Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease.

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.

Treatment with synchronized radiofrequency and facial muscle stimulation: Histologic analysis of human skin for changes in collagen and elastin fibers.

BACKGROUND: Skin's exposure to intrinsic and extrinsic factors causes age-related changes, leading to a lower amount of dermal collagen and elastin. AIM: This study investigated the effects of a novel facial muscle stimulation technology combined with radiofrequency (RF) heating on dermal collagen and elastin content for the treatment of facial wrinkles and skin laxity. METHODS: The active group subjects (N = 6) received four 20-min facial treatments with simultaneous RF and facial muscle stimulation, once weekly. The control subject (N = 1) was untreated. Skin biopsies obtained at baseline, 1-month and 3-month follow-up were evaluated histologically to determine collagen and elastin fibers content. A group of independent aestheticians evaluated facial skin appearance and wrinkle severity. Patient safety was followed. RESULTS: In the active group, collagen-occupied area reached 11.91 ± 1.80 × 106 µm2 (+25.32%, p < 0.05) and 12.35 ± 1.44 × 105 µm2 (+30.00%, p < 0.05) at 1-month and 3-month follow-up visits. Elastin-occupied area at 1-month and 3-month follow-up was 1.64 ± 0.14 × 105 µm2 (+67.23%, p < 0.05), and 1.99 ± 0.21 × 105 µm2 (+102.80%, p < 0.05). In the control group, there was no significant difference (p > 0.05) in collagen and elastin fibers. Active group wrinkle scores decreased from 5 (moderate, class II) to 3 (mild, class I). All subjects, except the control, improved in appearance posttreatment. No adverse events or side effects occurred. CONCLUSION: Decreased dermal collagen and elastin levels contributes to a gradual decline in skin elasticity, leading to facial wrinkles and unfirm skin. Study results showed noticeable improvement in facial appearance and increased dermal collagen and elastin content subsequent to simultaneous, noninvasive RF, and facial muscle stimulation treatments.

Effect of patient factors, center, and era on Fontan timing: An observational study using the Pediatric Health Information Systems Database.

BACKGROUND: There are no consensus guidelines defining optimal timing for the Fontan operation, the last planned surgery in staged palliation for single-ventricle heart disease. OBJECTIVES: Identify patient-level characteristics, center-level variation, and secular trends driving Fontan timing. METHODS: A retrospective observational study of subjects who underwent Fontan from 2007 to 2021 at centers in the Pediatric Health Information Systems database was performed using linear mixed-effects modeling in which age at Fontan was regressed on patient characteristics and date of operation with center as random effect. RESULTS: We included 10,305 subjects (40.4% female, 44% non-white) at 47 centers. Median age at Fontan was 3.4 years (IQR 2.6-4.4). Hypoplastic left heart syndrome (-4.4 months, 95%CI -5.5 to -3.3) and concomitant conditions (-2.6 months, 95%CI -4.1 to -1.1) were associated with younger age at Fontan. Subjects with technology-dependence (+4.6 months, 95%CI 3.1-6.1) were older at Fontan. Black (+4.1 months, 95%CI 2.5-5.7) and Asian (+8.3 months, 95%CI 5.4-11.2) race were associated with older age at Fontan. There was significant variation in Fontan timing between centers. Center accounted for 10% of variation (ICC 0.10, 95%CI 0.07-0.14). Center surgical volume was not associated with Fontan timing (P = .21). Operation year was associated with age at Fontan, with a 3.1 month increase in age for every 5 years (+0.61 months, 95%CI 0.48-0.75). CONCLUSIONS: After adjusting for patient-level characteristics there remains significant inter-center variation in Fontan timing. Age at Fontan has increased. Future studies addressing optimal Fontan timing are warranted.

A review of nonsurgical facial rejuvenation and the role of oxymetazoline hydrochloride ophthalmic solution, 0.1% in periorbital revitalization.

BACKGROUND: The demand for nonsurgical facial rejuvenation options is growing, yet the periorbital region remains an area of relative unmet need. This review explores nonsurgical options for facial rejuvenation and the role of oxymetazoline hydrochloride ophthalmic solution, 0.1%, in treating age-related blepharoptosis as part of periorbital rejuvenation. METHODS: Advisors experienced in facial rejuvenation met to discuss existing literature on the upper face and periorbital rejuvenation and the role of oxymetazoline hydrochloride ophthalmic solution, 0.1%, in treating facial aging. RESULTS: An array of nonsurgical options exist to address the signs of aging, including minimally invasive treatments, such as botulinum toxin injections and dermal fillers, and noninvasive therapy, such as lasers, chemical peels, and microdermabrasion. However, treating age-related ptosis in periorbital rejuvenation is mainly addressed surgically. The newly approved α-adrenergic receptor agonist oxymetazoline hydrochloride ophthalmic solution, 0.1%, provides a novel non-interventional approach to blepharoptosis. CONCLUSIONS: Facial rejuvenation is highly sought-after in this post-pandemic era. Each nonsurgical treatment option has its advantages and drawbacks. A patient-centered approach is necessary to select the appropriate procedure considering the patient's concerns and aesthetic sensibilities. The eyes are an area of primary concern for patients, yet surgery is the gold standard for treating ptosis. Oxymetazoline hydrochloride ophthalmic solution, 0.1%, is a safe and effective nonsurgical treatment for blepharoptosis.

Induction of fat apoptosis by a combination of synchronized radiofrequency and HIFEM technology: Human histology study.

PURPOSE: With the growing demand for more effective fat reduction techniques, a combination of synchronized radiofrequency (RF) and HIFEM has been introduced. Preceding studies evidenced the ability of RF+HIFEM to maintain the fat tissue temperature at the levels necessary for adipocyte apoptosis while documenting the induced changes to the fat tissue during the several weeks after the treatment. This study aims to demonstrate the induction of apoptosis by RF+HIFEM technology in the early stages through the assessment of caspase-3 protein, one of the apoptosis-executing proteases. DESIGN: In this two-arm, single-center, randomized trial, nine human subjects were enrolled and assigned into two groups, either the active group (N = 6) treated with both RF+HIFEM set at the highest tolerated levels or the sham group (N = 3) treated with 5% of the maximum RF+HIFEM power, serving as a control. All patients were scheduled to undergo one treatment visit of the abdominal area, two follow-up visits at 8 and 24 h, and one safety visit 7 days after the treatment. A punch biopsy (5 mm in diameter, approximately 10 mm in depth) was obtained from the abdominal area at the baseline and consecutive follow-up visits. Samples were fixed, and cut into 5 µm thick slices, and immunohistochemical staining was used to visualize the Caspase-3, revealing the adipocyte nuclei where apoptosis processes are in progress. FINDINGS: Documented findings suggest that the temperature threshold of 43-45°C is required to initiate fat apoptosis and consequent reduction in adipocyte number was achieved during the combined treatment with RF+HIFEM. The active group showed an elevated ratio of positively stained nuclei versus all adipocyte nuclei found on the evaluated slices-referred to as the apoptotic index (AI). The AI significantly (p < 0.001) increased at both 8 h (47.01 ± 10.56%) and 24 h (43.58 ± 6.35%) posttreatment. The Sham group showed no significant change in the AI (p > 0.05). No adverse events or side effects related to the treatments were observed. SUMMARY: This study supports previously published evidence on fat reduction after RF+HIFEM treatment, documenting the safe initiation of adipocyte programmed cell death posttreatment.

Macrocystis pyrifera ferment-containing creams for optimizing facial skin rejuvenation.

BACKGROUND: There is an increasing demand for facial skin rejuvenation. Specialized aesthetic skincare treatments may be one of the first steps to help prevent or treat facial signs of aging. This article discusses aesthetic skin care for facial skin rejuvenation, particularly data on two creams containing Macrocystis pyrifera ferment. METHODS: The authors convened a dermatology advisory board to discuss challenges and practices in using skincare for facial rejuvenation, combining their expert opinion and experience on facial rejuvenation with preclinical and clinical data on two creams containing Macrocystis pyrifera ferment and a review of the literature. RESULTS: Preclinical and clinical studies on Macrocystis pyrifera ferment and two creams containing the ferment exhibit anti-inflammatory, anti-aging, and healing properties. In preclinical studies, the ferment demonstrated collagen type I enhancing properties in ex vivo skin models, and skin cells treated with the ferment migrated faster than untreated cells in the in vitro study. In clinical studies measuring visible anti-inflammatory activity, the ferment alone and the ferment-containing products significantly decreased erythema, and in anti-aging studies, they improved visible skin aging parameters. Finally, in clinical studies on the stratum corneum, the two creams increased moisture levels and decreased transepidermal water loss (TEWL), reflecting healing by enhancing barrier strength and recovery. CONCLUSIONS: The Macrocystis pyrifera ferment and creams containing the ferment are effective skin care treatment products to decrease the visible effects of inflammation and signs of aging while promoting healing by enhancing barrier resilience and recovery.

Cryolipolysis: A promising nonsurgical technique for localized fat reduction.

BACKGROUND: Cryolipolysis, also known as fat freezing, is a nonsurgical technique specialized for localized fat reduction. Utilizing targeted cold exposure to adipose tissue, cryolipolysis devices induce cellular apoptosis in adipocytes while sparing surrounding tissues, resulting in the selective disruption of fat cells and subsequent removal of damaged cells by macrophages. A reduction of the fat layer produces a noninvasive cosmetic benefit that provides an accessible alternative to liposuction. Objective and subjective measurements have demonstrated significant reduction in fat volume and high patient satisfaction rates. Cryolipolysis has been proven to be safe with minimal adverse effects. However, further research is needed to fully understand the mechanism of cryolipolysis and its efficacy in different treatment areas. This paper aims to provide a comprehensive overview of cryolipolysis, including its mechanism of action, indications, contraindications, adverse effects, results and outcomes, safety profile, and areas requiring further research. METHODS: Our primary phase of literature review consisted of a PubMed search looking for all published literature around cryolipolysis. We employed a review approach that examined over 30 papers with the key search terms of "cryolipolysis," "fat-freezing," "cosmetic dermatology," "body contouring," "adverse effects," "adipocyte apoptosis," "Coolsculpting®," "cold panniculitis," and "localized fat reduction." We then analyzed each paper, extracting relevant information to gain a multidimensional understanding of cryolipolysis to provide a comprehensive review. CONCLUSION: Cryolipolysis, with its ability to target and reduce localized adipose tissue, has emerged as a promising nonsurgical technique in the field of body contouring. It offers patients a valuable option for achieving their desired fat reduction without the need for a lengthy recovery period or major surgery. Cryolipolysis has shown to reduce the number of adipocytes in the treated area, a phenomenon that can be objectively quantified through various means, including fat caliper measurements, ultrasound assessments, and 3D imaging, or subjectively observed through patient satisfaction rates, clinical observations, and investigator assessments. In addition to its effectiveness in reducing localized adipose tissue, cryolipolysis also holds potential in the area of skin tightening. Preliminary studies suggest that cryolipolysis may have a positive impact on skin elasticity and tightening. Further investigation of this mechanism is needed to provide a better understanding of its potential in achieving optimal cosmetic outcomes for patients. By combining the benefits of fat reduction and skin tightening, cryolipolysis has the potential to offer a comprehensive nonsurgical solution for body contouring.

Hereditary haemorrhagic telangiectasia and SMAD4 mutation in a patient with complex single ventricle heart disease.

We report a case of hypoplastic left heart syndrome and with subsequent aortopathy and then found to have hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome due to a germline SMAD4 pathologic variant. The patient's staged palliation was complicated by the development of neoaortic aneurysms, arteriovenous malformations, and gastrointestinal bleeding thought to be secondary to Fontan circulation, but workup revealed a SMAD4 variant consistent with hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome. This case underscores the importance of genetic modifiers in CHD, especially those with Fontan physiology.

Insights into acne and the skin barrier: Optimizing treatment regimens with ceramide-containing skincare.

INTRODUCTION: Acne is a common, complex, multifactorial inflammatory skin disease associated with epidermal barrier dysfunction. Beginning in childhood, acne affects many adolescents and adults. Acne is associated with lower self-esteem, anxiety, and depression and may cause scars and pigmentary sequelae. The review explores the relationships between acne and the skin barrier function and discusses nuances in the prevention, treatment, and maintenance of acne and its impact on the skin barrier. METHODS: The advisors' previous publications addressed prescription and nonprescription pediatric acne treatment and skincare using cleansers, moisturizers, and a practical algorithm for treatment and maintenance, including skincare recommendations for pediatric acne patients and an algorithm for skin of color patients with acne. Before the meeting, literature was culled on the relationship between the skin barrier and acne and current best practices in acne, addressing prescription and nonprescription acne products and skincare as monotherapy, adjunctive, and maintenance treatment. RESULTS: After discussing 13 draft statements, the advisors applied the selected literature and drew from their clinical knowledge and experience, and agreed on five statements. The follicular epithelial barrier is directly involved with changes that occur during both comedogenesis and in stages of inflammation, especially with follicular rupture compromising the barrier's integrity. In acne-affected skin, sebaceous glands are larger, sebum excretion and filaggrin expression higher, and stratum corneum lipids are reduced. Educating patients and clinicians about inflammation's central role in acne and measures to reduce inflammation is essential. Skin irritation and xerosis from acne and treatments lead to poor treatment adherence. A skincare regimen should be included in the acne prevention, treatment, and maintenance care regimen and should be ongoing. Maintenance treatment with topical agents and skincare using gentle ceramide-containing cleansers and moisturizers is a recommended strategy after successfully controlling the disease. CONCLUSIONS: Epidermal barrier dysfunction contributes to acne exacerbation. Using the appropriate treatment and skincare helps to minimize irritation and inflammation, enhance treatment adherence, and improve patient outcomes.

Treatment of mild to severe acne with 1726 nm laser: A safe alternative to traditional acne therapies.

INTRODUCTION: Acne is the most common reason for dermatology consultation in adolescents and young adults. Consultation is often delayed despite unsuccessful self-treatment. Postponing effective treatment places acne sufferers at higher risk for permanent acne scars and post-inflammatory pigment changes. AIM: This review discusses clinical challenges with present therapeutic options for acne treatment and the role of a 1726 nm laser for acne. METHODS: Current acne treatment guidelines were reviewed. A literature review was conducted for trials of light-based acne therapy. The selectivity of previous light-based therapies was reviewed. RESULTS: Available acne therapy is effective, but treatment-related side effects are common. Acne treatment guidelines do not include recommendations for light-based treatments. Different types of light-based treatments have been tried but until now no wavelength specifically targeted sebaceous glands. CONCLUSION: The 1726 nm laser is safe and effective for treating mild to severe acne in all Fitzpatrick skin types. Acne resolution is apparent within the first month and improves for up to 2 years beyond treatment.

Impact of Ventricular Dysfunction and Atrioventricular Valve Regurgitation on Pre-Fontan Attrition.

BACKGROUND: There is a significant incidence of pre-Fontan attrition-defined as failure to undergo Fontan completion-after superior cavopulmonary connection. This study investigated the impact of at least moderate ventricular dysfunction (VD) and atrioventricular valve regurgitation (AVVR) on pre-Fontan attrition. METHODS: This single-center retrospective cohort study included all infants who underwent Norwood palliation from 2008 to 2020 and subsequently underwent superior cavopulmonary connection. Pre-Fontan attrition was defined as death, listing for heart transplantation before Fontan completion, or unsuitability for Fontan completion. The study's secondary outcome was transplant-free survival. RESULTS: Pre-Fontan attrition occurred in 34 of 267 patients (12.7%). Isolated VD was not associated with attrition. However, patients with isolated AVVR had 5 times the odds of attrition (odds ratio, 5.4; 95% CI 1.8-16.2), and patients with both VD and AVVR had 20 times the odds of attrition (odds ratio, 20.1; 95% CI 7.7-52.8) compared with patients without VD or AVVR. Only patients with both VD and AVVR had significantly worse transplant-free survival compared with patients without VD or AVVR (hazard ratio, 7.7; 95% CI 2.8-21.6). CONCLUSIONS: The additive effect of VD and AVVR is a powerful contributor to pre-Fontan attrition. Future research investigating therapies that can mitigate the degree of AVVR may help improve Fontan completion rates and long-term outcomes.

A review of exosomes and their application in cutaneous medical aesthetics.

BACKGROUND: Exosomes have gained recent popularity in aesthetic medicine; however, there is still a dearth of understanding on the etiology of exosomes, their physiologic function, and regenerative capabilities. OBJECTIVE: The purpose of this article is to summarize some of the physiologic functions of exosomes, their mechanistic role, and current commercial landscape in regenerative aesthetics. METHODS: A Medline search was conducted with the keywords, exosomes, extracellular vesicles, stem cells, skin rejuvenation, and cutaneous aesthetics. MeSH term "exosomes" filtered by relevant subheadings was also utilized. Pertinent original articles encompassing animal studies, cell studies, and human studies were included. We restricted to articles published in the last 10 years. RESULTS: Pre-clinical studies have demonstrated the therapeutic capabilities of exosomes in wound healing, scar modulation, alopecia, and skin rejuvenation. Exosomes primarily exert their effects in a paracrine function and modulate the interactions between keratinocytes and other cells of the skin. Exogenous exosomes can be utilized in a variety of settings to bring about desired aesthetic outcomes and to date, has only been approved for topical administration. CONCLUSION: The safety, efficacy, potency, and dosages of exosomes remains to be determined via robust human clinical trials. Isolation and purification techniques have yet to be standardized, and this would be required for regulatory approval of all delivery modes. Overall, exosomes deliver yet another therapeutic option in regenerative aesthetics.

The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis.

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO2), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO2, work rate at the ventilatory anaerobic threshold (VAT), VO2 at VAT, and ventilatory efficiency (VE/VCO2) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO2, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115.

Modeling of the Tricuspid Valve and Right Ventricle in Hypoplastic Left Heart Syndrome With a Fontan Circulation.

BACKGROUND: In hypoplastic left heart syndrome, tricuspid regurgitation (TR) is associated with circulatory failure and death. We hypothesized that the tricuspid valve (TV) structure of patients with hypoplastic left heart syndrome with a Fontan circulation and moderate or greater TR differs from those with mild or less TR, and that right ventricle volume is associated with TV structure and dysfunction. METHODS: TV of 100 patients with hypoplastic left heart syndrome and a Fontan circulation were modeled using transthoracic 3-dimensional echocardiograms and custom software in SlicerHeart. Associations of TV structure to TR grade and right ventricle function and volume were investigated. Shape parameterization and analysis was used to calculate the mean shape of the TV leaflets, their principal modes of variation, and to characterize associations of TV leaflet shape to TR. RESULTS: In univariate modeling, patients with moderate or greater TR had larger TV annular diameters and area, greater annular distance between the anteroseptal commissure and anteroposterior commissure, greater leaflet billow volume, and more laterally directed anterior papillary muscle angles compared to valves with mild or less TR (all P<0.001). In multivariate modeling greater total billow volume, lower anterior papillary muscle angle, and greater distance between the anteroposterior commissure and anteroseptal commissure were associated with moderate or greater TR (P<0.001, C statistic=0.85). Larger right ventricle volumes were associated with moderate or greater TR (P<0.001). TV shape analysis revealed structural features associated with TR, but also highly heterogeneous TV leaflet structure. CONCLUSIONS: Moderate or greater TR in patients with hypoplastic left heart syndrome with a Fontan circulation is associated with greater leaflet billow volume, a more laterally directed anterior papillary muscle angle, and greater annular distance between the anteroseptal commissure and anteroposterior commissure. However, there is significant heterogeneity of structure in the TV leaflets in regurgitant valves. Given this variability, an image-informed patient-specific approach to surgical planning may be needed to achieve optimal outcomes in this vulnerable and challenging population.

High-Intensity Focused Electromagnetic Field With Synchronized Radiofrequency Achieves Superior Gluteal Muscle Contouring Than High-Intensity Focused Electromagnetic Field Procedure Alone.

Background: The high-intensity focused electromagnetic field (HIFEM) procedure is an effective method for noninvasive toning and shaping of buttocks. Objectives: To investigate and compare the efficacy of simultaneous application of HIFEM procedure with radiofrequency (RF) heating vs HIFEM standalone procedure on the buttocks. Methods: Sixty-seven subjects (21-67 years, BMI 16-34 kg/m2) were recruited and divided into two groups. Group A received simultaneous HIFEM + RF therapy, and group B received standalone HIFEM treatments. All participants underwent four 30-minute bilateral treatments on the buttocks. The MRI was used to evaluate the changes in muscle and fat thickness. Results: Data of 32 subjects from group A and 31 subjects from group B were reviewed at 1-month follow-up. On average, subjects from group A showed a 31.3% higher increase in muscle thickness, as shown in the MRI evaluation. The gluteal muscle thickness continued to grow and peaked at a 3-month follow-up, wherein 27 patients were evaluated in each group (n = 54). Group A showed on average +24.7% increase (gluteus maximus +8.5 ± 1.9 mm, medius +6.0 ± 1.1 mm, minimus +2.9 ± 0.8 mm), while group B exhibited only +15.9% increase in muscle thickness (gluteus maximus +5.2 ± 1.1 mm, medius +3.6 ± 1.0 mm, minimus +1.6 ± 0.4 mm). On average, group A showed a 35.6% higher growth in muscle thickness. Treatments were safe and comfortable with high satisfaction rates. No adverse event was reported throughout the study. Conclusions: Our results suggest that simultaneous use of HIFEM + RF is safe and significantly more effective for gluteal contouring than the HIFEM procedure alone.

Combined ventricular dysfunction and atrioventricular valve regurgitation after the Norwood procedure are associated with attrition prior to superior cavopulmonary connection.

Background: Infants with hypoplastic left heart syndrome (HLHS) or a variant are at risk of ventricular dysfunction (VD) and atrioventricular valve regurgitation (AVVR) prior to superior cavopulmonary connection (SCPC). Although the impact of these complications in isolation has been described, their effect in combination on attrition is poorly defined. Methods: A retrospective observational study of patients with HLHS or variants undergoing a Norwood procedure between 2008 and 2020 at a single center was performed. VD and AVVR were defined as moderate or severe when seen on 2 sequential echocardiograms outside the perioperative period. Attrition was defined as death, listing for heart transplant, or unsuitability for SCPC or transplant. Descriptive statistics and regression models were used for analysis. Results: A total of 397 patients were included, of whom 75% had HLHS and 57% had received a Blalock-Thomas-Taussig shunt. Isolated VD occurred in 9% of patients, AVVR occurred in 13%, and both occurred in 6%. Attrition prior to SCPC occurred in 19% of the overall cohort, in 52% of patients with combined VD and AVVR (odds ratio [OR], 5.2; 95% confidence interval [CI], 2.3-12.0; P < .01), 26% of those with VD (OR, 1.5; 95% CI, 0.7-3.3; P = .32), 25% of those with AVVR (OR, 1.5; 95% CI, 0.7-2.9; P = .27), and 15% in those with neither (OR, 0.3; 95% CI, 0.2-0.6; P < .01). Other factors associated with attrition included prematurity, total bypass time at Norwood, and extracorporeal membrane oxygenation after Norwood, whereas later year of Norwood was protective (P < .01 for all). Conclusions: The presence of combined VD and AVVR markedly increases the likelihood of attrition prior to SCPC, identifying a high-risk group.

Impact of Udenafil on Echocardiographic Indices of Single Ventricle Size and Function in FUEL Study Participants.

BACKGROUND: The FUEL trial (Fontan Udenafil Exercise Longitudinal) demonstrated statistical improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle function in this cohort has not been studied. METHODS: The 400 enrolled participants were randomized 1:1 to udenafil or placebo. Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline indices of single ventricle systolic, diastolic and global function, atrioventricular valve regurgitation, and mean Fontan fenestration gradient in the udenafil cohort versus placebo, controlling for ventricular morphology (left ventricle versus right ventricle/other) and baseline value. RESULTS: The udenafil participants (n=191) had significantly improved between baseline and 26 weeks visits compared to placebo participants (n=195) in myocardial performance index (P=0.03, adjusted mean difference [SE] of changes between groups -0.03[0.01]), atrioventricular valve inflow peak E (P=0.009, 3.95 [1.50]), and A velocities (P=0.034, 3.46 [1.62]), and annular Doppler tissue imaging-derived peak e' velocity (P=0.008, 0.60[0.23]). There were no significant differences in change in single ventricle size, systolic function, atrioventricular valve regurgitation severity, or mean fenestration gradient. Participants with a dominant left ventricle had significantly more favorable baseline values of indices of single ventricle size and function (lower volumes and areas, E/e' ratio, systolic:diastolic time and atrioventricular valve regurgitation, and higher annular s' and e' velocity). CONCLUSIONS: FUEL participants who received udenafil demonstrated a statistically significant improvement in some global and diastolic echo indices. Although small, the changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular compliance, which may help explain improved exercise performance in that cohort. REGISTRATION: URL: https://clinicaltrials.gov; Unique Identifier: NCT02741115.

Comparing Predicted Probability of Hepatocellular Carcinoma in Patients With Cirrhosis With the General Population: An Opportunity to Improve Risk Communication?

INTRODUCTION: Risk scores estimating a patient's probability of a hepatocellular carcinoma (HCC) diagnosis are abundant but are difficult to interpret in isolation. We compared the predicted HCC probability for individuals with cirrhosis and cured hepatitis C with the general population (GP). METHODS: All patients with cirrhosis achieving sustained viral response (SVR) in Scotland by April 2018 were included (N = 1,803). The predicted 3-year probability of HCC at time of SVR achievement was determined using the aMAP prognostic model. GP data on the total number of incident HCCs in Scotland, stratified by demographics, were obtained from Public Health Scotland. Predicted HCC risk of cirrhosis SVR patients was compared with GP incidence using 2 metrics: (i) incidence ratio: i.e., 3-year predicted probability for a given patient divided by the 3-year probability in GP for the equivalent demographic group and (ii) absolute risk difference: the 3-year predicted probability minus the 3-year probability in the GP. RESULTS: The mean predicted 3-year HCC probability among cirrhosis SVR patients was 3.64% (range: 0.012%-36.12%). Conversely, the 3-year HCC probability in the GP was much lower, ranging from <0.0001% to 0.25% depending on demographics. The mean incidence ratio was 410, ranging from 5 to >10,000. The mean absolute risk difference was 3.61%, ranging from 0.012% to 35.9%. An online HCC-GP comparison calculator for use by patients/clinicians is available at https://thrive-svr.shinyapps.io/RShiny/ . DISCUSSION: Comparing a patient's predicted HCC probability with the GP is feasible and may help clinicians communicate risk information and encourage screening uptake.