Genome Sequencing is Critical for Forecasting Outcomes following Congenital Cardiac Surgery.

While genome sequencing has transformed medicine by elucidating the genetic underpinnings of both rare and common complex disorders, its utility to predict clinical outcomes remains understudied. Here, we used artificial intelligence (AI) technologies to explore the predictive value of genome sequencing in forecasting clinical outcomes following surgery for congenital heart defects (CHD). We report results for a cohort of 2,253 CHD patients from the Pediatric Cardiac Genomics Consortium with a broad range of complex heart defects, pre- and post-operative clinical variables and exome sequencing. Damaging genotypes in chromatin-modifying and cilia-related genes were associated with an elevated risk of adverse post-operative outcomes, including mortality, cardiac arrest and prolonged mechanical ventilation. The impact of damaging genotypes was further amplified in the context of specific CHD phenotypes, surgical complexity and extra-cardiac anomalies. The absence of a damaging genotype in chromatin-modifying and cilia-related genes was also informative, reducing the risk for adverse postoperative outcomes. Thus, genome sequencing enriches the ability to forecast outcomes following congenital cardiac surgery.

Sex differences in ascending aortic size reporting and growth on chest computed tomography and magnetic resonance imaging.

PURPOSE: Diameter-based guidelines for prophylactic repair of ascending aortic aneurysms have led to routine aortic evaluation in chest imaging. Despite sex differences in aneurysm outcomes, there is little understanding of sex-specific aortic growth rates. Our objective was to evaluate sex-specific temporal changes in radiologist-reported aortic size as well as sex differences in aortic reporting. METHOD: In this cohort study, we queried radiology reports of chest computed tomography or magnetic resonance imaging at an academic medical center from 1994 to 2022, excluding type A dissection. Aortic diameter was extracted using a custom text-processing algorithm. Growth rates were estimated using mixed-effects modeling with fixed terms for sex, age, and imaging modality, and patient-level random intercepts. Sex, age, and modality were evaluated as predictors of aortic reporting by logistic regression. RESULTS: This study included 89,863 scans among 46,622 patients (median [interquartile range] age, 64 [52-73]; 22,437 women [48%]). Aortic diameter was recorded in 14% (12,722/89,863 reports). Temporal trends were analyzed in 7194 scans among 1998 patients (age, 68 [60-75]; 677 women [34%]) with ≥2 scans. Aortic growth rate was significantly higher in women (0.22 mm/year [95% confidence interval 0.17-0.28] vs. 0.09 mm/year [0.06-0.13], respectively). Aortic reporting was significantly less common in women (odds ratio, 0.54; 95% CI, 0.52-0.56; p < 0.001). CONCLUSIONS: While aortic growth rates were small overall, women had over twice the growth rate of men. Aortic dimensions were much less frequently reported in women than men. Sex-specific standardized assessment of aortic measurements may be needed to address sex differences in aneurysm outcomes.

Current Therapeutic Options in Aortic Stenosis.

Aortic stenosis is the most common valvular disease requiring valve replacement. Valve replacement therapies have undergone progressive evolution since the 1960s. Over the last 20 years, transcatheter aortic valve replacement has radically transformed the care of aortic stenosis, such that it is now the treatment of choice for many, particularly elderly, patients. This review provides an overview of the pathophysiology, presentation, diagnosis, indications for intervention, and current therapeutic options for aortic stenosis.

De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease.

BACKGROUND: De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown. METHODS: We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network). RESULTS: Two hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10-12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10-04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10-05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation. CONCLUSIONS: In patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

Risk of reoperative valve surgery for endocarditis associated with drug use.

BACKGROUND: We aimed to quantify incidence and operative risks associated with reoperative valve surgeries (RVS) in patients with drug-associated infective endocarditis in a multi-center setting. METHODS: We formed a registry of patients with drug-associated infective endocarditis who underwent valve surgeries at 8 US centers between 2011 and 2017. Outcomes of first-time valve surgery (FVS) and RVS were compared. Multivariable logistic regression models related RVS to 30-day mortality. Poisson regression models were fitted to evaluate temporal trends in overall case volume and proportions of patients undergoing RVS. RESULTS: The cohort consisted of 925 patients with drug-associated infective endocarditis who underwent a valve surgery, of which 652 were FVS and 273 were RVS. Patients undergoing FVS had fewer comorbidities than those undergoing RVS. Overall case volume increased from 108 in 2012 to 229 cases in 2017 (P < .001). The proportion of redo valve cases increased from 19% in 2012 to 28% in 2017 (P < .001). The 30-day mortality in RVS was higher compared with FVS (8.1% vs 4.8%; P = .049). An increase in unadjusted mortality rates were observed as the number of prior cardiac surgeries increased, from 4.8% in FVS to 11.8% in ≥3 RVS. Multivariable model demonstrated that RVS was associated with an increased risk of 30-day mortality (odds ratio, 2.22; 95% confidence interval, 1.22-4.06; P = .010). CONCLUSIONS: An increasing proportion of valve surgery for drug-associated infective endocarditis is for RVS. Despite being young and harboring few comorbidities, the RVS cohort is still susceptible to increased risk of 30-day mortality compared with those undergoing FVS.

Outcomes of Transcatheter Aortic Valve Replacement in Patients With Severe Aortic Stenosis: A Review of a Disruptive Technology in Aortic Valve Surgery.

Importance: Medically treated symptomatic severe aortic stenosis has poor outcomes, and in the past 6 decades, it has successfully been treated with surgical aortic valve replacement (SAVR). However, one-third of patients with indications for SAVR are not offered surgery because of the high risk of complications. Transcatheter aortic valve replacement (TAVR), initially developed as a less invasive treatment for inoperable patients, has successfully been used in healthier patient cohorts. In 2017, TAVR became the most common approach for aortic valve replacement in the United States. Observations: During the past decade, the Placement of Aortic Transcatheter Valve (PARTNER) trials (for balloon-expandable valves) and the CoreValve trials (for self-expandable valves) investigated the performance of TAVR in progressively lower-risk patient cohorts. The initial trials demonstrated TAVR to be superior (PARTNER B) and noninferior (CoreValve Extreme Risk) to optimal medical therapy in inoperable patients. Subsequent trials showed both balloon-expandable and self-expandable valves to have good results in high-risk, medium-risk, and low-risk surgical patients when compared with SAVR. However, owing to the fundamentally different nature of the procedure, some complications have been more prevalent with TAVR, most notably moderate or severe paravalvular leak, conduction abnormalities necessitating permanent pacemaker placement, and vascular complications. When present, these complications have been associated with worse outcomes. Conclusions and Relevance: The results of the groundbreaking TAVR trials from the past decade have led to a revolution in the treatment of aortic stenosis. There are now 3 US Food and Drug Administration-approved TAVR devices, and with the encouraging results from the latest low-risk trials, TAVR is likely going to become the dominant treatment for symptomatic severe aortic stenosis. New devices on the horizon are looking to improve the complication rates of TAVR, and ongoing trials are looking to further expand the indications of TAVR and answer 1 of the main remaining questions, ie, long-term durability of percutaneously placed devices.

A video-based, flipped classroom, simulation curriculum for dermatologic surgery: A prospective, multi-institution study.

BACKGROUND: Medical education is evolving to emphasize trainee engagement. The impact of a flipped classroom curriculum and surgical simulation on dermatology resident education has not been evaluated. OBJECTIVE: To assess the impact of video education and surgical simulation on dermatology resident procedural skills. METHODS: We created a curriculum on foundational surgical skills for 31 first- and second-year dermatology residents at 3 institutions. The flipped classroom approach replaces traditional in-person lectures with at-home viewing of instructional videos. After this self-directed learning, trainees had 3 hands-on sessions using simulated skin models. The Objective Structured Assessment of Technical Skills (OSATS) instrument was used to assess residents performing a simulated elliptical excision with intermediate repair before and after the curriculum. Residents completed precurriculum and postcurriculum surveys evaluating operative confidence and perceived value of the curriculum. RESULTS: Residents' total OSATS score increased from a median of 27 (interquartile range, 22-38.5) before the curriculum to 46 (interquartile range, 39.5-51.5) after the curriculum (P < .001). Self-reported confidence in surgical performance significantly improved, and residents were highly satisfied. LIMITATIONS: Limitations include the small sample size and potential influence from concurrent learning on surgical rotations. CONCLUSIONS: Video education and simulation are effective for improving dermatology residents' procedural skills. We hope to serve as a template for other institutions and nondermatology trainees hoping to improve procedural skills.

Robust identification of deletions in exome and genome sequence data based on clustering of Mendelian errors.

Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome-wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs). Using our Mendelian Error Method (MEM), we identified 127 deletions (inherited and de novo) in 2,601 WES trios from the Pediatric Cardiac Genomics Consortium, with a validation rate of 88% by digital droplet PCR. MEM identified additional de novo deletions compared with XHMM, and a significant enrichment of 15q11.2 deletions compared with controls. In addition, MEM identified eight cases of uniparental disomy, sample switches, and DNA contamination. We applied MEM to WGS data from the Genome In A Bottle Ashkenazi trio and identified deletions with 97% specificity. MEM provides a robust, computationally inexpensive method for identifying deletions, and an orthogonal approach for verifying deletions called by other tools.

Robust identification of mosaic variants in congenital heart disease.

Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (n = 715) and a cohort of healthy individuals (n = 416). This is a novel application of the somatic variant caller designed for cancer to WES trio data. We identified two cases with mosaic KMT2D mutations that are likely pathogenic for CHD, but conclude that, overall, mosaicism detectable in peripheral blood or saliva does not account for a significant portion of CHD etiology.

Minimally invasive aortic valve replacement versus aortic valve replacement through full sternotomy: the Brigham and Women's Hospital experience.

BACKGROUND: Minimally invasive aortic valve surgery (mini AVR) is a safe and effective treatment option at many hospital centers, but there has not been widespread adoption of the procedure. Critics of mini AVR have called for additional evidence with direct comparison to aortic valve replacement (AVR) via full sternotomy (FS). METHODS: Our mini AVR approach is through a hemi-sternotomy (HS). We performed a propensity-score matched analysis of all patients undergoing isolated AVR via FS or HS at our institution since 2002, resulting in 552 matched pairs. Baseline characteristics were similar. Operative characteristics, transfusion rates, in-hospital outcomes as well as short and long term survival were compared between groups. RESULTS: Median cardiopulmonary bypass and cross clamp times were shorter in the HS group: 106 minutes [inter-quartile ranges (IQR) 87-135] vs. 124 minutes (IQR 90-169), P≤0.001, and 76 minutes (IQR 63-97) vs. 80 minutes (IQR 62-114), P≤0.005, respectively. HS patients had shorter ventilation times (median 5.7 hours, IQR 3.5-10.3 vs. 6.3 hours, IQR 3.9-11.2, P≤0.022), shorter intensive care unit stay (median 42 hours, IQR 24-71 vs. 45 hours, IQR 24-87, P≤0.039), and shorter hospital length of stay (median 6 days, IQR 5-8 vs. 7 days, IQR 5-10, P≤0.001) compared with the FS group. Intraoperative transfusions were more common in FS group: 27.9% vs. 20.0%, P≤0.003. No differences were seen in short or long term survival, or time to aortic valve re-intervention. CONCLUSIONS: Our study confirms the clinical benefits of minimally invasive AVR via HS, which includes decreased transfusion requirements, ventilation times, intensive care unit and hospital length of stay without compromising short and long term survival compared to conventional AVR via FS.

Acroparesthesia and carpal tunnel syndrome: a historical perspective.

This article presents the history of acroparesthesia and its contribution to the discovery of idiopathic carpal tunnel syndrome (CTS). We used primary sources from the middle of the nineteenth century onward to show that the first short descriptions of patients with nocturnal and early morning paresthesias, numbness, pain, and weakness in the hands, without accompanying physical signs, were published around 1850. The condition was named acroparesthesia in 1890 and, in the following years, was accepted as a disease in medical textbooks. Almost all of the patients with acroparesthesia, described at the end of the nineteenth and the first half of the twentieth century, would today be diagnosed with idiopathic CTS. Although physicians proposed many hypotheses for the etiology of acroparesthesia throughout its 100-year history, they did not understand that the condition arose from compression of the median nerve in the carpal tunnel, and the concept of acroparesthesia did not lead to the discovery of CTS. Even Russell Brain-who, in 1946 and 1947, showed that the "syndrome of partial thenar atrophy" was due to compression of the median nerve in the carpal tunnel-did not realize that acroparesthesia shared the same origin. This understanding developed in the late 1940s and through the 1950s, and the disease came to be accepted under the name carpal tunnel syndrome.

Carpal tunnel syndrome, syndrome of partial thenar atrophy, and W. Russell Brain: a historical perspective.

This article presents the history of the discovery of compression of the median nerve in the carpal tunnel without an identifiable cause as a distinct clinical entity. By analyzing primary sources, we show that, at the beginning of the twentieth century, physicians described patients with paresthesias and numbness in the hands, most prominent at night, accompanied by bilateral symmetrical atrophy along the radial side of thenar eminence. At the time, the 2 most influential hypotheses regarding etiology were, first, compression of the lower trunk of the brachial plexus by a cervical or first rib, and second, compression of the thenar branch of the median nerve as it passes beneath the anterior annular ligament of the wrist. The condition was named syndrome of partial thenar atrophy and was considered a distinct clinical entity. In 1946, after extensive analysis, neurologist Walter Russell Brain concluded that both sensory and motor symptoms of the syndrome were caused by "compression neuritis" of the median nerve in the carpal tunnel. At his suggestion, surgeon Arthur Dickson Wright performed decompression of the nerve by "an incision of the carpal ligament," with excellent results. Brain presented this work at the Royal Society of Medicine in London in 1946 and published his landmark paper in Lancet the following year. In so doing, he established the basis for the disease we know today as idiopathic carpal tunnel syndrome. Unfortunately, in 1947, Brain did not realize that another "condition" with the same clinical picture but without atrophy of the thenar muscles, known as acroparesthesia at the time, was actually the same disease as syndrome of partial thenar atrophy, but of lesser severity. As a result of Brain's influence, 7 other papers were published by 1950. Between 1946 and 1950, there were at least 10 papers that presented, in total, 31 patients (26 women) who exhibited symptoms of compression of the median nerve without an identifiable cause and underwent section of the transverse carpal ligament.

The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality.

Heterotaxy is a disorder of left-right body patterning, or laterality, that is associated with major congenital heart disease. The aetiology and mechanisms underlying most cases of human heterotaxy are poorly understood. In vertebrates, laterality is initiated at the embryonic left-right organizer, where motile cilia generate leftward flow that is detected by immotile sensory cilia, which transduce flow into downstream asymmetric signals. The mechanism that specifies these two cilia types remains unknown. Here we show that the N-acetylgalactosamine-type O-glycosylation enzyme GALNT11 is crucial to such determination. We previously identified GALNT11 as a candidate disease gene in a patient with heterotaxy, and now demonstrate, in Xenopus tropicalis, that galnt11 activates Notch signalling. GALNT11 O-glycosylates human NOTCH1 peptides in vitro, thereby supporting a mechanism of Notch activation either by increasing ADAM17-mediated ectodomain shedding of the Notch receptor or by modification of specific EGF repeats. We further developed a quantitative live imaging technique for Xenopus left-right organizer cilia and show that Galnt11-mediated Notch1 signalling modulates the spatial distribution and ratio of motile and immotile cilia at the left-right organizer. galnt11 or notch1 depletion increases the ratio of motile cilia at the expense of immotile cilia and produces a laterality defect reminiscent of loss of the ciliary sensor Pkd2. By contrast, Notch overexpression decreases this ratio, mimicking the ciliopathy primary ciliary dyskinesia. Together our data demonstrate that Galnt11 modifies Notch, establishing an essential balance between motile and immotile cilia at the left-right organizer to determine laterality, and reveal a novel mechanism for human heterotaxy.

Embryonic exposure to propylthiouracil disrupts left-right patterning in Xenopus embryos.

Antithyroid medications are the preferred therapy for the treatment of Graves' disease during pregnancy. Propylthiouracil (PTU) is favored over methimazole (MMI) due to potential teratogenic concerns with MMI. This study was to determine the teratogenic potential of MMI and PTU using a validated Xenopus tropicalis embryo model. Embryos were exposed to 1 mM PTU (EC(50)=0.88 mM), 1 mM MMI, or vehicle control (water) from stages 2 to 45. Treated embryos were examined for gross morphological defects, ciliary function, and gene expression by in situ hybridization. Exposure to PTU, but not MMI, led to cardiac and gut looping defects and shortening along the anterior-posterior axis. PTU exposure during gastrulation (stage 8-12.5) was identified as the critical period of exposure leading to left-right (LR) patterning defects. Abnormal cilia polarization, abnormal cilia-driven leftward flow at the gastrocoel roof plate (GRP), and aberrant expression of both Coco and Pitx2c were associated with abnormal LR symmetry observed following PTU exposure. PTU is teratogenic during late blastula, gastrulation, and neurulation; whereas MMI is not. PTU alters ciliary-driven flow and disrupts the normal genetic program involved in LR axis determination. These studies have important implications for women taking PTU during early pregnancy.

Lymphangioma of the gallbladder in adults: review of the literature and a case report.

INTRODUCTION: Lymphangiomas of the gallbladder in adults are extremely rare with only 10 cases published worldwide to date. CASE PRESENTATION: We herein report a case of a 26-year-old male who presented with abdominal right upper quadrant pain, nausea, vomiting, and diarrhea. An ultrasound, computer tomography scan, and magnetic resonance imaging showed a cystic mass interposed between the gallbladder and the liver with characteristics identical to those of lymphangiomas in more common locations. The patient underwent an open excision of the large spongy mass en bloc with the gallbladder. CONCLUSION: Histological findings confirmed the diagnosis of lymphangioma. Also, we provide a review of 10 cases presented in the literature, with a discussion of the clinical features, diagnosis, and surgical approach.

Transmitral flow velocity-contour variation after premature ventricular contractions: a novel test of the load-independent index of diastolic filling.

The new echocardiography-based, load-independent index of diastolic filling (LIIDF) M was assessed using load-/shape-varying E-waves after premature ventricular contractions (PVCs). Twenty-six PVCs in 15 subjects from a preexisting simultaneous echocardiography-catheterization database were selected. Perturbed load-state beats, defined as the first two post-PVC E-waves, and steady-state E-waves, were subjected to conventional and model-based analysis. M, a dimensionless index, defined by the slope of the peak driving-force vs. peak (filling-opposing) resistive-force regression, was determined from steady-state E-waves alone, and from load-perturbed E-waves combined with a matched number of subsequent beats. Despite high degrees of E-wave shape variation, M derived from load-varying, perturbed beats and M derived from steady-state beats alone were indistinguishable. Because the peak driving-force vs. peak resistive-force relation determining M remains highly linear in the extended E-wave shape and load variation regime observed, we conclude that M is a robust LIIDF.