Outcomes of repeat transcatheter aortic valve replacement with balloon-expandable valves: a registry study.

BACKGROUND: With increasing numbers of patients undergoing transcatheter aortic valve replacement (TAVR), data on management of failed TAVR, including repeat TAVR procedure, are needed. The aim of this study was to assess the safety and efficacy of redo-TAVR in a national registry. METHODS: This study included all consecutive patients in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from Nov 9, 2011, to Dec 30, 2022 who underwent TAVR with balloon-expandable valves in failed transcatheter heart valves (redo-TAVR) or native aortic valves (native-TAVR). Procedural, echocardiographic, and clinical outcomes were compared between redo-TAVR and native-TAVR cohorts using propensity score matching. FINDINGS: Among 350 591 patients (1320 redo-TAVR; 349 271 native-TAVR), 1320 propensity-matched pairs of patients undergoing redo-TAVR and native-TAVR were analysed (redo-TAVR cohort: mean age 78 years [SD 9]; 559 [42·3%] of 1320 female, 761 [57·7%] male; mean predicted surgical risk of 30-day mortality 8·1%). The rates of procedural complications of redo-TAVR were low (coronary compression or obstruction: four [0·3%] of 1320; intraprocedural death: eight [0·6%] of 1320; conversion to open heart surgery: six [0·5%] of 1319) and similar to native-TAVR. There was no significant difference between redo-TAVR and native-TAVR populations in death at 30 days (4·7% vs 4·0%, p=0·36) or 1 year (17·5% vs 19·0%, p=0·57), and stroke at 30 days (2·0% vs 1·9%, p=0·84) or 1 year (3·2% vs 3·5%, p=0·80). Redo-TAVR reduced aortic valve gradients at 1 year, although they were higher in the redo-TAVR group compared with the native-TAVR group (15 mm Hg vs 12 mm Hg; p<0·0001). Moderate or severe aortic regurgitation rates were similar between redo-TAVR and native-TAVR groups at 1 year (1·8% vs 3·3%, p=0·18). Death or stroke after redo-TAVR were not significantly affected by the timing of redo-TAVR (before or after 1 year of index TAVR), or by index transcatheter valve type (balloon-expandable or non-balloon-expandable). INTERPRETATION: Redo-TAVR with balloon-expandable valves effectively treated dysfunction of the index TAVR procedure with low procedural complication rates, and death and stroke rates similar to those in patients with a similar clinical profile and predicted risk undergoing TAVR for native aortic valve stenosis. Redo-TAVR with balloon-expandable valves might be a reasonable treatment for failed TAVR in selected patients. FUNDING: Edwards Lifesciences.

Assessing the lack of diversity in genetics research across neurodegenerative diseases: A systematic review of the GWAS Catalog and literature.

The under-representation of non-European cohorts in neurodegenerative disease genome-wide association studies (GWAS) hampers precision medicine efforts. Despite the inherent genetic and phenotypic diversity in these diseases, GWAS research consistently exhibits a disproportionate emphasis on participants of European ancestry. This study reviews GWAS up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. We conducted a systematic review of GWAS results and publications up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. Rigorous article inclusion and quality assessment methods were employed. Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study identified over 90 risk loci, compared to a total of 50 novel loci in identified in all non-European or multi-ancestry studies. Notably, only six of the loci have been replicated. The significant under-representation of non-European ancestries in NDD GWAS hinders comprehensive genetic understanding. Prioritizing genomic diversity in future research is crucial for advancing NDD therapies and understanding. HIGHLIGHTS: Eighty-two percent of neurodegenerative genome-wide association studies (GWAS) focus on Europeans. Only 6 of 50 novel neurodegenerative disease (NDD) genetic loci have been replicated. Lack of diversity significantly hampers understanding of NDDs. Increasing diversity in NDD genetic research is urgently required. New initiatives are aiming to enhance diversity in NDD research.

Polygenic Parkinson's Disease Genetic Risk Score as Risk Modifier of Parkinsonism in Gaucher Disease.

BACKGROUND: Biallelic pathogenic variants in GBA1 are the cause of Gaucher disease (GD) type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. Heterozygous GBA1 variants are also a common genetic risk factor for Parkinson's disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk for PD. OBJECTIVE: The objective of this study was to investigate the contribution of PD risk variants to risk for PD in patients with GD1. METHODS: We studied 225 patients with GD1, including 199 without PD and 26 with PD. All cases were genotyped, and the genetic data were imputed using common pipelines. RESULTS: On average, patients with GD1 with PD have a significantly higher PD genetic risk score than those without PD (P = 0.021). CONCLUSIONS: Our results indicate that variants included in the PD genetic risk score were more frequent in patients with GD1 who developed PD, suggesting that common risk variants may affect underlying biological pathways. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Transcatheter Mitral Valve Repair for Degenerative Mitral Regurgitation.

Importance: There are limited data on the outcomes of transcatheter edge-to-edge mitral valve repair for degenerative mitral regurgitation (MR) in a real-world setting. Objective: To evaluate the outcomes of transcatheter mitral valve repair for degenerative MR. Design, Setting, and Participants: Cohort study of consecutive patients in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry who underwent nonemergent transcatheter mitral valve repair for degenerative MR in the US from 2014 through 2022. Exposure: Transcatheter edge-to-edge mitral valve repair with the MitraClip device (Abbott). Main Outcomes and Measures: The primary end point was MR success, defined as moderate or less residual MR and a mean mitral gradient of less than 10 mm Hg. Clinical outcomes were evaluated based on the degree of residual MR (mild or less MR or moderate MR) and mitral valve gradients (≤5 mm Hg or >5 to <10 mm Hg). Results: A total of 19 088 patients with isolated moderate to severe or severe degenerative MR who underwent transcatheter mitral valve repair were analyzed (median age, 82 years; 48% women; median Society of Thoracic Surgeons predicted risk of mortality with surgical mitral valve repair, 4.6%). MR success was achieved in 88.9% of patients. At 30 days, the incidence of death was 2.7%; stroke, 1.2%; and mitral valve reintervention, 0.97%. MR success compared with an unsuccessful procedure was associated with significantly lower mortality (14.0% vs 26.7%; adjusted hazard ratio, 0.49; 95% CI, 0.42-0.56; P < .001) and heart failure readmission (8.4% vs 16.9%; adjusted hazard ratio, 0.47; 95% CI, 0.41-0.54; P < .001) at 1 year. Among patients with MR success, the lowest mortality was observed in patients who had both mild or less residual MR and mean mitral gradients of 5 mm Hg or less compared with those with an unsuccessful procedure (11.4% vs 26.7%; adjusted hazard ratio, 0.40; 95% CI, 0.34-0.47; P < .001). Conclusions and Relevance: In this registry-based study of patients with degenerative MR undergoing transcatheter mitral valve repair, the procedure was safe and resulted in successful repair in 88.9% of patients. The lowest mortality was observed in patients with mild or less residual MR and low mitral gradients.

Long-Term Impact of Small Mitral Valve Orifice Area after Transcatheter Edge-to-Edge Mitral Valve Repair on Clinical Outcome: A Three-Dimensional Echocardiography Study.

BACKGROUND: Iatrogenic mitral stenosis is a complication associated with transcatheter edge-to-edge mitral valve repair. Some reports revealed the impact of mean transmitral pressure gradient after procedure on long-term clinical outcomes. However, the association between prognosis and mitral valve orifice area (MVA) after the procedure has been poorly studied. This study aimed to investigate the association between postprocedural small MVA, derived from three-dimensional (3D) transesophageal echocardiography (TEE), and long-term clinical outcomes in 2 cohorts: the degenerative mitral regurgitation (MR) cohort and the functional MR cohort. METHODS: This retrospective study assessed 279 consecutive patients with 3D TEE data during transcatheter edge-to-edge mitral valve repair between January 2010 and December 2016. Mitral valve orifice area after device implantation was measured by 3D planimetry. The patients with degenerative and functional MR were stratified separately into 2 groups according to postprocedural MVA: normal MVA (MVA > 1.5 cm2) group and small MVA (MVA ≤ 1.5 cm2) group. RESULTS: Of the 279 patients, 142 (51%) had degenerative MR and 137 (49%) had functional MR. The number of degenerative MR patients with small MVA was 38, whereas 42 patients were in the functional MR cohort. Patients with small MVA had higher rate of all-cause mortality in the degenerative MR group (log-rank test: P = .01) but not in the functional MR group (log-rank test: P = .52). In multivariate analysis small MVA was independently associated with all-cause mortality but not postprocedural transmitral pressure gradient. Neither small MVA nor transmitral pressure gradient was associated with all-cause mortality in patients with functional MR. CONCLUSION: Small MVA measured by 3D TEE after transcatheter mitral edge-to-edge repair was associated with poor prognosis in patients with degenerative MR.

Assessing the lack of diversity in genetics research across neurodegenerative diseases: a systematic review of the GWAS Catalog and literature.

Importance: The under-representation of participants with non-European ancestry in genome-wide association studies (GWAS) is a critical issue that has significant implications, including hindering the progress of precision medicine initiatives. This issue is particularly significant in the context of neurodegenerative diseases (NDDs), where current therapeutic approaches have shown limited success. Addressing this under-representation is crucial to harnessing the full potential of genomic medicine in underserved communities and improving outcomes for NDD patients. Objective: Our primary objective was to assess the representation of non-European ancestry participants in genetic discovery efforts related to NDDs. We aimed to quantify the extent of inclusion of diverse ancestry groups in NDD studies and determine the number of associated loci identified in more inclusive studies. Specifically, we sought to highlight the disparities in research efforts and outcomes between studies predominantly involving European ancestry participants and those deliberately targeting non-European or multi-ancestry populations across NDDs. Evidence Review: We conducted a systematic review utilizing existing GWAS results and publications to assess the inclusion of diverse ancestry groups in neurodegeneration and neurogenetics studies. Our search encompassed studies published up to the end of 2022, with a focus on identifying research that deliberately included non-European or multi-ancestry cohorts. We employed rigorous methods for the inclusion of identified articles and quality assessment. Findings: Our review identified a total of 123 NDD GWAS. Strikingly, 82% of these studies predominantly featured participants of European ancestry. Endeavors specifically targeting non-European or multi-ancestry populations across NDDs identified only 52 risk loci. This contrasts with predominantly European studies, which reported over 90 risk loci for a single disease. Encouragingly, over 65% of these discoveries occurred in 2020 or later, indicating a recent increase in studies deliberately including non-European cohorts. Conclusions and relevance: Our findings underscore the pressing need for increased diversity in neurodegenerative research. The significant under-representation of non-European ancestry participants in NDD GWAS limits our understanding of the genetic underpinnings of these diseases. To advance the field of neurodegenerative research and develop more effective therapies, it is imperative that future investigations prioritize and harness the genomic diversity present within and across global populations.

Transjugular Transcatheter Tricuspid Valve Replacement: Early Compassionate Use Outcomes.

BACKGROUND: Data on procedural and early outcomes after transjugular transcatheter tricuspid valve replacement (TTVR) are limited. OBJECTIVES: This study sought to evaluate first-in-man procedural and clinical outcomes after transjugular TTVR with a special focus on patients who received large device sizes in whom TTVR outcomes have been questioned. METHODS: The retrospective registry included patients who underwent TTVR using the LuX-Valve Plus system (Jenscare Biotechnology Co Ltd) for symptomatic tricuspid regurgitation (TR) from January 2022 until February 2024 at 15 international centers in a compassionate use setting. The endpoints were procedural TR reduction, in-hospital death, adverse events, and 1-month survival. We further stratified results according to the size of the implanted device (<55 vs ≥55 mm). RESULTS: The registry included a total of 76 patients at a median age of 78 years (Q1-Q3: 72-83 years, 47.4% women). TR was reduced to ≤2+ and ≤1+ in 94.7% and 90.8% of patients (75.0% of patients received TTVR devices ≥55 mm) with well-sustained results at 1-month follow-up (TR ≤2+ in 95.0% and ≤1+ 86.8%). Residual TR was paravalvular in all cases. In-hospital death occurred in 4 patients (5.3%). Four patients (5.3%) underwent cardiac surgery during index hospitalization. Major in-hospital bleeding events occurred in 5 patients (6.6%). New in-hospital pacemaker implantation was required in 3.9% of patients in the overall cohort (5.7% in "pacemaker-naive" individuals). No cases of valve thrombosis, stroke, myocardial infarction, or pulmonary embolism were observed. At 1-month follow-up, survival was 94.4%, and NYHA functional class significantly improved. One further patient received a pacemaker, 1 further bleeding event occurred, and 2 patients underwent reintervention or surgery within the first 30 days after TTVR. No differences in procedural outcomes or adverse events were observed after stratification for valve size. CONCLUSIONS: Transjugular TTVR appears to be a safe and effective treatment option for patients with severe TR with comparable outcomes in very large tricuspid anatomies.

Impact of Intraprocedural Mitral Regurgitation and Gradient Following Transcatheter Edge-to-Edge Repair for Primary Mitral Regurgitation.

BACKGROUND: The impact of intraprocedural results following transcatheter edge-to-edge repair (TEER) in primary mitral regurgitation (MR) is controversial. OBJECTIVES: This study sought to investigate the prognostic impact of intraprocedural residual mitral regurgitation (rMR) and mean mitral valve gradient (MPG) in patients with primary MR undergoing TEER. METHODS: The PRIME-MR (Outcomes of Patients Treated With Mitral Transcatheter Edge-to-Edge Repair for Primary Mitral Regurgitation) registry included consecutive patients with primary MR undergoing TEER from 2008 to 2022 at 27 international sites. Clinical outcomes were assessed according to intraprocedural rMR and mean MPG. Patients were categorized according to rMR (optimal result: ≤1+, suboptimal result: ≥2+) and MPG (low gradient: ≤5 mm Hg, high gradient: > 5 mm Hg). The prognostic impact of rMR and MPG was evaluated in a Cox regression analysis. The primary endpoint was 2-year all-cause mortality or heart failure hospitalization. RESULTS: Intraprocedural rMR and mean MPG were available in 1,509 patients (median age = 82 years [Q1-Q3: 76.0-86.0 years], 55.1% male). Kaplan-Meier analysis according to rMR severity showed significant differences for the primary endpoint between rMR ≤1+ (29.1%), 2+ (41.7%), and ≥3+ (58.0%; P < 0.001), whereas there was no difference between patients with a low (32.4%) and high gradient (42.1%; P = 0.12). An optimal result/low gradient was achieved in most patients (n = 1,039). The worst outcomes were observed in patients with a suboptimal result/high gradient. After adjustment, rMR ≥2+ was independently linked to the primary endpoint (HR: 1.87; 95% CI: 1.32-2.65; P < 0.001), whereas MPG >5 mm Hg was not (HR: 0.78; 95% CI: 0.47-1.31; P = 0.35). CONCLUSIONS: Intraprocedural rMR but not MPG independently predicted clinical outcomes following TEER for primary MR. When performing TEER in primary MR, optimal MR reduction seems to outweigh the impact of high transvalvular gradients.

Hemodynamic and Mid-Term Outcomes for Transcatheter Aortic Valve Replacement in Degenerated Internally Stented Valves.

BACKGROUND: Valve-in-valve (ViV) transcatheter aortic valve replacement is indicated in patients undergoing repeat intervention for degenerative aortic valve bioprostheses. Patients with internally stented valves (ie, Mitroflow and Trifecta) are at high risk for coronary artery obstruction during ViV procedures because of valve design, as the leaflets are mounted outside the valve stent. OBJECTIVES: The aim of this study was to compare the hemodynamic and clinical outcomes of transcatheter aortic valve replacement within internally stented valves (ViV-IS) vs other surgical valves (ViV-OS). METHODS: Baseline characteristics, hemodynamic parameters, and clinical outcomes of patients who underwent ViV-IS were retrospectively collected and compared with those of patients who underwent ViV-OS. RESULTS: A total of 250 patients (65% men, median Society of Thoracic Surgeons score 4.4% [IQR: 2.2%-8.4%]) were included. Seventy-one patients (28%) underwent ViV-IS, and 179 (72%) patients underwent ViV-OS. Patients who underwent ViV-OS had better periprocedural hemodynamic status compared with those who underwent ViV-IS (median mean gradient 6 [IQR: 2-13] vs 12 [IQR: 6-16]; P < 0.001). This was not significantly different when both groups were matched on the basis of age, sex, and valve internal diameter size (median mean gradient: 18 [IQR: 13-25] for ViV-OS vs 18 [IQR: 11-24] for ViV-IS; P = 0.36). Coronary protection for potential occlusion was performed more in ViV-IS vs ViV-OS pr (79% vs 6%, respectively; P < 0.001). Patients who underwent ViV-IS had a higher risk for coronary occlusion, requiring stent deployment, compared with those who underwent ViV-OS (54% vs 3%, respectively; P < 0.001. There was no difference in mortality at 3 years between the 2 groups (P = 0.59). CONCLUSIONS: Patients who underwent ViV-IS had a very high incidence of coronary compromise that can be safely and effectively treated. In the setting of a systematic coronary protection strategy, ViV-OS and ViV-IS provide similar mid-term outcome, and periprocedural hemodynamic status (following adjustment for age, sex, and true internal diameter).

The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism.

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.

Impact of Left Ventricular Global Longitudinal Strain on Outcomes After Transcatheter Edge-to-Edge Repair in Secondary Mitral Regurgitation.

Assessment of left ventricular (LV) systolic function is essential in patient selection for transcatheter edge-to-edge repair (TEER) in secondary mitral regurgitation (MR). Although LV ejection fraction (EF) is mostly used for assessing LV function, it represents the change of LV chamber size, but not myocardial contractility. LV global longitudinal strain (GLS) provides an alternative to assess LV systolic function in patients with secondary MR. This study included 380 patients with secondary MR (mean age 71.0 ± 13.0 years; 61.1% male) who underwent TEER. Patients were dichotomized based on baseline LV GLS (more impaired GLS [<7.0%] vs less impaired GLS [≥7%]) based on existing literature. The primary outcome was all-cause mortality, whereas the secondary outcome was the composite end point of all-cause mortality and heart failure hospitalization. The mean LV GLS was 8.1 ± 3.8%, and 162 patients had GLS <7%. Patients with more impaired GLS (<7%) were more likely to be male (68.5% vs 55.5%; p = 0.01) and have larger LV end-diastolic volume (110.5 ± 36.5 ml/m2 vs 92.9 ± 34.3 ml/m2; p <0.001) and lower LVEF (22.2 ± 8.9% vs 36.4 ± 14.5%; p <0.001) than those with less impaired GLS (≥7%). The number of clips used and residual MR were similar between the 2 groups. Patients with more impaired LV GLS (<7%) had significantly higher 2-year event rates of the primary outcome (38.2% vs 25.9%; log-rank p = 0.003) and the secondary outcome (52.5% vs 36.3%; log-rank p <0.001). Multivariate analysis showed that LV GLS (<7%) was independently associated with the primary outcome (hazard ratio 1.65, 95% confidence interval 1.16 to 2.34, p = 0.005) and the secondary outcome (hazard ratio 1.54, 95% confidence interval 1.08 to 2.20, p = 0.016) whereas such associations were not observed with LVEF. In conclusion, LV GLS (<7%) was independently associated with a higher risk of adverse events in patients with secondary MR who underwent TEER.

Optimal Medical Therapy Following Transcatheter Aortic Valve Implantation.

Limited data exist on optimal medical therapy post-transcatheter aortic valve implantation (TAVI) for late cardiovascular events prevention. We aimed to evaluate the benefits of beta-blocker (BB), renin-angiotensin system inhibitor (RASi), and their combination on outcomes following successful TAVI. In a consecutive cohort of 1,684 patients with severe aortic stenosis undergoing TAVI, the status of BB and RASi treatment at discharge was collected, and patients were classified into 4 groups: no-treatment, BB alone, RASi alone, and combination groups. The primary outcome was a composite of all-cause mortality and rehospitalization for heart failure (HHF) at 2-year. There were 415 (25%), 462 (27%), 349 (21%), and 458 (27%) patients in no-treatment, BB alone, RASi alone, and combination groups, respectively. The primary outcome was lower in RASi alone (21%; adjusted hazard ratio [HR]adj: 0.58; 95% confidence interval [CI]: 0.42 to 0.81) and combination (22%; HRadj: 0.53; 95% CI: 0.39 to 0.72) groups than in no-treatment group (34%) but no significant difference between RASi alone and combination groups (HRadj: 1.14; 95% CI: 0.80 to 1.62). The primary outcome results were maintained in a sensitivity analysis of patients with reduced left ventricular systolic function. Furthermore, RASi treatment was an independent predictor of 2-year all-cause mortality (HRadj: 0.68; 95% CI: 0.51 to 0.90), while that was not observed in BB therapy (HRadj: 0.94; 95% CI: 0.71 to 1.25). In conclusion, post-TAVI treatment with RASi, but not with BB, was associated with lower all-cause mortality and HHF at 2-year. The combination of RASi and BB did not add an incremental reduction in the primary outcome over RASi alone.

Transcatheter Edge-to-Edge Mitral Valve Repair With the MitraClip G4 System.

OBJECTIVES: The primary objective of this study was to evaluate the effectiveness of the MitraClip G4 in the reduction of mitral regurgitation (MR). BACKGROUND: The next-generation MitraClip G4 system was recently introduced for the treatment of MR in the United States. METHODS: The study included consecutive patients undergoing transcatheter mitral edge-to-edge repair for MR with the MitraClip G4. The key outcome was the proportion of patients with MR reduction to ≤2+ at 30 days. RESULTS: Fifty-nine patients (median age 77 years, 62.7% men) were treated with the MitraClip G4. Reduction of MR to ≤2+ was achieved in 57 patients (96.6%) during the procedure, 58 patients (98.3%) at discharge, and 57 patients (96.6%) by 30 days. The median number of MitraClips used per patient was 2 (interquartile range: 1 to 3). Wide clips (NTW/XTW) were used in 82.7% of patients. The XTW clip was used most frequently as the first clip in patients with degenerative MR (65.4%) and the NTW clip in those with secondary MR (72.7%). The independent grasping mechanism was used in 49.2% of patients. CONCLUSIONS: Use of the MitraClip G4 system was associated with excellent reduction in MR to ≤2+ in 96.6% of patients at 30 days. The availability of multiple MitraClip G4 sizes, especially the wide clips, and the ability to independently grasp leaflets are the likely contributors to MR reduction.

Harlequin ichthyosis due to novel splice site mutation in the ABCA12 gene: postnatal to prenatal diagnosis.

BACKGROUND: Harlequin ichthyosis (HI) is a severe genetic disorder caused by the mutation in the ABCA12 gene. Infants born with this condition have markedly thickened, hard stratum corneum skin all over the body. METHODS: A female child born with a thick white plate of skin with deep cracks all over the body was investigated for genes associated with congenital Ichthyosis by Next Generation sequencing. The variant relevant to the clinical indications was identified using Picard and GATK version 3.6. Variant's pathogenicity was predicted by "in silico" tools like Mutation Taster 2, Mutation Assessor and LRT. Bidirectional Sanger sequencing further validated the same variant detected in the proband and confirmed in the parental blood and CVS. RESULTS: A homozygous 5' splice site variation that affects the position at 4 nucleotides downstream to the donor proximal splice site of intron 40 (c.5939+4A>G; ENST00000272895) of the ABCA12 gene was detected in the proband, and the parents were heterozygous for the same variant. This led to the confirmation of diagnosis of Harlequin ichthyosis in the proband. "In silico" prediction of the variant was found to be damaging by MutationTaster2. The CVS sample during subsequent pregnancy was confirmed to be heterozygous for the same variant. CONCLUSIONS: The novel intronic mutation found in the proband confirmed the clinical diagnosis as a severe type of HI and has helped the family in providing precise genetic counseling for further prevention of the disease and carrier screening of other family members.

Inhibitory effect of quercetin on epithelial to mesenchymal transition in SK-MEL-28 human melanoma cells defined by in vitro analysis on 3D collagen gels.

Considering the emerging concept of complementary and alternative medicine under the paucity of effective treatment for melanoma, we aimed to understand the effect of quercetin (Qu) on collagen I-induced epithelial-mesenchymal transition (EMT) in melanoma cells. To investigate the effect of Qu in melanoma cells, we used multiple methods, including real-time reverse transcription polymerase chain reaction, migration assay, and wound healing assay. We found that EMT was altered by Qu in melanoma cells. Qu-treated cells exhibited decreased migration and invasion activities. Mechanistically, a high expression of epithelial markers and a decrease in the expression of mesenchymal markers were found to be associated with reversal of EMT in melanoma cells. Time-dependent apoptosis was observed in Qu-treated melanoma cells, which was further confirmed by the upregulation in the protein levels of Caspase 3, a proapoptotic marker. Thus, our findings suggest Qu as a promising dietary compound under the new complementary and alternative medicine category of therapeutic drugs in the chemoprevention of melanoma.