Mitral valve prolapse: From new mechanisms to diagnostic challenges

Mitral valve prolapse (MVP) is the most common primary valvular abnormality, associated with various degrees of incompetence and sequelae, including heart failure and sudden cardiac death. Recent improvements in echocardiographic techniques and new insights into mitral valve anatomy and physiology have rendered the diagnosis of this condition more accurate and reliable. Here we review the genetic etiology, clinical significance, diagnosis, and treatment options for MVP patients

Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve.

IMPORTANCE Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. OBJECTIVE To identify a new gene for nsBAV. DESIGN, SETTING, AND PARTICIPANTS This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. MAIN OUTCOMES AND MEASURES To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. RESULTS A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. CONCLUSIONS AND RELEVANCE This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.This study was supported in part by grants PID2019-104776RB-I00 and CB16/ 11/00399 (Dr de la Pompa) from the Spanish Ministerio de Ciencia e Innovación (MCIN/ AEI/ 10.13039/501100011033/); a grant from Hadassah France Association (Drs Gilon and Tessler); a grant from the Center for Interdisciplinary Data Science Research of the Hebrew University of Jerusalem (Dr Tessler); grant R35 CA220340 from the National Institutes of Health (Dr Blacklow), and grants R21HL150373, R01HL114823 (Dr Body); BSF grants 2013269 and 2017245 (Drs. Sprinzak and Blacklow); a consolidator grant from the European Research Council (Genomia – ERC-COG-2017-771945; Dr Loeys); the European Reference Network on rare multisystemic vascular disorders (VASCERN - project ID: 769036 partly cofunded by the European Union Third Health Programme (Drs Loeys and Verstraeten); funding from the Outreach project (Dutch Heart Foundation; Dr Luyckx); funding from Heart and Stroke Foundation of Canada/Robert M Freedom Chair of Cardiovascular Science (Dr Mital); sample biobanking and sequencing from Canada were supported by grants from the Leducq Foundation Transatlantic Networks of Excellence grant, and the Ted Rogers Centre for Heart Research; ISF grant 1053/12 (Dr Durst); and grant R01HL150401 from National Heart, Lung, and Blood Institute (Dr Muehlschlegel).S

Is There a Role for Molecular Testing for Low-Risk Differentiated Thyroid Cancer? A Cost-Effectiveness Analysis

Molecular testing for thyroid nodules has been rapidly developed in recent years, aiming to predict the presence of malignancy and aggressive features. While commonly utilized to predict malignancy, its role in guiding the management approach is still developing. The high cost of genetic tests and long-term sequences of thyroid cancer is limiting to real-life studies. Objective: To evaluate the cost effectiveness of molecular testing for low-risk differentiated thyroid cancer (lrDTC). Methods: We developed a Markovian decision tree model of a simulated lrDTC cohort, comparing two management strategies: (I) Conducting genetic tests (GT)—patients are stratified into three risk groups for distant metastasis by the identified molecular markers: low-, intermediate- and high-risk molecular profile; followed by management accordingly: patients with low-risk will undergo hemithyroidectomy (HT), patients with intermediate-risk will undergo total thyroidectomy (TT), and high-risk patients will undergo TT with central neck dissection; (II) Without genetic tests (wGT)—all patients will undergo HT according to the ATA recommendations for lrDTC. Outcomes were measured as quality-adjusted life years (QALYs) and costs of each strategy. Results: GT was found as cost effective, leading to a gain of 1.7 QALYs with an additional cost of $327 per patient compared to wGT strategy. This yielded an incremental cost-effectiveness ratio of$190 per QALY. Sensitivity analysis demonstrated robust results across the variables’ ranges. The most impactful variable was the benefit from performing TT rather than HT for intermediate to high-risk patients. Conclusions: Our model found that molecular testing for lrDTC is cost-effective, allowing tailored management according to the patient’s personal risk level reflected in the genetic profile, hence improving outcomes

Is There a Role for Molecular Testing for Low-Risk Differentiated Thyroid Cancer? A Cost-Effectiveness Analysis

Molecular testing for thyroid nodules has been rapidly developed in recent years, aiming to predict the presence of malignancy and aggressive features. While commonly utilized to predict malignancy, its role in guiding the management approach is still developing. The high cost of genetic tests and long-term sequences of thyroid cancer is limiting to real-life studies. Objective: To evaluate the cost effectiveness of molecular testing for low-risk differentiated thyroid cancer (lrDTC). Methods: We developed a Markovian decision tree model of a simulated lrDTC cohort, comparing two management strategies: (I) Conducting genetic tests (GT)—patients are stratified into three risk groups for distant metastasis by the identified molecular markers: low-, intermediate- and high-risk molecular profile; followed by management accordingly: patients with low-risk will undergo hemithyroidectomy (HT), patients with intermediate-risk will undergo total thyroidectomy (TT), and high-risk patients will undergo TT with central neck dissection; (II) Without genetic tests (wGT)—all patients will undergo HT according to the ATA recommendations for lrDTC. Outcomes were measured as quality-adjusted life years (QALYs) and costs of each strategy. Results: GT was found as cost effective, leading to a gain of 1.7 QALYs with an additional cost of $327 per patient compared to wGT strategy. This yielded an incremental cost-effectiveness ratio of$190 per QALY. Sensitivity analysis demonstrated robust results across the variables’ ranges. The most impactful variable was the benefit from performing TT rather than HT for intermediate to high-risk patients. Conclusions: Our model found that molecular testing for lrDTC is cost-effective, allowing tailored management according to the patient’s personal risk level reflected in the genetic profile, hence improving outcomes

Bicuspid Aortic Valve: Genetic and Clinical Insights

International audienceBicuspid aortic valve (BAV) is the most common valvular congenital heart disease, with a prevalence of 0.5 to 2% in the general population. Patients with BAV are at risk for developing cardiovascular complications, some of which are life-threatening. BAV has a wide spectrum of clinical presentations, ranging from silent malformation to severe and even fatal cardiac events. Despite the significant burden on both the patients and the health systems, data are limited regarding pathophysiology, risk factors, and genetics. Family studies indicate that BAV is highly heritable, with autosomal dominant inheritance, incomplete penetrance, variable expressivity, and male predominance. Owing to its complex genetic model, including high genetic heterogenicity, only a few genes were identified in association with BAV, while the majority of BAV genetics remains obscure. Here, we review the different forms of BAV and the current data regarding its genetics. Given the clear heritably of BAV with the potential high impact on clinical outcome, the clinical value and cost effectiveness of cascade screening are discussed

Impact and Stability of Mandibular Setback after Intraoral Vertical Ramus Osteotomy

(1) Background: The purpose of this study was to evaluate stability and complications following mandibular setback using intraoral vertical ramus osteotomy (IVRO) and provide an assessment of IMF (Inter-maxillary Fixation) compliance. (2) Methods: This is a retrospective cohort study. It included a total of 39 patients who underwent 78 IVRO for the treatment of mandibular prognathism between 2005 and 2021 at Sheba Medical Center. Radiographic and clinical examinations were performed preoperatively (T0), 3 days post-surgery (T1) and 8 months post-surgery (T2). Measurements of dental and skeletal stability, as well as neurosensory disturbances and TMJ dysfunctions, were statistically analyzed. (3) Results: The mean mandibular setback was 5.6 mm. A relapse of less than 2 mm was observed at T2. A short-term neurological disturbance was reported in 38.46% of the 39 patients, and 17.94% of them showed full recovery by T2. In 21 patients who underwent IVRO without genioplasty, only 14.28% reported long-term sensory disturbance. In addition, when a vertical osteotomy was performed, neurological damage was 174% higher as compared to oblique osteotomy. The IMF compliance rate for the 6 weeks postoperatively was 100%. (4) Conclusions: IVRO is still a relevant and valid technique for the treatment of mandibular prognathism that provides stable results with minimal complications rate

Impact and Stability of Mandibular Setback after Intraoral Vertical Ramus Osteotomy

(1) Background: The purpose of this study was to evaluate stability and complications following mandibular setback using intraoral vertical ramus osteotomy (IVRO) and provide an assessment of IMF (Inter-maxillary Fixation) compliance. (2) Methods: This is a retrospective cohort study. It included a total of 39 patients who underwent 78 IVRO for the treatment of mandibular prognathism between 2005 and 2021 at Sheba Medical Center. Radiographic and clinical examinations were performed preoperatively (T0), 3 days post-surgery (T1) and 8 months post-surgery (T2). Measurements of dental and skeletal stability, as well as neurosensory disturbances and TMJ dysfunctions, were statistically analyzed. (3) Results: The mean mandibular setback was 5.6 mm. A relapse of less than 2 mm was observed at T2. A short-term neurological disturbance was reported in 38.46% of the 39 patients, and 17.94% of them showed full recovery by T2. In 21 patients who underwent IVRO without genioplasty, only 14.28% reported long-term sensory disturbance. In addition, when a vertical osteotomy was performed, neurological damage was 174% higher as compared to oblique osteotomy. The IMF compliance rate for the 6 weeks postoperatively was 100%. (4) Conclusions: IVRO is still a relevant and valid technique for the treatment of mandibular prognathism that provides stable results with minimal complications rate

A Five-Decade Text Mining Analysis of Cochlear Implant Research: Where We Started and Where We Are Heading

Background and Objectives: Since its invention in the 1970s, the cochlear implant (CI) has been substantially developed. We aimed to assess the trends in the published literature to characterize CI. Materials and Methods: We queried PubMed for all CI-related entries published during 1970–2022. The following data were extracted: year of publication, publishing journal, title, keywords, and abstract text. Search terms belonged to the patient’s age group, etiology for hearing loss, indications for CI, and surgical methodological advancement. Annual trends of publications were plotted. The slopes of publication trends were calculated by fitting regression lines to the yearly number of publications. Results: Overall, 19,428 CIs articles were identified. Pediatric-related CI was the most dominant sub-population among the age groups, with the highest rate and slope during the years (slope 5.2 ± 0.3, p p p Conclusions: Publications regarding CI among pediatrics outnumbered all other indications, supporting the rising, pivotal role of CI in the rehabilitation of children with sensorineural hearing loss. Hearing-preservation publications have recently rapidly risen, identified as the primary trend of the current era, followed by a sharp rise of robotic surgery that is evolving and could define the next revolution

Is Bicuspid Aortic Valve Morphology Genetically Determined? A Family-Based Study

International audienceBicuspid aortic valve (BAV) is a common congenital heart disease, with a 10-fold higher prevalence in first-degree relatives. BAV has different phenotypes based on the morphology of cusp fusion. These phenotypes are associated with different clinical courses and prognoses. Currently, the determinants of the valve phenotype are unknown. In this study we evaluated the role of genetics using familial cohorts. Patients with BAV and their first-degree relatives were evaluated by echocardiography. The concordance in BAV phenotype between pairs of family members was calculated and compared with the concordance expected by chance. We then performed a systematic literature review to identify additional reports and calculated the overall concordance rate. During the study period, 70 cases from 31 families and 327 sporadic cases were identified. BAV was diagnosed in 14% of the screened relatives. The proportions of the morphologies identified was: 12.3% for type 0, 66.2% for type 1-LR, 15.4% for type 1-RN, 4.6% for type 1-NL, and 1.5% for type 2. For the assessment of morphologic concordance, we included 120 pairs of first-degree relatives with BAV from our original cohort and the literature review. Concordance was found only in 62% of the pairs which was not significantly higher than expected by chance. In conclusion, our finding demonstrates intrafamilial variability in BAV morphology, suggesting that morphology is determined by factors other than Mendelian genetics. As prognosis differs by morphology, our findings may suggest that clinical outcomes may vary even between first-degree relatives