Background: Open carpal tunnel release (OCTR) and endoscopic carpal tunnel release (ECTR) are the 2 operative approaches used to treat carpal tunnel syndrome (CTS). This study aims to identify whether differences between OCTR and ECTR rates exist, and, if so, are these differences associated with patient demographics or hospital characteristics. Methods: The 2018 Nationwide Ambulatory Surgery Sample (NASS) was filtered for patient encounters including either OCTR or ECTR operations. All patients undergoing either OCTR or ECTR were included, regardless of surgical specialty. Patient demographics and hospital characteristics data, provided and predefined by the NASS database, were collected and compared between the 2 treatment groups. Results: A total of 180 740 patient encounters were collected for both procedure types (OCTR: 62.4% women, mean age, 58 years; ECTR: 62.2% women, mean age, 58 years). Patients from lower income zip codes were more likely to undergo OCTR ( P < .001). Patients either self-paying ( P < .008) or covered by Medicare ( P < .001) or Medicaid insurance ( P < .001) were also more likely to undergo OCTR. In contrast, patients who received care at academic centers and centers with >300 beds were more likely to undergo ECTR ( P < .001). Patients <65 years old were more likely to undergo ECTR ( P < .001), and patients > 75 years old were more likely to undergo OCTR ( P < .001). In addition, ECTR was found to be more expensive, with average total charges $1568 greater than charges for OCTR ( P < .001). Conclusions: Significant differences exist in treatment strategies for CTS and are related to patient income, location, and primary payor status. Differences in OCTR and ECTR rates are also present, and are related to the size and academic status of hospitals.

Background:The relation between ventricular arrhythmia and fibrosis in mitral valve prolapse (MVP) is reported, but underlying valve-induced mechanisms remain unknown. We evaluated the association between abnormal MVP-related mechanics and myocardial fibrosis, and their association with arrhythmia. Methods:We studied 113 patients with MVP with both echocardiogram and gadolinium cardiac magnetic resonance imaging for myocardial fibrosis. Two-dimensional and speckle-tracking echocardiography evaluated mitral regurgitation, superior leaflet and papillary muscle displacement with associated exaggerated basal myocardial systolic curling, and myocardial longitudinal strain. Follow-up assessed arrhythmic events (nonsustained or sustained ventricular tachycardia or ventricular fibrillation). Results:Myocardial fibrosis was observed in 43 patients with MVP, predominantly in the basal-midventricular inferior-lateral wall and papillary muscles. Patients with MVP with fibrosis had greater mitral regurgitation, prolapse, and superior papillary muscle displacement with basal curling and more impaired inferior-posterior basal strain than those without fibrosis (P<0.001). An abnormal strain pattern with distinct peaks pre-end-systole and post-end-systole in inferior-lateral wall was frequent in patients with fibrosis (81 versus 26%, P<0.001) but absent in patients without MVP with basal inferior-lateral wall fibrosis (n=20). During median follow-up of 1008 days, 36 of 87 patients with MVP with >6-month follow-up developed ventricular arrhythmias associated (univariable) with fibrosis, greater prolapse, mitral annular disjunction, and double-peak strain. In multivariable analysis, double-peak strain showed incremental risk of arrhythmia over fibrosis. Conclusions:Basal inferior-posterior myocardial fibrosis in MVP is associated with abnormal MVP-related myocardial mechanics, which are potentially associated with ventricular arrhythmia. These associations suggest pathophysiological links between MVP-related mechanical abnormalities and myocardial fibrosis, which also may relate to ventricular arrhythmia and offer potential imaging markers of increased arrhythmic risk.

Background The anterolateral thigh (ALT) perforator flap is a commonly used flap with a predictable, though often variable, perforator anatomy. Preoperative imaging with color Doppler ultrasound (CDU) and computed tomography angiography (CTA) of ALT flap perforators can be a useful tool for flap planning. This study provides a complete review and analysis of the relevant preoperative ALT imaging literature. Methods Studies related to preoperative CDU and CTA imaging were reviewed, and information related to imaging method, sensitivity, false-positive rates, and perforator course identification (musculocutaneous vs. septocutaneous) were analyzed. Results A total of 23 studies related to preoperative ALT flap CDU and CTA imaging were included for review and analysis. Intraoperative perforator identification was compared with those found preoperatively using CDU ( n = 672) and CTA ( n = 531). Perforator identification sensitivity for CDU was 95.3% (95% CI: 90.9-97.6%) compared with the CTA sensitivity of 90.4% (95% confidence interval [CI]: 74.4-96.9%). The false-positive rate for CDU was 2.8% (95% CI: 1.1-4.5%) compared with 2.4% (95% CI: 0.7-4.1%) for CTA. Accuracy of perforator course identification was 95.5% (95% CI: 93.6-99.2%) for CDU and 96.9% (95% CI: 92.7-100.1%) for CTA. Conclusion CDU provides the reconstructive surgeon with greater preoperative perforator imaging sensitivity compared with CTA; however, false-positive rates are marginally higher with preoperative CDU. Preoperative imaging for ALT flap design is an effective tool, and the reconstructive surgeon should consider the data presented here when selecting a flap imaging modality.

Background: Distal radioulnar joint (DRUJ) instability and arthritis are often painful and functionally limiting pathologies. Two common salvage procedures for DRUJ dysfunction are the Darrach and Sauvé-Kapandji (S-K) procedures. This study aims to provide an analysis of national Darrach and S-K procedure utilization rates and patient demographics. Methods: A national ambulatory surgery database, the 2018 Nationwide Ambulatory Surgery Sample, was filtered for Darrach and S-K procedure encounters. Data related to patient demographics and medical history, indications for DRUJ salvage, and concurrent hand/wrist procedures were collected. Results: Database analysis revealed 1044 Darrach and 223 S-K procedure encounters. Patients undergoing Darrach procedures were older (60 vs 57, P = .002) and more likely to be women (66.1% vs 54.6%, P < .05). Patients aged <35 years underwent S-K procedures at greater rates compared with Darrach (13.9% vs 8.6%, P < .05). Primary osteoarthritis proved to be the most common indication for DRUJ salvage (64.8%) compared with rheumatoid arthritis (23.2%) and post-traumatic osteoarthritis (12.0%). Darrach and S-K procedures were accompanied by a secondary procedure at rates of 64% and 41%, respectively. The most common secondary procedures were tendon transfer, implant removal, neuroplasty, nerve resections, and wrist arthroscopy. Conclusions: Patient age and sex are associated with DRUJ salvage procedure selection. Sauvé-Kapandji procedures are used in higher rates in male and younger patient populations. Furthermore, primary osteoarthritis and rheumatoid arthritis are the main underlying pathologies for Darrach and S-K procedures.

Purpose Although growth in cosmetic surgery remains constant in the private setting, academic cosmetic surgery practices are often underdeveloped. Our study aims to determine which patient populations access academic cosmetic surgery services. Methods The 2018 Health Care Utilization Project Nationwide Ambulatory Surgery Sample database was used for data analysis. Encounters for the following American Society of Plastic Surgery top 5 procedures for 2020 were selected: blepharoplasty, breast augmentation, liposuction, rhinoplasty, and rhytidectomy. Patient encounter data were collected because it relates to median income, geographic location, and primary payer status. Results The 2018 Nationwide Ambulatory Surgery Sample data set contained 44,078 encounters at academic surgical centers for the procedures listed previously. Low-income patients account for 13.7% of academic cosmetic surgery encounters compared with 37.9% for high-income patients. Breast augmentation rates are higher among low-income patients (20.5% vs 17.2%, P < 0.001), and high-income patients undergo rhytidectomy more frequently (5.7% vs 3.0%, P < 0.001). In the academic setting, patients from large metropolitan areas encompass the majority of cosmetic encounters (71.0%), and these patients are more likely to proceed with rhinoplasty, rhytidectomy, and liposuction procedures (P < 0.001). Patients from smaller metropolitan areas undergo blepharoplasty more frequently compared with those from larger metropolitan areas (56.4% vs 41.8%, P < 0.001). Self-pay and privately insured patients comprise the majority of academic cosmetic surgery encounters (40.8% and 29.9%, respectively). Eighty-eight percent of Medicare patients within this cohort underwent blepharoplasty, whereas self-pay patients accessed breast augmentation, liposuction, and rhytidectomy more often than other insured patients. Conclusions Income status, patient location, and primary payer status play an important role in academic cosmetic surgery access rates and procedure preferences. Academic cosmetic practices can use these insights to tailor their services to the populations they serve.

Mitral valve prolapse (MVP) is a common cardiac valve disease that often progresses to serious secondary complications requiring surgery. MVP manifests as extracellular matrix disorganization and biomechanically incompetent tissues in the adult setting. However, MVP has recently been shown to have a developmental basis, as multiple causal genes expressed during embryonic development have been identified. Disease phenotypes have been observed in mouse models with human MVP mutations as early as birth. This study focuses on the developmental function of DCHS1, one of the first genes to be shown as causal in multiple families with non-syndromic MVP. By using various biochemical techniques as well as mouse and cell culture models, we demonstrate a unique link between DCHS1-based cell adhesions and the septin-actin cytoskeleton through interactions with cytoplasmic protein Lix1-Like (LIX1L). This DCHS1-LIX1L-SEPT9 axis interacts with and promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape.

Purpose Although growth in cosmetic surgery remains constant in the private setting, academic cosmetic surgery practices are often underdeveloped. Our study aims to determine which patient populations access academic cosmetic surgery services. Methods The 2018 Health Care Utilization Project Nationwide Ambulatory Surgery Sample database was used for data analysis. Encounters for the following American Society of Plastic Surgery top 5 procedures for 2020 were selected: blepharoplasty, breast augmentation, liposuction, rhinoplasty, and rhytidectomy. Patient encounter data were collected because it relates to median income, geographic location, and primary payer status. Results The 2018 Nationwide Ambulatory Surgery Sample data set contained 44,078 encounters at academic surgical centers for the procedures listed previously. Low-income patients account for 13.7% of academic cosmetic surgery encounters compared with 37.9% for high-income patients. Breast augmentation rates are higher among low-income patients (20.5% vs 17.2%, P < 0.001), and high-income patients undergo rhytidectomy more frequently (5.7% vs 3.0%, P < 0.001). In the academic setting, patients from large metropolitan areas encompass the majority of cosmetic encounters (71.0%), and these patients are more likely to proceed with rhinoplasty, rhytidectomy, and liposuction procedures (P < 0.001). Patients from smaller metropolitan areas undergo blepharoplasty more frequently compared with those from larger metropolitan areas (56.4% vs 41.8%, P < 0.001). Self-pay and privately insured patients comprise the majority of academic cosmetic surgery encounters (40.8% and 29.9%, respectively). Eighty-eight percent of Medicare patients within this cohort underwent blepharoplasty, whereas self-pay patients accessed breast augmentation, liposuction, and rhytidectomy more often than other insured patients. Conclusions Income status, patient location, and primary payer status play an important role in academic cosmetic surgery access rates and procedure preferences. Academic cosmetic practices can use these insights to tailor their services to the populations they serve.

BACKGROUND  The anterolateral thigh (ALT) perforator flap is a commonly used flap with a predictable, though often variable, perforator anatomy. Preoperative imaging with color Doppler ultrasound (CDU) and computed tomography angiography (CTA) of ALT flap perforators can be a useful tool for flap planning. This study provides a complete review and analysis of the relevant preoperative ALT imaging literature. METHODS  Studies related to preoperative CDU and CTA imaging were reviewed, and information related to imaging method, sensitivity, false-positive rates, and perforator course identification (musculocutaneous vs. septocutaneous) were analyzed. RESULTS  A total of 23 studies related to preoperative ALT flap CDU and CTA imaging were included for review and analysis. Intraoperative perforator identification was compared with those found preoperatively using CDU (n = 672) and CTA (n = 531). Perforator identification sensitivity for CDU was 95.3% (95% CI: 90.9-97.6%) compared with the CTA sensitivity of 90.4% (95% confidence interval [CI]: 74.4-96.9%). The false-positive rate for CDU was 2.8% (95% CI: 1.1-4.5%) compared with 2.4% (95% CI: 0.7-4.1%) for CTA. Accuracy of perforator course identification was 95.5% (95% CI: 93.6-99.2%) for CDU and 96.9% (95% CI: 92.7-100.1%) for CTA. CONCLUSION  CDU provides the reconstructive surgeon with greater preoperative perforator imaging sensitivity compared with CTA; however, false-positive rates are marginally higher with preoperative CDU. Preoperative imaging for ALT flap design is an effective tool, and the reconstructive surgeon should consider the data presented here when selecting a flap imaging modality.

Introduction: Imaging studies patients with mitral valve prolapse (MVP) have previously shown cross sectional evidence of left ventricular (LV) fibrosis as well as increased risk for sudden cardiac death. This, along with evidence for post-repair ventricular dysfunction in Mitral valve surgery patients support a link between fibrosis and MVP. The development of fibrosis as a result of MVP, however, remains poorly understood. Hypothesis: Regionalized LV Fibrosis in MVP patients is driven by increased mechanical tension through the chordae tendineae by billowing leaflets. Methods: We performed histopathologic analysis on cardiac biopsies of 6 patients who underwent surgical repair for MV prolapse. We additionally performed longitudinal histopathologic analysis on hearts harvested from a mouse modal of human non-syndromic MVP (Dzip1 S14R/+). To assess the cellular response to increased mechanical tension, pathological stretch assays on human cardiac fibroblasts were performed in tandem with RNA seq, as well ATP luminescence assays to assess ATP release from stretched cells. Results: Biopsies from peripapillary regions, inferobasal wall, LV septum, and LV apex demonstrated regionalized myocardial fibrosis that correlated with increased macrophages and myofibroblasts. Our mouse model demonstrated similar regionalized deposition of collagen that increased over time, as well as an increase in macrophages and myofibroblasts. Stretching of human cardiac fibroblasts caused significant changes in 232 transcripts (Bonferroni corrected P value <1.72*10-6), and pushed fibroblasts into a pro-fibrotic state, upregulating alpha-Smooth Muscle actin, Collagen, PLOD1, and decreasing MMP1. Additionally, pathologic stretch of fibroblasts increased secretion of ATP, a known chemoattractant for innate inflammatory cells. Conclusions: A mouse model of human MVP phenocopied regionalized myocardial fibrosis seen in humans and will provide a useful tool to investigate mechanisms of myocardial fibrosis in MVP patients. Stretch initiates changes in pro-fibrotic gene transcription, and causes ATP release from human cardiac fibroblasts.

Mitral valve prolapse (MVP) is a common and progressive cardiovascular disease with developmental origins. How developmental errors contribute to disease pathogenesis are not well understood.A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and β-catenin. Co-expression during valve development revealed overlap at the basal body of the primary cilia. Biochemical studies revealed a DZIP1 peptide required for stabilization of the complex and suppression of β-catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of β-catenin with effects on transcriptional activity. A mutation within this domain was identified in a family with inherited non-syndromic MVP. This novel mutation and our previously identified DZIP1S24R variant resulted in reduced DZIP1 and CBY1 stability and increased β-catenin activities. The β-catenin target gene, MMP2 was up-regulated in the Dzip1S14R/+ valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype.Dzip1 functions to restrain β-catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear β-catenin/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype.

Background Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease and affects 2% to 3% of the population. Previous imaging reports have indicated that myocardial fibrosis is common in MVP and described its association with sudden cardiac death. These data combined with evidence for postrepair ventricular dysfunction in surgical patients with MVP support a link between fibrosis and MVP. Methods and Results We performed histopathologic analysis of left ventricular (LV) biopsies from peripapillary regions, inferobasal LV wall and apex on surgical patients with MVP, as well as in a mouse model of human MVP (Dzip1S14R /+ ). Tension‐dependent molecular pathways were subsequently assessed using both computational modeling and cyclical stretch of primary human cardiac fibroblasts in vitro. Histopathology of LV biopsies revealed regionalized fibrosis in the peripapillary myocardium that correlated with increased macrophages and myofibroblasts. The MVP mouse model exhibited similar regional increases in collagen deposition that progress over time. As observed in the patient biopsies, increased macrophages and myofibroblasts were observed in fibrotic areas within the murine heart. Computational modeling revealed tension‐dependent profibrotic cellular and molecular responses consistent with fibrosis locations related to valve‐induced stress. These simulations also identified mechanosensing primary cilia as involved in profibrotic pathways, which was validated in vitro and in human biopsies. Finally, in vitro stretching of primary human cardiac fibroblasts showed that stretch directly activates profibrotic pathways and increases extracellular matrix protein production. Conclusions The presence of prominent regional LV fibrosis in patients and mice with MVP supports a relationship between MVP and progressive damaging effects on LV structure before overt alterations in cardiac function. The regionalized molecular and cellular changes suggest a reactive response of the papillary and inferobasal myocardium to increased chordal tension from a prolapsing valve. These studies raise the question whether surgical intervention on patients with MVP should occur earlier than indicated by current guidelines to prevent advanced LV fibrosis and potentially reduce residual risk of LV dysfunction and sudden cardiac death.

Mitral valve prolapse (MVP) is a common form of valve disease and can lead to serious secondary complications. The recent identification of MVP causal mutations in primary cilia-related genes has prompted the investigation of cilia-mediated mechanisms of disease inception. Here, we investigate the role of platelet-derived growth factor receptor-alpha (PDGFRα), a receptor known to be present on the primary cilium, during valve development using genetically modified mice, biochemical assays, and high-resolution microscopy. While PDGFRα is expressed throughout the ciliated valve interstitium early in development, its expression becomes restricted on the valve endocardium by birth and through adulthood. Conditional ablation of Pdgfra with Nfatc1-enhancer Cre led to significantly enlarged and hypercellular anterior leaflets with disrupted endothelial adhesions, activated ERK1/2, and a dysregulated extracellular matrix. In vitro culture experiments confirmed a role in suppressing ERK1/2 activation while promoting AKT phosphorylation. These data suggest that PDGFRα functions to suppress mesenchymal transformation and disease phenotypes by stabilizing the valve endocardium through an AKT/ERK pathway.

Introduction: Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease, affecting 1 in 40 humans and ~70% of small breed dogs. There are no effective nonsurgical treatments for MVP and therapeutic efforts have been hindered due to an incomplete understanding of its fundamental causes. Recent studies by our group have described the genetic basis for non-syndromic MVP and have provided new insights into molecular processes that underlie the disease. We have used this genetic information to identify druggable targets that can provide a non-surgical option for humans. In particular, we have identified the MEK/ERK pathway as the major disease initiating pathway and prolonged hyperactivation of MEK/ERK drives disease progression and severity. Hypothesis: Pharmacological blockade of MEK/ERK activities will sufficiently arrest the disease pathway and maintain the valves in a sub-clinical condition. Methods and Results: The FDA-approved MEK1 inhibitor Trametinib was administered to Dzip1 S24R/+ mice; a disease model that phenocopies human MVP. Preliminary results suggest safety concerns in mice associated with chronic administration of Trametinib (1 mg/kg/day). Animals demonstrated signs of cardiotoxicity on echocardiography, including left atrial enlargement; a reduction in E/A wave intensity; left ventricular wall movement abnormalities; prolonged isovolumetric relaxation time, and a reduced ejection fraction. As such, our lab has focused our efforts on identifying novel MEK1 inhibitors with a favorable safety profile. Utilizing a machine learning based workflow, we have identified highly selective MEK1 inhibitors with retained activity (<100nM IC50 values); high gastrointestinal absorption (>85%); favorable predicted LD50 values (>1,000 mg/kg), and devoid of major cytochrome interactions. Conclusions: MEK1 may serve as a druggable target in the treatment of mitral valve prolapse; however, currently available MEK inhibitors demonstrate limiting toxicities. Future studies will involve in vivo administration of our novel compounds to Dzip1 S24R/+ mice. We envision results from this study will help guide the development of systemic or targeted therapies for the use in human patients with mitral valve prolapse.

Septin genes were originally identified in budding yeast in 1971. Since their original discovery, at least 13 mammalian genes have now been found, which give rise to a vast array of alternatively spliced proteins that display unique spatial-temporal function across organs systems. Septin's are now recognized as the 4th major component of the cytoskeleton. Their role in regulating ciliogenesis, actin and microtubule organization and their involvement in mechanotransduction clearly solidify their place as both a responder and driver of cellular activity. Although work on septin's has escalated over the past decades, knowledge of septin function in the heart remains rudimentary. Whereas many cardiovascular diseases have been associated with genetic loci that include septin genes, new and additional concerted efforts will likely uncover previously unrecognized mechanisms by which the septin class of proteins contribute to clinical cardiac phenotypes. In this review, we place known function of septin proteins in the context of heart development and disease and provide perspectives on how increased knowledge of these proteins can mechanistically inform cardiac pathologies.

Introduction: Mitral valve prolapse (MVP) is a major source of morbidity and mortality and is becoming one of the most common indications for cardiac surgery. Our group has previously reported that MVP is associated with missense mutations in DCHS1 , a gene widely implicated in tissue development and organization. Purpose: We recently performed two-hybrid screens and co-immunoprecipitation assays that define a novel complex between DCHS1, LIX1L, and SEPT9 (DLS). Our current studies investigate the role of this interaction in mitral valve morphogenesis. Methods: Wild-type (WT), DCHS1, and/or LIX1L heterozygous neonate murine heart tissue was isolated for primary culture of cardiac fibroblasts (CFs) and analyzed with immunocytochemistry, collagen, compaction, fibrin pillar to post assays, and actin sedimentation assays. Nuclear morphology and chromatin density were conducted for functional read-outs of cytoskeletal aberrations. Morphologic and functional analyses of murine mitral valves were completed. Results: Loss of actin architecture and collagen compaction capability were seen in CFs deficient of DCHS1 and/or LIX1L. Delivery of a peptide that disrupted the LIX1L-SEPT9 binding domain likewise destroyed actin architecture and reduced ECM compaction. In-vivo epistasis studies support these findings as mitral valve enlargement was exacerbated in DCHS1/LIX1L compound heterozygote mice compared to DCHS1 and LIX1L heterozygotes. Echocardiography of 11-month DCHS1/LIX1L compound heterozygote mice revealed pronounced MVP and increased left atrium diameter relative to DCHS1 and LIX1L heterozygotes. Filamentous SEPTIN9 localized to the actin ultrastructure and was also lost with disturbance of the DLS complex. Nuclei stretch and chromatin compaction were reduced in DCHS1/LIX1L compound heterozygote CFs. Further, histone H4 modifications were observed in DCHS1 KO mouse embryonic fibroblasts that indicate reductions in gene expression. Conclusion: DCHS1, through its interaction with the septin cytoskeleton, must regulate and stabilize actin dynamics in mitral VICs leading to proper valve development. Non-surgical interventions for MVP may be identified through establishing the downstream effects of DCHS1 mutations in our model.

Non-syndromic mitral valve prolapse (MVP) is the most common heart valve disease affecting 2.4% of the population. Recent studies have identified genetic defects in primary cilia as causative to MVP, although the mechanism of their action is currently unknown. Using a series of gene inactivation approaches, we define a paracrine mechanism by which endocardially-expressed Desert Hedgehog (DHH) activates primary cilia signaling on neighboring valve interstitial cells. High-resolution imaging and functional assays show that DHH de-represses smoothened at the primary cilia, resulting in kinase activation of RAC1 through the RAC1-GEF, TIAM1. Activation of this non-canonical hedgehog pathway stimulates α-smooth actin organization and ECM remodeling. Genetic or pharmacological perturbation of this pathway results in enlarged valves that progress to a myxomatous phenotype, similar to valves seen in MVP patients. These data identify a potential molecular origin for MVP as well as establish a paracrine DHH-primary cilium cross-talk mechanism that is likely applicable across developmental tissue types.

Abstract Introduction: Weight gain is a common source of apprehension for patients undergoing thyroidectomy. However, contradictory reports exist regarding the presence and degree of weight gain following thyroid surgery and all known studies have short term follow-up This study evaluated weight changes following total thyroidectomy (TT) and lobectomy (L) over an extended time period. Methods: Retrospective analysis was performed of weight changes following surgery for patients who underwent TT or L (n=387) as compared with those undergoing parathyroidectomy for primary hyperparathyroidism (n=201) in a tertiary referral hospital between 2007-2012. Clinical, demographic and pre- and postoperative weight data was collected with a median follow-up of 55.6 months. Results: Postoperative weight change was observed at 1, 6, 12, and 36-months in patients who underwent TT (μ=+0.21kg, μ=+1.33kg, μ=+0.59kg, μ=+0.60kg; p<0.05) and at 6-months for patients who underwent L (μ=+0.93kg, p<0.05) compared with those who underwent parathyroidectomy. Patients having TT and L showed a general trend of weight gain compared to the control group up to 108-months post-operation; however, this weight gain was non-significant (p<0.05). Significant postoperative weight gain was observed in patients who had TT (1-month μ=+0.40kg, 6-months μ=+2.14kg, and 12-months μ=+1.40kg) and L (6-months μ=+1.04kg) for benign conditions compared with the parathyroidectomy group. Patients who had TT gained 0.40kg more than L patients at 12-months post-op (p<0.05), but no significant difference existed at other time points up to 108-months. Tukey HSD post-hoc analysis showed weight gain in benign, thyroiditis, and thyroid cancer patient groups was not significantly different from 6-months to 108-months post-operation. Furthermore, neither race nor sex was correlated with weight gain. Relative risks with 95% CI for weight gain following TT and L compared to control are: 1-month TT=1.74, 0.96-3.14, L=1.59, 0.58-2.58; 6-month TT=1.27, 0.85-1.89, L=1.42, 0.85-2.11; 12-month TT=1.44, 0.92-2.28, L=1.34, 0.86-2.36; 24-month TT=1.17, 0.82-1.67, L=1.22, 0.69-1.60. In the group of patients who gained greater than 2kg, those who underwent TT had significant weight increase compared to the parathyroidectomy group at 6-months postoperatively (Mann-Whitney U, p=0.011). In the subgroup of patients with weight gain greater than 2kg, those who had L did not have significant weight increase at any time point. Conclusion: Weight change following TT when compared with parathyroidectomy is significant shortly after surgery. However, these changes are not significant at long-term follow-up.

β-catenin has been widely studied in many animal and organ systems across evolution, and gain or loss of function has been linked to a number of human diseases. Yet fundamental knowledge regarding its protein expression and localization remains poorly described. Thus, we sought to define whether there was a temporal and cell-specific regulation of β-catenin activities that correlate with distinct cardiac morphological events. Our findings indicate that activated nuclear β-catenin is primarily evident early in gestation. As development proceeds, nuclear β-catenin is down-regulated and becomes restricted to the membrane in a subset of cardiac progenitor cells. After birth, little β-catenin is detected in the heart. The co-expression of β-catenin with its main transcriptional co-factor, Lef1, revealed that Lef1 and β-catenin expression domains do not extensively overlap in the cardiac valves. These data indicate mutually exclusive roles for Lef1 and β-catenin in most cardiac cell types during development. Additionally, these data indicate diverse functions for β-catenin within the nucleus and membrane depending on cell type and gestational timing. Cardiovascular studies should take into careful consideration both nuclear and membrane β-catenin functions and their potential contributions to cardiac development and disease.

BACKGROUND:Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent comorbidities.METHODS:We performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based on P value and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, histology, and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia-dependent pathways were analyzed by Western and immunohistochemistry analyses, and assessment of aortic valve and cardiac function were determined by echocardiography.RESULTS:Genome-wide association study hits revealed an association between BAV and genetic variation in human primary cilia. The most associated single-nucleotide polymorphisms were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models.CONCLUSIONS:These data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated comorbidities in humans.

Objective: Non-syndromic Mitral Valve Prolapse (MVP) is a common disease with associated morbidities and mortality. The cause of the disease is poorly understood and to date only a couple of genes have been shown as causative. We have recently identified mutations in the cilia gene, DZIP1 in families with MVP. To initially identify the function of DZIP1 in valve development, we performed proteomics based approaches with the goal of identifying unique binding partners for DZIP1. These studies revealed a direct interaction with beta-catenin antagonist—Chibby1(CBY1). We hypothesize that DZIP1 regulates mitral valve development through Wnt signaling pathway by interacting with CBY1. Methods: Co-immunoprecipitation and immunofluorescence staining on valve tissues was performed for DZIP1 and CBY1. 3D reconstructions were performed on both DZIP1 conditional and CBY1-/- mitral valves. Staining for beta-catenin and the downstream effector lef1 was analyzed by Western and IHC in CBY1 and DZIP1 deficient mice. Results: DZIP1 interacts and co-localizes with CBY1 and this interaction is impaired in the context of DZIP1 familial mutations. Nucleus beta-catenin and lef1 expression are increased in DZIP1 mutant MEFs compared with wild type MEFs. However, rescue experiments by transfecting DZIP1 mutant MEFs with human CBY1 plasmid decreased Wnt signaling read out. Immunofluorescence suggests that beta-catenin is increased in NfatC1 Cre+;Dzip1 f/f and Dzip1 mutant valve tissues compared to wild type. Conclusions: DZIP1 suppresses Wnt activity to direct mitral valve development through interacting with and stabilizing CBY1. This study reveals a molecular mechanism by which mutations in DZIP1 alters valve development leading to increased b-catenin signaling. As mutations in DZIP1 cause MVP in humans, altered b-catenin signaling may be an early initiating signal in the pathogenesis of MVP.