Interferon regulatory factor 6 is required for proper wound healing in vivo.

BACKGROUND: Van der Woude syndrome (VWS) is the most common form of syndromic orofacial cleft caused predominantly by mutations in Interferon Regulatory Factor 6 (IRF6). We previously reported that individuals with VWS have increased risk of wound healing complications following cleft repair compared with individuals with nonsyndromic orofacial clefts (nonsyndromic cleft lip and palate-NSCLP). In vitro, absence of IRF6 leads to impaired keratinocyte migration and embryonic wound healing. However, there is currently no data on tissue repair in adult animals and cells with reduced levels of IRF6 like in VWS. RESULTS: Excisional wounds of Irf6+/- and wild-type animals were analyzed 4 and 7 days post-wounding. Although all wounds were reepithelialized after 7 days, the epidermal and wound volume of repaired wounds was larger in Irf6+/- . These data were supported by increased keratinocyte proliferation in the neoformed epidermis and a less mature granulation tissue with increased cytokine levels. This effect was not cell autonomous, as Irf6+/- neonatal keratinocytes in vitro did not exhibit defects in scratch wound closure or proliferation. Keratinocytes from individuals with VWS also migrated similarly to keratinocytes from NSCLP individuals. CONCLUSIONS: These data support a role for IRF6 in wound healing by regulating keratinocyte proliferation, granulation tissue maturation, and cytokine levels.

Safety and Effectiveness of Silicone Gel-Filled Breast Implants in Primary Augmentation Patients.

BACKGROUND: Results from the MemoryGel Breast Implants Core Clinical Study suggest these devices are safe and effective at 10 years after implantation. Although clinical trials are essential for measuring the safety and effectiveness of a device, real-world evidence can supplement clinical trials by providing information on outcomes observed in diverse clinical settings for a more heterogeneous population, without fixed treatment patterns, and without continuous patient monitoring, such that follow-up is more representative of normal clinical practice. OBJECTIVES: The aim of this study was to measure real-world outcomes, including safety and effectiveness, in patients who underwent primary breast augmentation with smooth MemoryGel implants. METHODS: This was a case series looking at patients, age 22 years and older, who underwent primary breast augmentation at a single site between December 2006 and December 2016 and who had a minimum of 2 years of follow-up. Descriptive statistics were used to summarize baseline characteristics and outcomes. Kaplan-Meier models were used to estimate safety outcomes for capsular contracture (Baker grade III/IV), infection, and rupture. RESULTS: A total of 50/777 (6.4%) patients reported a complication, with an average time to complication of 3.9 years (range, 19 days-11.8 years) postprocedure. Kaplan-Meier estimates of the 10-year cumulative incidence of capsular contracture (Baker grade III/IV), infection, and rupture were 4.7%, 0.1%, and 1.6%, respectively. CONCLUSIONS: Analyses of a large population from a single site provide further support for the long-term safety and effectiveness of MemoryGel breast implants in a primary augmentation cohort.

Device-Specific Findings of Imprinted-Texture Breast Implants: Characteristics, Risks, and Benefits.

BACKGROUND: The relative risks and benefits of various textured breast implants are the focus of considerable discussion. Studies have suggested different risk-benefit profiles for different implant surface topographies. OBJECTIVES: The study aim was to provide device-specific, quantitative information on Mentor's imprinted Siltex Textured breast implants with respect to textured surface characteristics and ISO 14607 classification, risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), and risk-reduction benefits relative to smooth implants. METHODS: Surface metrology was performed. Data for smooth and Siltex implants from the prospective MemoryGel Core Study were evaluated by Kaplan-Meier analysis for the most frequently occurring postoperative complications in augmentation and reconstruction leading to subsequent reoperation. RESULTS: The overall average surface roughness for Siltex MemoryGel and MemoryShape implants was 29.5 and 36.1 µm, respectively. A statistically significantly lower rate of reoperation in patients with Siltex compared with smooth devices over 10 years was observed for both capsular contracture in subglandular primary augmentation patients (4.21% vs 19.84%) and for asymmetry in primary reconstruction patients (3.88% vs 11.1%). CONCLUSIONS: Surface analysis demonstrated that Siltex implants fall within the ISO 14607 category of "microtexture" breast implants. These devices exhibited a rare risk of BIA-ALCL (0.0012%) based on the most extensive data available. Relative to smooth implants, these Siltex devices provided risk-reduction benefits for the most common reason of reoperation in patients who underwent primary augmentation (capsular contracture) or primary reconstruction (asymmetry) in the Core Study. These findings provide valuable risk-benefit information for surgeons and their patients.

Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

OBJECTIVE: Interferon Regulatory Factor 6 (IRF6) is critical for craniofacial development, epidermal differentiation, and tissue repair. IRF6 mutations cause Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome. Individuals with VWS exhibit craniofacial anomalies, including cleft lip and palate and lip pits. Furthermore, they have an increased risk for wound-healing complications following surgical repair when compared with patients with nonsyndromic cleft lip and palate (NSCLP). However, nothing is known about the skin of these patients. The objective was to characterize the skin of patients with VWS. We hypothesize that IRF6 is required for proper skin homeostasis in humans. DESIGN: Discarded tissue from a hip was collected during surgical alveolar bone graft. Samples from children with VWS harboring IRF6 mutations (n = 2) were compared with samples from children with NSCLP (n = 7). Histology was assessed following hematoxylin and eosin staining. The expressions of Proliferating Cell Nuclear Antigen, IRF6, P63, and Keratin 10 were determined by immunofluorescence. Keratinocytes were isolated and their proliferation potential was assessed by colony-forming efficiency assay. RESULTS: Hip skin from children with VWS showed a thicker epidermis when compared with that from children with NSCLP. Proliferating Cell Nuclear Antigen staining revealed an increase in proliferation in syndromic tissues when compared with controls. However, P63 and Keratin 10 expression were similar between groups. Finally, keratinocytes from VWS showed increased long-term proliferation when compared with NSCLP. CONCLUSIONS: These results support, in vivo and in vitro, a previously described role for IRF6 in epidermal proliferation in humans. They further demonstrate a critical function for IRF6 in cutaneous homeostasis.

Applying Principles of Evolutionary Biology to Plastic Surgery at an Organizational Level Predicts an Extinction Event.

As an organized profession, plastic surgery struggles delivering a clear message regarding scope of practice to patients given the diversity of procedures performed. Whereas granting licensure to practice medicine resides with governmental bodies, certification rests with organizations. However, certification is not required to practice plastic surgery. Since plastic surgery operationalizes techniques rather than working within a defined body organ, competition for patients is intense. Mapping territorial interactions between healthcare providers while parsing taxonomy elucidates individual, community, organizational, and governmental levels, creating various selection pressures. Applying evolutionary biology as a framework predicts the termination of plastic surgery over time as a unique specialty. An entirely new domain, Restorative Healthcare, is proposed which circumvents an extinction outcome.

Downstream Impact for Plastic Surgeons in the United States from the "No Surprises Act".

The No Surprises Act, signed into the US federal law in 2020, establishes a floor for reimbursement determined by insurance payors for out-of-network charges rendered by providers in emergency services. Physicians are not permitted to balance bill patients for the difference. An arbitration process is outlined for mediation between provider and payor if needed. Methods: Policy analysis demonstrates many plastic surgeons utilize a revenue stream including both fee-for-service cosmetic work and insurance-covered reconstructive intervention. For Maintenance of Certification from the American Board of Plastic Surgery and/or membership to the American Society of Plastic Surgeons, plastic surgeons must operate only in accredited facilities, which in turn require that similar privileges are held in a hospital. Results: Given rapidly developing economic pressures, hospitals no longer remain neutral sites for surgical privileging as they seek strategies to mitigate financial loss by directly competing for patients. A downstream consequence of the requirement for hospital privileging is that plastic surgeons are forced to manage increasing on-call responsibilities despite shrinking reimbursement. Plastic surgeons whose board certification was the first to be time-limited are now reaching the stage of practice where they may transition exclusively to out-patient services. Conclusions: Plastic surgeons in independent solo or small group practices are rendered vulnerable since they may not be able to find coverage of in-patient responsibilities at lower reimbursement rates. Rather than allowing loss of board certification in this population, rational alternatives on an organizational level are proposed for keeping the process equitable as plastic surgeons progress along the practice pathway.

MemoryGel Breast Implants: Final Safety and Efficacy Results after 10 Years of Follow-Up.

BACKGROUND: Mentor MemoryGel Breast Implants were approved by the U.S. Food and Drug Administration in November of 2006. Patients in the Core clinical study supporting this approval were followed for 10 years. METHODS: This prospective, multicenter, clinical study included primary augmentation, revision augmentation, primary reconstruction, and revision reconstruction patients implanted with smooth or Siltex Texture MemoryGel Implants. Incidence, severity, and method of resolution for all postoperative complications were assessed on per-patient and per-implant bases. The primary effectiveness endpoints were overall mean change in chest circumference and bra cup size following the implantation procedure. RESULTS: Primary augmentation (n = 552), revision augmentation (n = 145), primary reconstruction (n = 251), and revision reconstruction (n = 60) patients were enrolled in the study. Kaplan-Meier estimated 10-year cumulative incidence rates for key complications at the subject level for Baker grade III/IV capsular contracture were as follows: primary augmentation, 12.1 percent; revision augmentation, 24.4 percent; primary reconstruction, 20.5 percent; and revision reconstruction, 36.9 percent. For infection, rates were as follows: primary augmentation, 1.6 percent; revision augmentation, 1.4 percent; primary reconstruction, 6.2 percent; and revision reconstruction, 0 percent. For explantation with or without replacement, rates were as follows: primary augmentation, 11.6 percent; revision augmentation, 24.1 percent; primary reconstruction, 33.4 percent; and revision reconstruction; 37.8 percent. For rupture, rates were as follows: primary augmentation, 24.2 percent; revision augmentation, 23.7 percent; primary reconstruction, 32.7 percent; and revision reconstruction, 38.7 percent. For any reoperation, rates were as follows: primary augmentation, 25.5 percent; revision augmentation, 43.6 percent; primary reconstruction, 49.0 percent; and revision reconstruction, 50.7 percent. CONCLUSION: The results of this study demonstrate that MemoryGel Implants are safe and effective for use in women undergoing breast augmentation or reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Results from the MemoryGel Post-approval Study.

The approval of Mentor MemoryGel Breast Implants in November 2006 was conditional on conducting a 10-year study designed to collect long-term experience in US women with MemoryGel Breast Implants, known as the MemoryGel Post-Approval Study. METHODS: This prospective, observational 10-year follow-up study used a current cohort design that began in 2007, which included both MemoryGel Breast Implant participants and concurrent saline controls to assess rheumatologic and neurologic signs and symptoms. The protocol was amended in 2015, which limited the scope of further data collection for the study to only secondary procedure/re-operation data for MemoryGel participants. RESULTS: Primary augmentation (n = 6743), revision augmentation (n = 2071), primary reconstruction (n = 1763), and revision reconstruction (n = 557) participants were enrolled in the Re-operation Phase Safety Set. Kaplan-Meier-estimated 10-year cumulative incidence of re-operation and explantation on a participant-level were 10.5% and 4.2% (primary augmentation), 14.1% and 7.7% (revision augmentation), 20.8% and 12.8% (primary reconstruction), and 25.0% and 16.6% (revision reconstruction). CONCLUSIONS: The Re-operation Phase of the post-approval study addressed the Kaplan-Meier implant removal and re-operation rates over time, and provided the reasons for re-operation over time. Overall, no significant new hazards, increased risk, or unexpected adverse events were identified in the MemoryGel Post-Approval Study Re-operation Phase Safety Set.

Safety of CPX4 Breast Tissue Expanders in Primary Reconstruction Patients.

In the United States, 2-stage expander-to-implant-based breast reconstruction accounts for more than half of all breast reconstruction procedures. Tissue expansion technology has undergone significant advancements in the past few decades. Previous reports suggest that the most common perioperative complications associated with breast tissue expanders are infection and skin flap necrosis. However, little clinical data are available for CPX4 Breast Tissue Expanders. The aim of the study was to measure real-world outcomes related to safety and effectiveness of the tissue expansion process, in patients who underwent primary breast reconstruction following the use of CPX4 Breast Tissue Expanders. METHODS: This was a single-arm retrospective cohort design looking at patients who underwent 2-stage, expander-to-implant-based primary breast reconstruction at a single site between April 2013 and December 2016 and who had a minimum of 2 years follow-up. Descriptive statistics were used to summarize baseline characteristics and safety outcomes. RESULTS: A total of 123 patients were followed for an average of 3.73 ± 0.94 years. At least 1 complication during the time of tissue expansion, before the permanent implant, was reported in 39/123 (31.7%) patients [51/220 implants (23.2%)]. The most frequently reported complications were delayed wound healing (13.8%) and cellulitis/infection (9.7%). CONCLUSION: Analyses of real-world data from a single site provide further support for the safety and effectiveness of the CPX4 Breast Tissue Expander for women undergoing 2-stage expander-to-implant primary breast reconstruction.

Wound complications after cleft repair in children with Van der Woude syndrome.

Van der Woude syndrome (VWS; OMIM 119300) is an autosomal-dominant condition associated with clefts of the lip and/or palate and lower lip pits and is caused by mutations in interferon regulatory factor 6 (IRF6). The standard of practice for children born with cleft lip/palate is surgical repair, which requires proper wound healing. We tested the hypothesis that children with VWS are more likely to have wound complications after cleft repair than children with nonsyndromic cleft lip/palate (NSCLP). Furthermore, we hypothesized that children with VWS have more surgical procedures. A retrospective, case-controlled study was performed. Seventeen children with VWS and 68 matched controls with NSCLP were scored for the presence of wound complications after cleft repair, for the severity of complications, and for number of surgeries from age 0 to 10. Of the 17 children with VWS, 8 had wound complications. Of 68 controls, 13 had wound complications (P = 0.02). Of 8 wound complications in the VWS group, 6 were major, whereas of 13 complications in the control group, 9 were major (P = 0.04). Most wound complications were fistulae and occurred in isolated cleft palate and bilateral cleft lip. The mean number of surgeries in the VWS group was 3.0 compared with 2.8 in the control group (P = 0.67). Our studies suggest that children with VWS have an increased risk for wound complications after cleft repair compared with children with NSCLP. Furthermore, these data support a role for IRF6 in wound healing.

Cerebellum structure differences and relationship to speech in boys and girls with nonsyndromic cleft of the lip and/or palate.

OBJECTIVE: To identify regional cerebellar structural differences in boys and girls with nonsyndromic cleft of the lip and/or palate and determine whether these differences are related to speech impairment. DESIGN: Between 2003 and 2007, measures on cerebellar volume were obtained on 43 children with nonsyndromic cleft of the lip and/or palate and 43 age- and sex-matched, healthy controls. Children with the cleft condition also received speech evaluations. Children with nonsyndromic cleft of the lip and/or palate were recruited from clinic records, and controls (screened for medical, psychiatric, speech/language, and behavioral concerns) were recruited from the local community. All tests were administered at a large midwestern hospital. Boys and girls with nonsyndromic cleft of the lip and/or palate were compared with the healthy controls on global and regional measures of cerebellar volume. Areas of significant difference were then correlated with measures of speech to assess relationships in children with nonsyndromic cleft of the lip and/or palate. RESULTS: Boys with nonsyndromic cleft of the lip and/or palate had smaller cerebellums than controls (p = .002); whereas, for girls, only regional reductions in size reached significance (corpus medullare, p = .040). Cerebellum size was correlated with articulation for boys (p = .045). CONCLUSIONS: These findings lend support to previous research documenting abnormal brain structure in children with nonsyndromic cleft of the lip and/or palate and suggest that the cerebellum may play a role in speech deficits along with other structural causes, at least in boys.

Incidence of neurological soft signs in children with isolated cleft of the lip or palate.

The purpose of this study was to assess neurological soft signs in children and adolescents with isolated cleft of the lip or palate (iCL/P) compared with healthy controls. Children with iCL/P were recruited through the university cleft clinic. Control subjects were recruited through advertisements. Of the 166 subjects who participated (age range 7 to 17 years, M = 12.5, SD = 3.2), 77 had iCL/P (48 male) and 89 were healthy controls (44 male). All participants took the Physical and Neurological Examination of Subtle Signs and selected tests of motor coordination. A multivariate analysis of variance assessed differences between subjects with and without iCL/P. Also, a Pearson correlation estimated the relationship between the neurological soft signs and age. Subjects with iCL/P scored significantly higher on all neurological soft signs variables. These higher scores were associated with younger age. Findings lend support to the hypothesis of aberrant brain development in children with iCL/P.

Abnormal brain structure in children with isolated clefts of the lip or palate.

OBJECTIVE: To evaluate brain structure in a sample of children with isolated clefts of the lip and/or palate (ICLP). DESIGN: Case-control study. SETTING: Tertiary care center. PARTICIPANTS: A large sample of 74 children aged 7 to 17 years with ICLP was compared with a healthy control group, matched by age and sex. MAIN EXPOSURE: Isolated cleft lip and/or palate. OUTCOME MEASURES: General measures of height and head circumference were obtained. Brain structure was evaluated using magnetic resonance imaging, generating both general and regional brain measures (volumes). RESULTS: Height was significantly lower in the ICLP group (F = 4.83, P = .03). After controlling for this smaller body size, children with ICLP had abnormally small brains with both cerebrum (F = 4.47, P = .04) and cerebellum (F = 14.56, P <.001) volumes substantially decreased. Within the cerebrum, the frontal lobe was preferentially decreased (F = 7.22, P = .008) and subcortical nuclei were also substantially smaller (F = 4.18, P = .003). Tissue distribution of cortical gray matter and white matter within the cerebrum were abnormal in boys with ICLP (larger cortical volume, smaller volume of white matter) but proportional to controls in girls with ICLP. CONCLUSIONS: Children with ICLP have abnormal brain structure, potentially due to abnormal brain development. The fact that the pattern of brain abnormalities in children with ICLP is dramatically different from the pattern of brain abnormalities seen in adults with ICLP suggests that brain growth and development trajectory is also abnormal in subjects with ICLP.

X-chromosome inactivation patterns in monozygotic twins and sib pairs discordant for nonsyndromic cleft lip and/or palate.

Nonsyndromic clefts of the lip and/or palate are common birth defects with a strong genetic component. Based on unequal gender ratios for clefting phenotypes, evidence for linkage to the X chromosome and the occurrence of several X-linked clefting syndromes, we investigated the role of skewed X chromosome inactivation (XCI) in orofacial clefts. Our samples consisted of female monozygotic (MZ) twins (n = 8) and sister pairs (n = 152) discordant for nonsyndromic clefting. We measured the XCI pattern in peripheral blood lymphocyte DNA using a methylation based androgen receptor gene assay. Skewing of XCI was defined as the deviation in inactivation pattern from a 50:50 ratio. Our analysis revealed no significant difference in the degree of skewing between twin pairs (P = 0.3). However, borderline significant differences were observed in the sister pairs (P = 0.02), with the cleft lip with cleft palate group showing the most significant result (P = 0.01). We did not find evidence for involvement of skewed XCI in the discordance for clefting in our sample of female MZ twins. However, results from the paired sister study suggest the potential contribution of skewed XCI to orofacial clefting, particularly cleft lip and palate.

Social function in boys with cleft lip and palate: relationship to ventral frontal cortex morphology.

Isolated clefts of the lip and/or palate (ICLP) are developmental craniofacial abnormalities that have consistently been linked to increased social inhibition or shyness. Two explanations have been proposed: (1) psychosocial factors related to differences in facial appearance may lead to low self-concept and subsequent shyness, or (2) abnormal development of brain structures involved in social function, such as the ventral frontal cortex (VFC), may underlie the difference. To investigate these two possibilities this study was designed to evaluate measures of social function in relation to measures of self-concept and VFC morphology. Subjects included 30 boys (age 7-12) with ICLP and a comparison group of 43 boys without cleft in the same age category. Social function and self-concept were assessed using questionnaires with standardized scoring filled out by subjects and one of their parents. The cortical volume and surface area of the VFC, composed of the orbitofrontal cortex (OFC) and straight gyrus (SG), were evaluated using structural magnetic resonance imaging. The ICLP subjects had significantly impaired social function relative to the comparison group. No difference in self-concept was identified. VFC morphology revealed significant differences between groups, particularly decreased volume and surface area in the left SG of the ICLP group. Moreover, abnormal VFC measures were correlated with social dysfunction but measures of self-concept were not. These results are consistent with the possibility that aberrant VFC development may partially underlie social dysfunction in boys with ICLP.

Mentor Contour Profile Gel Implants: Clinical Outcomes at 10 Years.

BACKGROUND: Contour Profile Gel/MemoryShape breast implants consist of a textured silicone elastomer shell filled with silicone gel. The objective of this clinical study was to assess the safety and effectiveness of Contour Profile Gel/MemoryShape breast implants in women who were undergoing primary breast augmentation, primary breast reconstruction, or revision surgery (revision-augmentation or revision-reconstruction). METHODS: This was a prospective, open-label, multicenter clinical study involving Contour Profile Gel/MemoryShape breast implants in 955 female subjects, including 572 primary augmentation, 124 revision-augmentation, 190 primary reconstruction, and 69 revision-reconstruction subjects. Safety was assessed based on the incidence, severity, and method of resolution of all complications. Endpoints were examined on both a per-subject and a per-implant basis. RESULTS: For the primary augmentation, revision-augmentation, primary reconstruction, and revision-reconstruction cohorts, the Kaplan-Meier estimated 10-year cumulative incidence rates for the key complications at the subject level were as follows: Baker grade III/IV capsular contracture, 3.6 (primary augmentation), 15.5 (revision-augmentation), 14.3 (primary reconstruction), and 16.4 (revision-reconstruction) percent; infection, 0.7 (primary augmentation), 1.9 (revision-augmentation), 1.6 (primary reconstruction), and 2.9 (revision-reconstruction) percent; explantation with or without replacement, 9.2 (primary augmentation), 25.9 (revision-augmentation), 34.1 (primary reconstruction), and 49.0 (revision-reconstruction) percent; explantation with replacement with study device, 4.0 (primary augmentation), 10.8 (revision-augmentation), 16.7 (primary reconstruction), and 27.9 (revision-reconstruction) percent; and any reoperation, 22.3 (primary augmentation), 35.0 (revision-augmentation), 52.7 (primary reconstruction), and 59.7 (revision-reconstruction) percent. CONCLUSION: The results of this study demonstrate that Contour Profile Gel/MemoryShape breast implants are safe and effective for primary and revision breast augmentation and reconstruction for women at least 22 years old.