Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.

BACKGROUND: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features. METHODS: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative. RESULTS: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes. CONCLUSIONS: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals: Responses from a survey of vaccines and biological therapeutics manufacturers.

The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) has been tasked by the World Health Organization (WHO) to review the extent to which animal-based testing methods are described in their manuals, guidelines and recommendations for vaccines and biotherapeutics. The aim is to identify and recommend where updates to these documents can lead to an increased and more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction and Refinement of animal tests) in the quality control and batch release testing requirements for vaccines and biotherapeutics. Developing recommendations that are widely applicable by both the manufacturers and national regulatory authorities for vaccines and biologicals globally requires a detailed understanding of how different organisations view the opportunities and barriers to better integration of the 3Rs. To facilitate this, we developed and distributed a survey aimed at vaccine and biotherapeutics manufacturers in July 2021. In this paper, we present the key findings from this survey and how these will help inform the recommendations for wider integration of 3Rs approaches by WHO in their guidance documents applicable to the quality control and batch testing of vaccines and biotherapeutics.

Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals: Responses from a survey of National Control Laboratories and National Regulatory Authorities.

The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) is reviewing World Health Organization (WHO) manuals, guidelines and recommendations for vaccines and biotherapeutics to identify the extent to which animal-based testing methods are described. The aim is to recommend where updates to these documents can lead to an increased and more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction and Refinement of animal tests) in the quality control and batch release testing requirements for vaccines and biotherapeutics. Improved adoption of 3Rs principles and non-animal testing strategies will help to reduce the delays and costs associated with product release testing. Developing recommendations that are widely applicable by both the manufacturers and national regulatory authorities for vaccines and biological therapeutics globally requires a detailed understanding of how different organisations view the opportunities and barriers to better integration of the 3Rs. To facilitate this, we developed and distributed a survey aimed at individuals who work for national regulatory authorities (NRAs) and/or national control laboratories (NCLs). In this paper, we present the key findings from this survey and how these will help inform the recommendations for wider integration of 3Rs approaches by WHO in their guidance documents applicable to the quality control and batch release testing of vaccines and biotherapeutics.

Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals.

Animal testing has long been integral to the development of biologicals, including vaccines. The use of animals can provide important information on potential toxicity, insights into their mechanism of action, pharmacokinetics and dynamics, physiologic distribution, and potency. However, the use of these same methods is often adopted into the post-licensure phase of the product life cycle for the monitoring of product qualities, such as potency or safety, as part of their routine batch release. The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) and the World Health Organization (WHO) are collaborating on a project to review animal-based testing methods described in WHO manuals, guidelines and recommendations for biologicals to identify where updates can lead to a more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction, and Refinement of animal tests) in batch release testing requirements. An international working group consisting of more than 30 representatives from pharmaceutical and biotechnology companies, national control laboratories and regulatory bodies is performing this review. This project aims to address concerns about inconsistencies in the guidance for the scientifically justified use of animal methods required for the post-licensure quality control and batch release testing of biologicals, and the near absence of recommendations for the application of 3Rs principles within the relevant guidelines. Improved adoption of 3Rs principles and non-animal testing strategies will help to reduce the delays and costs associated with product release testing and help support faster access to products by the global communities who need them most urgently.

Is myocardial repolarization duration associated with repolarization heterogeneity?

BACKGROUND: Dispersion of repolarization is theorized as one mechanism by which myocardial repolarization prolongation causes lethal torsades de pointes, (TdP). Our primary purpose was to determine whether prolongation of myocardial repolarization as measured by the heart rate-corrected J-to-T peak interval (JTpkc), is associated with repolarization heterogeneity as measured by transmural dispersion, defined as the median duration from the peak to the end of the T wave (TpTe). METHODS: A retrospective cohort study was performed at a single urban tertiary ED from July 2011-September 2012. Inclusion criteria included all consecutive ED patients with ECG based on QTc and QRS intervals. Automated measurements of all intervals were performed. The association of JTpkc with the dependent variable TpTe was assessed after adjustment for QRS and RR interval durations with a multiple linear regression model. A secondary analysis included a similar adjusted assessment of the association of JTpkc with QT dispersion, QTd. Finally, we constructed two multiple regression models to assess the association of clinical causative factors of TdP with TpTe and JTpkc. RESULTS: Eight hundred seventy-four cases were included: 186 with QTc <500 ms, 118 with QTc ≥500 and QRS ≥120 ms, and 570 with QTc ≥500 and QRS <120 ms. The coefficient for association of JTpkc with TpTe was -0.10 (95%CI -0.15 to -0.05), and for JTpkc with QTd was 0.03 (95% CI -0.01 to 0.06). Clinical causative TdP factors were associated more with JTpkc than TpTe. CONCLUSION: Repolarization duration as measured by JTpkc is not positively associated with dispersion of repolarization as measured by TpTe or QTd. Dispersion of repolarization may not be a critical mechanistic link between QTc prolongation and TdP.

Percutaneous versus surgical cut-down access in transfemoral transcatheter aortic valve replacement: A meta-analysis.

BACKGROUND: The transfemoral (TF) approach has become the preferred approach for transcatheter aortic valve replacement (TAVR) because of its low risk profile. However, the relative safety of the percutaneous approach (PC) compared to surgical cut-down (SC) remains unclear. Our aim was to compare the outcomes between PC versus SC access in patients undergoing TF-TAVR using a meta-analysis. METHODS: We conducted a systematic electronic database search for studies reporting major and minor vascular complications (VC), major and minor bleeding, and perioperative all-cause mortality, in PC versus SC TF-TAVR cases. Complications were reported based on the Valve Academic Research Consortium criteria. A random-effects model was used to calculate odds ratios and 95% confidence intervals. RESULTS: Eight observational cohort studies and one randomized control trial (2513 patients in PC and 1767 patients in SC) were included in the analysis. Major and minor VC, as well as bleeding complications, were comparable between the two approaches. The need for surgical intervention for VC was comparable between PC and SC. There was no difference in perioperative all-cause mortality. CONCLUSIONS: PC and SC have similar safety profiles and outcomes when used appropriately in selected patients.

Impact of transcatheter aortic valve implantation on left atrial appendage flow velocities.

PURPOSE: Left atrial appendage (LAA) flow velocity has not been extensively studied in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). The aim of this study was to assess the impact of TAVI on LAA flow velocity. METHODS: Medical records of consecutive TAVI recipients were reviewed retrospectively. Patients with persistent atrial fibrillation were excluded. LAA velocities were measured before and after TAVI by transesophageal echocardiography. RESULTS: Sixty-one patients were included. Mean LAA emptying (EV) and filling (FV) flow velocity before TAVI were 33 ± 16 cm/s and 31 ± 14 cm/s, respectively. They increased to 37 ± 20 (p = 0.0036) and 33 ± 13 cm/s (p = 0.047) after TAVI in the whole population sample, but not in patients with normal flow AS. In low-flow, low-gradient (LFLG) AS patients, EV and FV increased from 36 ± 22 to 47 ± 30 cm/s (p < 0.01), and from 29 ± 12 to 40 ± 15 cm/s (p < 0.01), respectively, after TAVI. There was no difference between normal flow and LFLG AS patients in the number of patients who achieved EV ≥ 40 cm/s post-TAVI (35% versus 47%, p = 0.54, respectively). CONCLUSIONS: LAA EV and FV were low prior to TAVI and increased significantly after TAVI only in patients with LFLG AS. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:375-382, 2016.

Iatrogenic Ventricular Septal Defect Following Transcatheter Aortic Valve Replacement: A Systematic Review.

BACKGROUND: Ventricular septal defects (VSD) are rarely reported as a complication following transcatheter aortic valve replacement (TAVR). We sought to characterise the patients, clinical management, and outcomes regarding this rare phenomenon. METHODS: Relevant articles were identified by a systematic search of MEDLINE and EMBASE databases from January, 2002 to September, 2015. RESULTS: A total of 18 case reports, including 20 patients, were identified. The median age was 83 years and six were male. Twelve were performed by trans-femoral approach. Pre-dilation was performed in 12 patients and post-dilation in four. Balloon expandable valves were used in the majority (85%) of cases. The clinical presentation varied from asymptomatic to progressive heart failure. The timing of the diagnosis also varied significantly from immediately post valve implantation to one year afterwards. There were two cases of Gerbode-type defect while the rest were inter-ventricular defects. The location was mostly membranous or perimembranous (79%) and adjacent to the valve landing zone. A total of seven interventions (one open surgery and six percutaneous closure) were performed. Four patients died during the same hospital admission. Sixteen survived past discharge (range 12 days to two years). CONCLUSIONS: Ventricular septal defects post-TAVR were seen more with balloon expandable valves and with pre-dilation or post-dilation. Percutaneous treatment of the VSD was preferred over open cardiac surgery given the high surgical risk in this patient population. Some, but not all, patients survived TAVR and VSD and had a good prognosis for both patient groups with or without VSD closure.

Human tissue models for a human disease: what are the barriers?

Asthma represents an area of significant unmet medical need, with few new drugs making it to the clinic in the past 50 years. Much asthma research is currently carried out in non-human models. However, as asthma is a uniquely human condition, it is difficult to translate findings from these models to efficacious therapies. Based on the results of a survey of the UK asthma research community carried out jointly between the NC3Rs, Asthma UK, the UK Respiratory Research Collaborative and the Human Tissue Authority, we propose that more emphasis be placed on the use of human tissue studies to provide more relevant models that better translate to the clinic and which reduce the reliance of the asthma community on less predictive animal models.

Midline Cleft Lip and Bifid Nose Deformity: Description, Classification, and Treatment.

BACKGROUND: Midline facial clefts are rare and challenging deformities caused by failure of fusion of the medial nasal prominences. These anomalies vary in severity, and may include microform lines or midline lip notching, incomplete or complete labial clefting, nasal bifidity, or severe craniofacial bony and soft tissue anomalies with orbital hypertelorism and frontoethmoidal encephaloceles. In this study, the authors present 4 cases, classify the spectrum of midline cleft anomalies, and review our technical approaches to the surgical correction of midline cleft lip and bifid nasal deformities. Embryology and associated anomalies are discussed. METHODS: The authors retrospectively reviewed our experience with 4 cases of midline cleft lip with and without nasal deformities of varied complexity. In addition, a comprehensive literature search was performed, identifying studies published relating to midline cleft lip and/or bifid nose deformities. Our assessment of the anomalies in our series, in conjunction with published reports, was used to establish a 5-tiered classification system. Technical approaches and clinical reports are described. RESULTS: Functional and aesthetic anatomic correction was successfully achieved in each case without complication. A classification and treatment strategy for the treatment of midline cleft lip and bifid nose deformity is presented. CONCLUSIONS: The successful treatment of midline cleft lip and bifid nose deformities first requires the identification and classification of the wide variety of anomalies. With exposure of abnormal nasolabial anatomy, the excision of redundant skin and soft tissue, anatomic approximation of cartilaginous elements, orbicularis oris muscle repair, and craniofacial osteotomy and reduction as indicated, a single-stage correction of midline cleft lip and bifid nasal deformity can be safely and effectively achieved.

Longitudinal study of the neurodevelopmental characteristics of treated and untreated nonsyndromic craniosynostosis in infancy.

PURPOSE: Nonsyndromic craniosynostosis (NSC) are a group of congenital disorders sharing premature fusion of one or more of the cranial sutures that restricts and distorts growth of the skull and underlying brain. This study examined the neurodevelopmental sequelae of NSC both prior to and following reconstructive cranial surgery. METHODS: Sixty-four consecutive referrals with mixed forms of untreated NSC aged 4 to 16 months (M = 8.9, SD = 2.9) comprised the pre-operative cohort. Forty-four of these patients aged 6 to 32 months (M = 21.2, SD = 4.5) underwent post-operative developmental evaluation. Neurodevelopmental function was assessed with the mental (Mental Development Index) and motor (Psychomotor Development Index) scales of the Bayley Scales of Infant Development-2nd edition. RESULTS: Children with untreated NSC displayed significantly lower mental (M = 97.5) and motor (M = 87.7) scores than normative expectations, with the distribution of scores also differing significantly from the normative distribution. Post-operatively, children continued to display significantly lower mental (M = 89.5) and motor (M = 88.0) abilities, with mental abilities falling significantly lower than pre-operative levels. An increased prevalence of severe motor delay was found, and no child displayed accelerated development. Subgroup comparisons revealed no differences in mental or motor skills between the primary diagnostic subtypes (sagittal and metopic synostosis) both prior to and following corrective surgery. CONCLUSIONS: NSC is associated with an increased incidence of developmental delay in both treated and untreated conditions. Timing of surgery appears unrelated to developmental outcome.

Associations of physical and social workplace characteristics with movement behaviors at work.

Introduction/Purpose: Sedentary behavior (SB) is common in desk-based work and prolonged periods of SB are associated with negative health outcomes. This study assessed associations between workplace characteristics and setting and movement patterns during working hours. Methods: This secondary analysis used baseline data from the Reducing Sedentary Behavior to Decrease Blood Pressure (RESET BP) clinical trial which enrolled inactive, desk-based workers with elevated blood pressure (n=271; mean age: 45.3±11.6 years; body mass index (BMI): 30.66±7.1 kg/m2; 59.4% women). Physical and social workplace characteristics were assessed by a study-developed questionnaire and the Office Environment and Sitting Scale (OFFESS). Participants also wore an activPAL activity monitor for 7 days and reported working hours in a diary to measure SB and physical activity (PA) specifically while working. Linear regression was used to analyze cross-sectional associations between workplace characteristics and SB and PA. A stratified analysis was also conducted to assess associations among home-based and in-office desk workers separately. Analyses were adjusted for age, gender, BMI, and work wear time. Results: Participants spent 77% of working hours in SB. Public vs. private offices, working in-office vs. at home, higher local connectivity, and greater overall connectedness were associated with lower SB and/or greater PA (all p<0.05). Higher frequency of face-to-face interactions, and greater visibility and proximity to co-workers was associated with less SB and more PA (all p<0.05). For example, home-based workers had more total SB (+17.2±8.4 mins/day), more SB bouts ≥30 mins (+39.1±12.8 mins/day), and less steps (695±201 steps/day) than in-office employees. Stratification by office setting revealed differences in associations between SB and PA and workplace characteristics. Conclusions: More public, open spaces with more social interactions and physical walkways could improve SB and PA patterns during work. Home-based workers had more SB, less PA, and unique associations of these activities with workplace characteristics, suggesting a need for tailored interventions.

Neurodevelopmental functioning of infants with untreated single-suture craniosynostosis during early infancy.

PURPOSE: Single-suture craniosynostosis (SSC) is a congenital craniofacial disorder, in which premature fusion of one of the skull sutures restricts and distorts growth of the cranium and underlying brain. This disorder of prenatal onset occurs during a critical phase of rapid growth and development of the immature brain. Craniosynostosis carries a known risk of developmental impairment. The neurodevelopmental sequelae of SSC prior to treatment remains however incompletely understood. This study sought to determine the neurodevelopmental sequelae of untreated single-suture craniosynostosis during early infancy. METHODS: Fifty-six consecutive patients with unoperated SSC (sagittal, metopic and unicoronal) comprised the sample cohort. Patients were aged between 4 and 16 months (M = 8.9 months, SD = 2.9 months). Neurodevelopmental functioning was assessed with the mental (Mental Development Index) and motor (Psychomotor Development Index) scales of the Bayley Scales of Infant Development, second edition. RESULTS: Children with SSC displayed significantly lower mean mental (M = 97.7, SD = 6.7, p < 0.05) and motor (M = 87.7, SD = 13.0, p < 0.001) scores than normative population averages. The distribution of these scores also differed significantly from the normative distribution; an increased rate of significant motor developmental delay was found, and none of the children displayed accelerated development. Subgroup comparisons between the primary diagnostic subtypes in this sample revealed no significant differences in mental or motor skill functioning. CONCLUSIONS: Untreated SSC is associated with an increased incidence of developmental delay during early infancy, with motor skills appearing the most vulnerable to impairment during this developmental phase.

Delayed sagittal sinus tear: a complication of spring cranioplasty for sagittal craniosynostosis.

Spring cranioplasty is now a well-established surgical technique in the treatment of sagittal craniosynostosis. It is widely regarded as a less invasive modality compared with operations such as cranial vault remodeling. Indeed, very few complications have been described in the literature in association with spring cranioplasty. We present a case of delayed sagittal sinus tear with hemorrhage following spring cranioplasty in a 4-month-old patient with sagittal craniosynostosis. Likely causes of the injury are discussed highlighting sagittal sinus injury as a potential risk of spring cranioplasty.

Analysis of morbidity and mortality in surgical management of craniosynostosis.

Multidisciplinary care involving plastic surgery and neurosurgery is generally accepted as optimal to manage craniosynostosis to avoid complications and to identify patients at risk. We conducted a retrospective 30-year review of craniosynostosis surgery at a single major craniofacial institute to establish the rate and predictors of complications. Medical records of 796 consecutive patients who underwent primary surgery for craniosynostosis from 1981 to 2010 at our institute were analyzed for complications. Complications were defined as intraoperative and postoperative adverse events requiring changed management. Reoperation was defined as a repeat transcranial procedure. Multivariate logistic regression was used to identify predictors for complications or revision. Across the years, the procedures evolved from technically simple to complex, which increased complications but better outcomes. Complications occurred in 111 patients (14%), and 33 (5.4%) needed major revision. Multivariate analysis identified multisuture and syndromic craniosynostosis, more recent surgeries, younger age (<9 months), spring-assisted cranioplasty, longer surgery, and greater transfusion as predictors of complications. Patients with syndromic and multisutural craniosynostosis and those operated on younger than 9 months had increased risk of major revision surgery for regression to phenotype. Our experience over 30 years indicates that pediatric transcranial craniosynostosis surgery can be safely carried out in our tertiary referral center. There were no deaths from primary surgery, and complication and reoperation rates mirror those of other published studies. Syndromic and complex craniosynostosis predicted both complications and need for major revision. Spring cranioplasty was associated with higher complications. Overall results support a recommended age for craniosynostosis surgery between 9 and 12 months.

Changing epidemiology of nonsyndromic craniosynostosis and revisiting the risk factors.

Recent studies in Europe and the United States report increased incidence of metopic synostosis. Whether a similar trend had occurred in Australia remains unknown. This research aimed to determine changes in incidence and subtypes of craniosynostosis in Victoria and to identify perinatal risk factors. A retrospective audit of patients (n = 522) presenting to the Royal Children's Hospital in Melbourne with nonsyndromic craniosynostosis from 1982 to 2008 was undertaken. Perinatal data were sourced from the Victorian Perinatal Data Collection. The changes in incidence of craniosynostosis subtypes were calculated based on Poisson regression, and risk factors for craniosynostosis and subtypes were analyzed by univariate logistic regression analysis. The prevalence of nonsyndromic craniosynostosis was 3.1 in 10,000 live births in Victoria. On average, the incidence of nonsyndromic craniosynostosis increased by 2.5% per year among Victorian live births. Over 25 years, metopic synostosis incidence significantly increased by 7.1% per year in the population of Victoria, outpacing other subtypes. The risk factors for metopic synostosis include being male, multiple births (ie, twins), preterm gestation, low birth weight, high maternal age, and emergency cesarean birth. This study revealed a true increase in incidence of metopic synostosis in Victoria, which could be a result of increased frequency of multiple births, preterm gestation, low birth weight, and high maternal age in the Victorian population from 1982 to 2008. The incidence of other nonsyndromic craniosynostoses, which include sagittal, unicoronal, and multisutural craniosynostoses, however, has remained unchanged.

Harnessing the power of microphysiological systems for COVID-19 research.

The pharmaceutical industry is constantly striving for innovative ways to bridge the translational gap between preclinical and clinical drug development to reduce attrition. Substantial effort has focused on the preclinical application of human-based microphysiological systems (MPS) to better identify compounds not likely to be safe or efficacious in the clinic. The Coronavirus 2019 (COVID-19) pandemic provides a clear opportunity for assessing the utility of MPS models of the lungs and other organ systems affected by the disease in understanding the pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in the development of effective therapeutics. Here, we review progress and describe the establishment of a global working group to coordinate activities around MPS and COVID-19 and to maximize their scientific, human health, and animal welfare impacts.

Nasal reconstruction for maxillonasal dysplasia.

BACKGROUND: Maxillonasal dysplasia, Binder type (Binder syndrome and nasomaxillary hypoplasia), is a spectrum of deficient nasomaxillary osteocartilaginous framework, deficient nasal soft tissues, and a short columella. The correction of these deformities is challenging, and results are often disappointing. Tissue expansion with multiple bone grafts for nasal augmentation from childhood has been advocated as a means to address the constricted soft tissues. However, bone grafts in children have been associated with unpredictable growth and resorption. Agreeing with the principle of serial nasal augmentation that commences in childhood, we used alloplastic material for tissue expansion followed by definitive reconstructive rhinoplasty at the completion of growth and orthognathic surgery as required. Definitive rhinoplasty mainly used a 1-piece costochondral graft cantilevered to the frontal bone. MATERIALS AND METHODS: Thirty-one patients over a period of 27 years were reviewed. The patients were divided into 2 groups based on the age of presentation, namely, prepubertal and postpubertal. The prepubertal group underwent serial tissue expansion of the constricted nasal envelope with customized silicone implants and final reconstruction by costochondral rhinoplasty at the end of puberty. The postpubertal group underwent 1-stage costochondral rhinoplasty. The definitive rhinoplasty used a cantilevered 1-piece costochondral graft retaining the dorsal periosteum that was dowelled into the frontal sinus wall. RESULTS: In the prepubertal group (n = 20), 41 silicone implants were placed in the childhood years for tissue expansion of the nasal envelope. One patient developed implant infection, and another required replacement after extrusion. Long-term follow-up showed minimal resorption of the costochondral graft in the pre-expanded prepubertal group and minimal to moderate graft resorption in the postpubertal group. CONCLUSIONS: Successful treatment of maxillonasal dysplasia is dependent on the following: an understanding of the underlying pathologic anatomy, namely, that of the constricted nasal tissues, serial tissue expansion of the nasal envelope in childhood, and definitive costochondral rhinoplasty at the end of growth. Early tissue expansion with the placement of alloplastic silicone implants effectively stretches the constricted nasal soft tissues in Binder syndrome to limit graft resorption after definitive nasal reconstruction with costochondral rib grafts. There is a possible role for similar tissue expansion in the postpubertal patient with alloplastic material before costochondral grafting if the soft tissues are inadequate. Long-term resorption of cantilevered, 1-piece, periosteum-covered costochondral grafts was minimal.