A practical appraisal.

The accurate quantification of primary mitral regurgitation (MR) and its consequences on cardiac remodeling is of paramount importance to determine the best timing for surgery in these patients. The recommended echocardiographic grading of primary MR severity relies on an integrated multiparametric approach. It is expected that the large number of echocardiographic parameters collected would offer the possibility to check the measured values regarding their congruence in order to conclude reliably on MR severity. However, the use of multiple parameters to grade MR can result in potential discrepancies between one or more of them. Importantly, many factors beyond MR severity impact the values obtained for these parameters including technical settings, anatomic and hemodynamic considerations, patient's characteristics and echocardiographer' skills. Hence, clinicians involved in valvular diseases should be well aware of the respective strengths and pitfalls of each of MR grading methods by echocardiography. Recent literature highlighted the need for a reappraisal of the severity of primary MR from a hemodynamic perspective. The estimation of MR regurgitation fraction by indirect quantitative methods, whenever possible, should be central when grading the severity of these patients. The assessment of the MR effective regurgitant orifice area by the proximal flow convergence method should be used in a semi-quantitative manner. Furthermore, it is crucial to acknowledge specific clinical situations in MR at risk of misevaluation when grading severity such as late-systolic MR, bi-leaflet prolapse with multiple jets or extensive leak, wall-constrained eccentric jet or in older patients with complex MR mechanism. Finally, it is debatable whether the 4-grades classification of MR severity would be still relevant nowadays, since the indication for mitral valve (MV) surgery is discussed in clinical practice for patients with 3+ and 4+ primary MR based on symptoms, specific markers of adverse outcome and MV repair probability. Primary MR grading should be seen as a continuum integrating both quantification of MR and its consequences, even for patients with presumed "moderate" MR.

Hypovitaminosis D and cardiovascular outcomes: A systematic review and meta-analysis.

Background: The relation between blood vitamin D levels and the risk of cardiovascular outcomes is debatable. To our knowledge this is the first comparative meta-analysis of more than 100,000 patients' data with the aim to inspect the relevance of low vitamin D levels with adverse cardiovascular events. Methods: Online databases including PubMed, Embase and Cochrane Central were queried to compare the cardiovascular outcomes among hypovitaminosis D (HVD) and control group. The outcomes assessed included differences in major adverse cardiovascular events (MACE), mortality, myocardial infarction, and heart failure. Unadjusted odds ratios (OR) were calculated using a random-effect model with a 95% confidence interval (CI) and P less than 0.05 as a statistical significance. Results: A total of 8 studies including 426,039 patients were included in this analysis. HVD group was associated with a higher incidence of MACE (OR 1.92, 95% CI 1.24 to 2.98, p = 0.003), while there was no significant association of HVD and all-cause mortality (OR 1.77, 95% CI 0.75 to 4.17, p = 0.19), risk of myocardial infarction (OR 0.69, 95% CI 0.39 to 1.24, p = 0.22), and heart failure (OR 1.20, 95% CI 0.34 to 4.25, p = 0.78). Conclusions: This meta-analysis suggested that low blood levels of vitamin D are associated with MACE, but no such difference in all-cause mortality, myocardial infarction or heart failure was observed. Appropriate supplementation of vitamin D in selected populations might be cardioprotective in nature and warrants extensive trials.

Valve Abnormalities, Risk Factors for Heart Valve Disease and Valve Replacement Surgery in Spondyloarthritis. A Systematic Review of the Literature.

Objective: Evaluate the evidence on the abnormalities of the aortic root and heart valves, risk and prognostic factors for heart valve disease and valve replacement surgery in spondyloarthritis. Methods: A systematic literature review was performed using Medline, EMBASE and Cochrane databases until July 2021. Prevalence, incidence, risk and prognostic factors for heart valve disease; dimension, morphology, and pathological abnormalities of the valves were analyzed. Patient characteristics (younger age, history of cardiac disease or longer disease duration) and period of realization were considered for the analysis. The SIGN Approach was used for rating the quality of the evidence of the studies. Results: In total, 37 out of 555 studies were included. Overall, the level of evidence was low. The incidence of aortic insufficiency was 2.5-3.9‰. Hazard Ratio for aortic insufficiency was 1.8-2.0. Relative risk for aortic valve replacement surgery in ankylosing spondylitis patients was 1.22-1.46. Odds ratio for aortic insufficiency was 1.07 for age and 1.05 for disease duration. Mitral valve abnormalities described were mitral valve prolapse, calcification, and thickening. Aortic valve abnormalities described were calcification, thickening and an echocardiographic "subaortic bump." Abnormalities of the aorta described were thickening of the wall and aortic root dilatation. The most common microscopic findings were scarring of the adventitia, lymphocytic infiltration, and intimal proliferation. Conclusions: A higher prevalence and risk of aortic valve disease is observed in patients with ankylosing spondylitis. Studies were heterogeneous and analysis was not adjusted by potential confounders. Most studies did not define accurate outcomes and may have detected small effects as being statistically significant.

The Putative Roles and Functions of Indel, Repetition and Duplication Events in Alphavirus Non-Structural Protein 3 Hypervariable Domain (nsP3 HVD) in Evolution, Viability and Re-Emergence.

Alphavirus non-structural proteins 1-4 (nsP1, nsP2, nsP3, and nsP4) are known to be crucial for alphavirus RNA replication and translation. To date, nsP3 has been demonstrated to mediate many virus-host protein-protein interactions in several fundamental alphavirus mechanisms, particularly during the early stages of replication. However, the molecular pathways and proteins networks underlying these mechanisms remain poorly described. This is due to the low genetic sequence homology of the nsP3 protein among the alphavirus species, especially at its 3' C-terminal domain, the hypervariable domain (HVD). Moreover, the nsP3 HVD is almost or completely intrinsically disordered and has a poor ability to form secondary structures. Evolution in the nsP3 HVD region allows the alphavirus to adapt to vertebrate and insect hosts. This review focuses on the putative roles and functions of indel, repetition, and duplication events that have occurred in the alphavirus nsP3 HVD, including characterization of the differences and their implications for specificity in the context of virus-host interactions in fundamental alphavirus mechanisms, which have thus directly facilitated the evolution, adaptation, viability, and re-emergence of these viruses.

Impact of Hypothyroidism on Echocardiographic Characteristics of Patients With Heart Valve Disease: A Single-Center Propensity Score-Based Study.

Background: Hypothyroidism is known to be correlated with multiple heart diseases. However, the influence of hypothyroidism on the patients with heart valve disease (HVD) is still unclear. The purpose of our study was to investigate the impact of hypothyroidism on echocardiographic characteristics of patients with heart valve disease. Methods: We conducted a retrospective cohort study which included 2,128 patients with HVD, and they were divided into euthyroid, subclinical hypothyroidism (SCHypoT), and overt hypothyroidism (OHypoT) group. Echocardiographic characteristics before and after valve surgery between groups were compared by using propensity score (PS) analysis. Kaplan-Meier analysis was used to compare the percent of recovery of left atrial (LA) enlargement between groups. Results: Overall, 463 patients had hypothyroidism (404 SCHypoT patients and 59 OHypoT patients), and 1,665 patients were euthyroid. At baseline, hypothyroidism was associated with significantly higher left atrial diameter (LAD), interventricular septum thickness, left ventricular posterior wall thickness, pulmonary artery systolic pressure, and lower left ventricular ejection fraction. After valve surgery, only LAD remained significantly higher in the patients with hypothyroidism. Additionally, patients with hypothyroidism had a significantly lower recovery rate of LA enlargement after valve surgery compared with euthyroid patients. Conclusion: Hypothyroidism was associated with a larger LAD in patients with HVD before and after surgery, which may suggest that hypothyroidism is a risk factor of LA enlargement of HVD. Besides, hypothyroidism was associated with a significantly lower recovery rate of LA enlargement after valve surgery.

ECG-derived respiration based on iterated Hilbert transform and Hilbert vibration decomposition.

Monitoring of the respiration using the electrocardiogram (ECG) is desirable for the simultaneous study of cardiac activities and the respiration in the aspects of comfort, mobility, and cost of the healthcare system. This paper proposes a new approach for deriving the respiration from single-lead ECG based on the iterated Hilbert transform (IHT) and the Hilbert vibration decomposition (HVD). The ECG signal is first decomposed into the multicomponent sinusoidal signals using the IHT technique. Afterward, the lower order amplitude components obtained from the IHT are filtered using the HVD to extract the respiration information. Experiments are performed on the Fantasia and Apnea-ECG datasets. The performance of the proposed ECG-derived respiration (EDR) approach is compared with the existing techniques including the principal component analysis (PCA), R-peak amplitudes (RPA), respiratory sinus arrhythmia (RSA), slopes of the QRS complex, and R-wave angle. The proposed technique showed the higher median values of correlation (first and third quartile) for both the Fantasia and Apnea-ECG datasets as 0.699 (0.55, 0.82) and 0.57 (0.40, 0.73), respectively. Also, the proposed algorithm provided the lowest values of the mean absolute error and the average percentage error computed from the EDR and reference (recorded) respiration signals for both the Fantasia and Apnea-ECG datasets as 1.27 and 9.3%, and 1.35 and 10.2%, respectively. In the experiments performed over different age group subjects of the Fantasia dataset, the proposed algorithm provided effective results in the younger population but outperformed the existing techniques in the case of elderly subjects. The proposed EDR technique has the advantages over existing techniques in terms of the better agreement in the respiratory rates and specifically, it reduces the need for an extra step required for the detection of fiducial points in the ECG for the estimation of respiration which makes the process effective and less-complex. The above performance results obtained from two different datasets validate that the proposed approach can be used for monitoring of the respiration using single-lead ECG.

Extramammary Paget disease of the vulva: immunohistochemical analysis of neoangiogenesis and epithelial-mesenchymal transition markers expression.

BACKGROUND: Extra-mammary Paget's disease of the vulva (EMPDV) is an infrequent chronic disease that often recurs. The aim of the study was to assess the presence of neoangiogenesis and the expression of epithelial-mesenchymal transition (EMT) markers in EMPDV, and their potential correlation with stromal invasion. METHODS: All the women consecutively treated for EMPDV at our Institute, between January 2011 and December 2014, were studied for neoangiogenesis, analysed by microvessel density (MVD) using antibodies against CD31 and CD34. Immunohistochemical expression of E- / N-cadherin, ß-catenin and SLUG was also evaluated. In each slide, three fields with the highest number of capillaries and small venules were identified at low power. In these three fields, the highest vessel density (HVD) and the average vessel density (AVD) at 200× and 400× magnification were counted. Immunohistochemical reactions for non-vascular markers were semiquantitatively scored by two pathologists, using a three-tier scale. RESULTS: Seventeen cases of EMPDV (including 10 cases of invasive disease) were included. The AVD at 200× and 400× and the HVD at 400× magnification were significantly associated with invasive EMPDV (p = 0.02, 0.03, 0.03 respectively). No significant correlation between MVD, EMT-markers expression and risk of recurrence was detected. CONCLUSION: These results indicate that MVD, as a measure of neoangiogenesis, may be associated with histological progression of EMPDV. EMT could also be linked to an invasive potential of EMPDV but larger series are required to confirm this hypothesis.

miR-27a protects human mitral valve interstitial cell from TNF-alpha-induced inflammatory injury via up-regulation of NELL-1

MicroRNAs (miRNAs) have been reported to be associated with heart valve disease, which can be caused by inflammation. This study aimed to investigate the functional impacts of miR-27a on TNF-α-induced inflammatory injury in human mitral valve interstitial cells (hMVICs). hMVICs were subjected to 40 ng/mL TNF-α for 48 h, before which the expressions of miR-27a and NELL-1 in hMVICs were altered by stable transfection. Trypan blue staining, BrdU incorporation assay, flow cytometry detection, ELISA, and western blot assay were performed to detect cell proliferation, apoptosis, and the release of proinflammatory cytokines. We found that miR-27a was lowly expressed in response to TNF-α exposure in hMVICs. Overexpression of miR-27a rescued hMVICs from TNF-α-induced inflammatory injury, as cell viability and BrdU incorporation were increased, apoptotic cell rate was decreased, Bcl-2 was up-regulated, Bax and cleaved caspase-3/9 were down-regulated, and the release of IL-1β, IL-6, and MMP-9 were reduced. NELL-1 was positively regulated by miR-27a, and NELL-1 up-regulation exhibited protective functions during TNF-α-induced cell damage. Furthermore, miR-27a blocked JNK and Wnt/β-catenin signaling pathways, and the blockage was abolished when NELL-1 was silenced. This study demonstrated that miR-27a overexpression protected hMVICs from TNF-α-induced cell damage, which might be via up-regulation of NELL-1 and thus modulation of JNK and Wnt/β-catenin signaling pathways.

Two-stage designs versus European scaled average designs in bioequivalence studies for highly variable drugs: Which to choose?

The usual approach to determine bioequivalence for highly variable drugs is scaled average bioequivalence, which is based on expanding the limits as a function of the within-subject variability in the reference formulation. This requires separately estimating this variability and thus using replicated or semireplicated crossover designs. On the other hand, regulations also allow using common 2 × 2 crossover designs based on two-stage adaptive approaches with sample size reestimation at an interim analysis. The choice between scaled or two-stage designs is crucial and must be fully described in the protocol. Using Monte Carlo simulations, we show that both methodologies achieve comparable statistical power, though the scaled method usually requires less sample size, but at the expense of each subject being exposed more times to the treatments. With an adequate initial sample size (not too low, eg, 24 subjects), two-stage methods are a flexible and efficient option to consider: They have enough power (eg, 80%) at the first stage for non-highly variable drugs, and, if otherwise, they provide the opportunity to step up to a second stage that includes additional subjects.

SLC45A2 mutation frequency in Oculocutaneous Albinism Italian patients doesn't differ from other European studies.

BACKGROUND: Oculocutaneous Albinism (OCA) is a heterogeneous group of inherited diseases involving hair, skin and eyes. To date, six forms are recognized on the effects of different melanogenesis genes. OCA4 is caused by mutations in SLC45A2 showing a heterogeneous phenotype ranging from white hair, blue irides and nystagmus to brown/black hair, brown irides and no nystagmus. The high clinic variety often leads to misdiagnosis. Our aim is to contribute to OCA4 diagnosis defining SLC45A2 genetic variants in Italian patients with OCA without any TYR, OCA2 and TYRP1 gene defects. MATERIALS AND METHODS: After the clinical diagnosis of OCA, all patients received genetic counseling and genetic test. Automatic sequencing of TYR, OCA2, and TYRP1 genes was performed on DNA of 117 albino patients. Multiplex Ligation-dependent Probe Amplification (MLPA) was carried out on TYR and OCA2 genes to increase the mutation rate. SLC45A2 gene sequencing was then executed in the patients with a single mutation in one of the TYR, OCA2, TYRP1 genes and in the patients, which resulted negative at the screening of these genes. RESULTS: SLC45A2 gene analysis was performed in 41 patients and gene alterations were found in 5 patients. Four previously reported SLC45A2 mutations were found: p.G100S, p.W202C, p.A511E and c.986delC, and three novel variants were identified: p.M265L, p.H94D, and c.1156+1G>A. All the alterations have been detected in the group of patients without mutations in the other OCA genes. CONCLUSIONS: Three new variants were identified in OCA4 gene; the analysis allowed the classification of a patient previously misdiagnosed as OA1 because of skin and hair pigmentation presence. The molecular defects in SLC45A2 gene represent the 3.4% in this cohort of Italian patients, similar to other Caucasian populations; our data differ from those previously published by an Italian researcher group, obtained on a smaller cohort of patients.