Calling small variants using universality with Bayes-factor-adjusted odds ratios.

The application of next-generation sequencing in research and particularly in clinical routine requires highly accurate variant calling. Here we describe UVC, a method for calling small variants of germline or somatic origin. By unifying opposite assumptions with sublation, we discovered the following two empirical laws to improve variant calling: allele fraction at high sequencing depth is inversely proportional to the cubic root of variant-calling error rate, and odds ratios adjusted with Bayes factors can model various sequencing biases. UVC outperformed other variant callers on the GIAB germline truth sets, 192 scenarios of in silico mixtures simulating 192 combinations of tumor/normal sequencing depths and tumor/normal purities, the GIAB somatic truth sets derived from physical mixture, and the SEQC2 somatic reference sets derived from the breast-cancer cell-line HCC1395. UVC achieved 100% concordance with the manual review conducted by multiple independent researchers on a Qiagen 71-gene-panel dataset derived from 16 patients with colon adenoma. UVC outperformed other unique molecular identifier (UMI)-aware variant callers on the datasets used for publishing these variant callers. Performance was measured with sensitivity-specificity trade off for called variants. The improved variant calls generated by UVC from previously published UMI-based sequencing data provided additional insight about DNA damage repair. UVC is open-sourced under the BSD 3-Clause license at https://github.com/genetronhealth/uvc and quay.io/genetronhealth/gcc-6-3-0-uvc-0-6-0-441a694.

Transitioning Cognitive Aids into Decision Support Platforms: Requirements and Design Guidelines.

Digital cognitive aids have the potential to serve as clinical decision support platforms, triggering alerts about process delays and recommending interventions. In this mixed-methods study, we examined how a digital checklist for pediatric trauma resuscitation could trigger decision support alerts and recommendations. We identified two criteria that cognitive aids must satisfy to support these alerts: (1) context information must be entered in a timely, accurate, and standardized manner, and (2) task status must be accurately documented. Using co-design sessions and near-live simulations, we created two checklist features to satisfy these criteria: a form for entering the pre-hospital information and a progress slider for documenting the progression of a multi-step task. We evaluated these two features in the wild, contributing guidelines for designing these features on cognitive aids to support alerts and recommendations in time- and safety-critical scenarios.

Intraoperative use of optical coherence tomography to differentiate normal and diseased thyroid and parathyroid tissues from lymph node and fat.

The purpose of this study is twofold: (1) to determine the feasibility of optical coherence tomography (OCT) to differentiate normal and diseased tissue of the neck region intraoperatively and (2) to evaluate how accurately a cohort of test subjects can identify various tissue types when shown a sample set of OCT images. In this in vivo, prospective, single institutional study, an OCT imaging system (Niris, Imalux, Cleveland, OH) was used to image parathyroid, thyroid, lymph node, and fat tissue in 76 patients during neck surgery. Biopsies were performed for comparison of OCT images with histology in select cases (n = 20). Finally, a group of either surgeons or scientists familiar with OCT (n = 17) were shown a sample of OCT images and asked to identify the tissue. A total of 437 OCT images were analyzed, and characteristic features of each tissue type were identified. OCT demonstrated distinct differences in structural architecture and signal intensity that allows differentiation between thyroid and parathyroid tissues, lymph nodes, and fat. OCT images were also compared with histology with good correlation. There was no difference in correctly identifying OCT-imaged tissue type between surgeons and scientists. This study is the first in vivo OCT imaging study to evaluate both normal and diseased tissues that may be encountered during neck surgery. OCT has the potential to become a valuable intraoperative tool to differentiate diseased and normal thyroid tissue intraoperatively to obtain an "optical biopsy" in real time without fixation, staining, or tissue resection.

Planning and Osteotomy Designs in the Correction of Single-Suture Craniosynostosis.

BACKGROUND: Craniosynostosis is among the abnormalities that are more commonly encountered by craniofacial surgeons. Although the overall concepts for cranial vault remodeling are relatively simple, osteotomy designs and methods for calvarial rearrangement are highly varied. In this work, we present a summary of the known designs for correction of single-suture craniosynostosis. METHODS: A review of the literature was performed of the more frequently used osteotomy designs for single-suture craniosynostosis, as well as their reported results and outcomes. Also reviewed are some of the current available approaches for the diagnosis and surgical planning for single-suture craniosynostosis. RESULTS: There remains a diversity of techniques available for the reconstruction of each fused cranial suture. Certain osteotomy designs are reported in the literature and are used by craniofacial surgeons more frequently. Each has its own benefits and disadvantages, and there is a growing body of outcome data available to guide surgical decision-making. Regarding diagnosis and surgical planning, computed tomography with 3-dimensional reconstruction remains the diagnostic standard of care, and efforts are ongoing to develop and implement new diagnostic modalities like Black Bone MRI to reduce radiation exposure. CONCLUSIONS: There has been ongoing evolution of the surgical techniques available to reconstruct single-suture craniosynostosis, leading to ever-improving patient outcomes.

Orbital Osteomyelitis in the Pediatric Patient.

ABSTRACT: Orbital osteomyelitis in the pediatric patient is a rare clinical entity with limited reports in the literature. Outcomes for orbital osteomyelitis can be potentially fatal, and effective diagnosis and treatment often requires an extensive differential and multidisciplinary team approach. As such, the authors systematically evaluated a pooled analysis of patients in published studies to better understand the clinical trends of this condition. Using the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement guidelines, the authors queried the PubMed, Cochrane Library, and ISI Web of Science databases. A total of 23 patients (47.8% males) participated in 10 studies between 1977 and 2017. Average age of included patients was 7.3 ±â€Š5.3 years old with follow-up of 8.7 ±â€Š9.8 months. Over half of the patients present with fistula (65.2%) and/or fever (43.5%). Sequestrum formation was common (52.2%) but only seen in chronic osteomyelitis patients. The most frequently infected orbital bone was the frontal bone (n = 10, 43.5%). Nearly all patients were cultured (82.6%) and received imaging, such as computerized tomography (43.5%) or X-ray (47.8%). Streptococcus pyogenes was the most common organism isolated (21.7%), while trauma was the most common source of infection (26.1%). Most patients were treated successfully with combined surgical debridement and antibiotics (73.9%). Significant differences between acute and chronic orbital osteomyelitis patients include clinical presentation, use of magnetic resonance imaging, methicillin-resistant Staphylococcus aureus infection, and procedure only treatments. The studies reviewed here provide a comprehensive overview of the clinical presentation, infection sources, diagnostic modalities, common organisms, and treatment options involved in pediatric orbital osteomyelitis.

Extensive Polyostotic Craniofacial Fibrous Dysplasia With Optic Nerve Impingement.

ABSTRACT: Fibrous dysplasia is a benign overgrowth of metaplastic fibrous material resulting in disorganized deposition of bony matrix. Surgical intervention is the primary treatment modality. Here the authors present the case of a 36-year-old male with extensive and severe fibrous dysplasia of the calvarium, orbit, sphenoid, and facial bones causing significant facial distortion and impingement of his optic nerve. Combined operative treatment with craniofacial plastic surgery and neurosurgery was performed. Repair consisted of extensive intra- and extracranial resection and contouring of involved bones followed by reconstruction of the superior orbital rims, forehead, orbital roof, and calvarium with custom polyetheretherketone (PEEK) implant. The authors discuss the advantages of using computer assisted design/modeling, intraoperative neuronavigation, and custom prosthetic cranioplasty for surgical treatment of extensive fibrous dysplasia; a review of the current surgical literature is provided.

Velopharyngeal Insufficiency in Craniofacial Microsomia: Prevalence, Diagnosis, and Treatment.

ABSTRACT: The purpose of this study was to analyze the prevalence, diagnosis, and management of velopharyngeal insufficiency (VPI) in patients with craniofacial microsomia (CFM).Craniofacial microsomia patients 13 years of age and above treated at 2 centers from 1997 to 2019 were reviewed retrospectively for demographics, prevalence of VPI, and management of VPI. Patients with isolated microtia were excluded. Comparisons were made between patients with and without VPI using chi-square and independent samples t tests.Among 68 patients with CFM (63.2% male, mean 20.7 years of age), VPI was diagnosed in 19 patients (27.9%) at an average age of 7.2 years old. Among the total cohort, 61 patients had isolated CFM, of which 12 (19.6%) were diagnosed with VPI. Of the patients with isolated CFM and VPI, 8 patients (66.7%) were recommended for nasoendoscopy, of which only 2 patients completed. Seven isolated CFM patients (58.3%) underwent speech therapy, whereas none received VPI surgery. In contrast, 7 patients were diagnosed with both CFM and cleft lip and/or palate (CL/P), all of whom had VPI and were recommended for nasoendoscopy, with 5 (71.4%) completing nasoendoscopy, 6 (85.7%) undergoing speech therapy, and 6 (85.7%) undergoing corrective VPI surgery. Overall, we demonstrated that VPI was present in 27.9% of all CFM patients. On subset analysis, VPI was diagnosed in 20% of patients with isolated CFM and 100% of patients with CFM and CL/P. In addition, despite clinical diagnosis of VPI, a sizeable proportion of isolated CFM patients did not undergo therapy or surgical interventions.

Asymptomatic Stroke After Hyaluronic Acid Filler Injection: Case Report and Literature Review.

Vascular compromise and blindness are reported but rare complications of facial soft tissue filler injections. Stroke is an even rarer complication resulting from intraarterial injection of fillers. We present a case of a patient suffering all 3 complications following hyaluronic acid filler injection: forehead skin vascular compromise, unilateral blindness, and ipsilateral subclinical strokes. Were it not for a stroke workup protocol, the incidental strokes may have otherwise gone undetected, suggesting the incidence of stroke from intraarterial injection may be higher than reported. Further, we review the literature and recommendations for prevention and management of threatened tissue ischemia and vision loss from facial filler injection.

Multiphoton Microscopy of Collagen Structure in Ex Vivo Human Skin Following Electrochemical Therapy.

OBJECTIVES: Injury to healthy dermis and the dermoepidermal junction initiates a robust healing process consisting of fibrous tissue overgrowth, collagen deposition, and scar formation. The conventional management of scars and other skin injuries has largely relied upon surgical soft tissue transfer to resurface and/or replace damaged and dysmorphic tissue with new skin. However, these strategies are invasive, expensive, and may further exacerbate integumentary injury. In this study, we examine the creation of in situ redox generated pH changes in fresh human skin. We believe this process of "electrochemical therapy" (ECT) leads to changes in collagen matrix structure. Our objective is to map local tissue pH landscapes and image changes in collagen structure of non-injured skin following ECT. STUDY DESIGN: Ex vivo human study involving ECT of human skin. METHODS: Remnant fresh ex vivo human facial skin from facelift operations was enveloped in saline-soaked gauze for a maximum of 2 hours prior to ECT and imaging. ECT was performed by inserting platinum-plated needle electrodes connected to a DC power supply. Voltage (4, 5, or 6 V) and time (3, 4, or 5 minutes) were varied systematically. High frequency ultrasound (25 MHz) was performed immediately after ECT on each sample. Treated samples were also imaged using multiphoton microscopy (MPM) with second harmonic generation (SHG) to specifically visualize collagen fibers in the dermis. The pH landscapes were mapped using indicator dyes in bisected specimens and the MPM images were compared with histologic findings. RESULTS: Above 4 V and 3 minutes, a profound reduction in dermal collagen SHG signal was observed at the anode. Although there was less blunting of SHG signal seen at the cathode, a decrease in the fluorescence of the dermoepidermal junction was observed. The pH application suggests ECT spatial selectivity and a direct relationship between voltage and application time. Ultrasound demonstrated gas formation between the anode and cathode, which is consistent with ECT's mechanism of action. Importantly, these electrochemical changes occurred without disrupting dermal and epidermal histologic architecture. CONCLUSION: ECT alters tissue pH leading to dermal collagen structural change. These results offer additional insight into the translational potential of ECT to locally remodel the soft-tissue matrix. Future directions aim to expand into a skin injury model to determine if similar collagen effects are observed in vivo. ECT is incredibly inexpensive (~$5) and may be a means to treat soft tissue injuries using simple needle-based devices and DC battery power supplies. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

The Effect of Multiple Surgeries on Psychosocial Outcomes in Pediatric Patients: A Scoping Review.

BACKGROUND: Birth defects affect 3% of all babies born in the United States each year. Unlike reconstruction for many acquired deformities, one hallmark of reconstruction for complex congenital conditions is the requirement of multiple surgeries, procedures, and therapies from birth to maturity. These interventions often result in significant medical burden on children during development with potential long-term psychosocial consequences. The aim of this study was therefore to better define the psychosocial impact of repetitive operations on the pediatric patient. METHODS: A scoping review was performed under the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Review guidelines. We searched the PubMed, Cochrane Library, Science Direct, and Web of Science databases using key words "number of surgeries," "psychosocial," "pediatric," and related terms. Primary articles published in English describing psychosocial outcomes in pediatric patients who underwent more than one procedure or surgery were included (n = 25). The Newcastle-Ottawa Scale was used to assess the quality of each study. RESULTS: We included 25 articles published between 1995 and 2019, which included 6520 patients. The most common diagnosis across all studies was congenital heart disease (CHD) (n = 4169, 63.9%), followed by cleft lip and palate (n = 1196, 18.3%). The average number of operations and procedures was 3.4 (range = 1-18) and 32.1 (range = 6-89), respectively. The association between repetitive surgeries and poorer psychosocial outcomes was demonstrated in children with early-onset scoliosis, CHD, hydrocephalus, bladder exstrophy, posterior urethral rupture, anorectal anomalies, and conditions requiring numerous nonsurgical procedures. There were also a few CHD, cleft lip and/or palate, and hydrocephalus studies that did not find a significant correlation. CONCLUSIONS: The studies here suggest that certain pediatric patient populations are at risk for impaired psychosocial functioning as a result of repetitive procedures. However, it is important to differentiate whether the association with poorer psychosocial outcomes is from the number of surgical procedures or whether the number if just a surrogate for increased disease complexity. Standardized psychosocial outcomes measures and future prospective, long-term, randomized clinical trials are also warranted.

A Critical Analysis of Prosthetic Augmentation of Autologous Microvascular Breast Reconstruction.

INTRODUCTION: The combined approach using both an implant and autologous tissue for breast reconstruction has become more common over the last 10 years. We sought to provide a systematic review and outcomes analysis of this technique. METHODS: We searched PubMed and the Cochrane Library database to identify studies that described implant augmentation of autologous flaps for breast reconstruction. The references of selected articles were also reviewed to identify any additional pertinent articles. RESULTS: We identified 11 articles, which included 230 patients and 378 flaps. Implants used ranged in size from 90 to 510 cc, with an average size of 198 cc. Implants were more frequently placed at the time of autologous reconstruction and in the subpectoral plane. There were no total flap losses, and partial flap loss occurred in 3 patients (1%). There were no cases of venous or arterial thrombosis and no early return to the operating room for flap compromise. Eight implants (2%) were lost because of infection or extrusion, and capsular contracture occurred in 9 breasts (3%). When stratified by the timing of implant placement (immediate vs delayed), there were no significant differences in any postoperative outcomes except the immediate group had a higher infection rate. CONCLUSIONS: The criteria for women to be candidates for autologous tissue breast reconstruction can be expanded by adding an implant underneath the flap. We found the overall flap loss rate is comparable with standard autologous flap reconstruction, and the implant loss rate is lower than that in patients who undergo prosthetic reconstruction alone.

Boomerang Modification of the Septal Extension Graft: Graft Design and Functional Outcomes.

Background: A "boomerang" graft is an end-to-end caudal septal extension graft (SEG) that conforms to the geometry of the anterior septal angle, and avoids septal overlap, unlike a side-to-side SEG. Objective: To compare breathing improvements in rhinoplasty patients receiving boomerang SEGs and patients receiving side-to-side SEGs. Methods: Retrospective cohort analysis of patients undergoing rhinoplasty with either end-to-end boomerang SEG or a side-to-side SEG. Functional outcomes were assessed through the Nasal Obstruction Symptom Evaluation (NOSE) survey. Results: The boomerang SEG cohort had a mean age of 34 years and were 68% female compared with 38 years and 67% female in the side-to-side SEG cohort (p > 0.05). The cohorts did not differ in the proportion of the lateral crural tensioning, spreader graft placement, or history of rhinoplasty. The boomerang cohort demonstrated a 67% reduction in NOSE scores compared with a 70% reduction among the side-to-side SEG cohort (p = 0.14). Men undergoing boomerang graft placement reported significantly less postoperative functional improvement than men undergoing placement of a side-to-side SEG (62% vs. 77%, p = 0.01). Conclusion: Use of a boomerang graft is not likely to negatively affect rhinoplasty functional outcomes when compared with a side-to-side SEG.

Gender Affirming Surgery in Nonbinary Patients: A Single Institutional Experience.

Background An increasing number of nonbinary patients are receiving gender-affirming procedures due to improved access to care. However, the preferred treatments for nonbinary patients are underdescribed. The purpose of this study was to investigate the goals and treatments of nonbinary patients. Methods A retrospective study of patients who self-identified as nonbinary from our institutional Gender Health Program was conducted. Patient demographics, clinical characteristics, surgical goals, and operative variables were analyzed. Results Of the 375 patients with gender dysphoria, 67 (18%) were nonbinary. Over half of the nonbinary patients were assigned male at birth ( n = 57, 85%) and nearly half preferred the gender pronoun they/them/theirs ( n = 33, 49%). A total of 44 patients (66%) received hormone therapy for an average of 2.5 ± 3.6 years, primarily estrogen ( n = 39). Most patients ( n = 46, 69%) received or are interested in gender-affirming surgery, of which, almost half were previously on hormone therapy ( n = 32, 48%). The most common surgeries completed or desired were facial feminization surgery ( n = 15, 22%), vaginoplasty ( n = 15, 22%), mastectomy ( n = 11, 16%), and orchiectomy ( n = 9, 13%). Nonbinary patients who were assigned male at birth (NB-AMAB) were more often treated with hormones compared to nonbinary patients assigned female at birth (NB-AFAB) (72% vs. 30%, p = 0.010). Conversely, patients who were AFAB were more likely to complete or desire surgical intervention than those who were AMAB (100% vs. 63.0%, p < 0.021). Conclusion Majority of nonbinary patients were assigned male at birth. NB-AFAB patients all underwent surgical treatment, whereas NB-AMAB patients were predominantly treated with hormone therapy.

Facial Fractures Have Similar Outcomes When Managed by Either Otolaryngology or Plastic Surgery: Encounters From a Single Level I Trauma Center.

Study Design: Retrospective cohort. Objective: Traumatic facial fractures (FFs) often require specialty consultation with Plastic Surgery (PS) or Otolaryngology (ENT); however, referral patterns are often non-standardized and institution specific. Therefore, we sought to compare management patterns and outcomes between PS and ENT, hypothesizing no difference in operative rates, complications, or mortality. Methods: We performed a retrospective analysis of patients with FFs at a single Level I trauma center from 2014 to 2017. Patients were compared by consulting service: PS vs. ENT. Chi-square and Mann-Whitney-U tests were performed. Results: Of the 755 patients with FFs, 378 were consulted by PS and 377 by ENT. There was no difference in demographic data (P > 0.05). Patients managed by ENT received a longer mean course of antibiotics (9.4 vs 7.0 days, P = 0.008) and had a lower rate of open reduction internal fixation (ORIF) (9.8% vs. 15.3%, P = 0.017), compared to PS patients. No difference was observed in overall operative rate (15.1% vs. 19.8%), use of computed tomography (CT) imaging (99% vs. 99%), time to surgery (65 vs. 55 hours, P = 0.198), length of stay (LOS) (4 vs. 4 days), 30-day complication rate (10.6% vs. 7.1%), or mortality (4.5% vs. 2.6%) (all P > 0.05). Conclusion: Our study demonstrated similar baseline characteristics, operative rates, complications, and mortality between FFs patients who had consultation by ENT and PS. This supports the practice of allowing both ENT and PS to care for trauma FFs patients, as there appears to be similar standardized care and outcomes. Future studies are needed to evaluate the generalizability of our findings.

Evaluation and treatment of facial feminization surgery: part II. lips, midface, mandible, chin, and laryngeal prominence.

Facial feminization surgery (FFS) refers to a set of procedures aimed at altering the features of a masculine face to achieve a more feminine appearance. In the second part of this twopart series, assessment and operations involving the midface, mandible, and chin, as well as soft tissue modification of the nasolabial complex and chondrolaryngoplasty, are discussed. Finally, we provide a review of the literature on patient-reported outcomes in this population following FFS and suggest a path forward to optimize care for FFS patients.

Early Alveolar Bone Grafting Is Associated with Lower Regraft Rates and Improvements in Long-Term Psychosocial Outcomes.

BACKGROUND: Late childhood (8 to 10 years of age) has emerged as a vulnerable period in children with cleft and craniofacial anomalies such that increased interventions during this period are associated with worse long-term patient-reported anxiety and depressive symptoms. These findings suggest that one possible practice change may be to consider changes in timing for surgical treatment algorithms. In this work, the authors investigated outcomes in altering the timing of the most common operation in late childhood for cleft lip and palate patients, alveolar bone grafting. METHODS: A two-part, multi-institutional cohort study was conducted. To understand the feasibility of changing alveolar bone graft timing with respect to surgical success, reoperation rates were retrospectively compared among patients grafted at different ages (4 to 7, 8 to 10, and 11 to 13 years of age). To understand the long-term effect of changing alveolar bone graft timing on psychosocial outcomes, the psychosocial suite of the Patient-Reported Outcomes Measurement Information System was prospectively administered to teenagers and adults with cleft lip and palate. RESULTS: Among the three age groups, early grafting (4 to 7 years of age) demonstrated the lowest regraft rates compared with the other groups. As these results suggested that early grafting is a viable alternative to standard timing, we next compared the differences in long-term psychosocial outcomes. Patients who were grafted early reported lower levels of anxiety and depressive symptoms as teenagers and adults. CONCLUSION: Altering timing of one stage in cleft lip and palate reconstruction to an earlier age decreases regraft rates and improves long-term patient-reported anxiety and depressive symptoms. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Role of Transient Receptor Potential Vanilloid 1 in Sonic Hedgehog-Dependent Taste Bud Differentiation.

Taste bud cell differentiation is extremely important for taste sensation. Immature taste bud cells cannot function during taste perception transmission to the nerve. In this study, we investigated whether hedgehog signaling affected taste bud cell differentiation and whether transient receptor potential vanilloid 1 (TRPV1) played a key role in dry mouth. The induction of dry mouth due to salivary gland resection (SGR) was confirmed on the basis of reduced salivation and disrupted fungiform papillae. The expression of keratin 8 (K8) of taste bud cells, neurofilament (NF), sonic hedgehog (Shh), and glioma-associated oncogene homolog 1 (Gli1) around taste bud cells was downregulated; however, the expression of TRPV1, P2X purinoceptor 3 (P2X3), and hematopoietic stem cell factor (c-Kit) was upregulated at the NF ends in the dry mouth group. To investigate the effect of TRPV1 defect on dry mouth, we induced dry mouth in the TRPV-/- group. The K8, NF, and P2X3 expression patterns were the same in the TRPV1 wild-type and TRPV1-/- dry mouth groups. However, Shh and c-Kit expression decreased regardless of dry mouth in the case of TRPV1 deficiency. These results indicated that TRPV1 positively regulated proliferation during taste bud cell injury by blocking the Shh/Gli1 pathway. In addition, not only cell proliferation but also differentiation of taste bud cells could not be regulated under TRPV1-deficiency conditions. Thus, TRPV1 positively regulates taste bud cell innervation and differentiation; this finding could be valuable in the clinical treatment of dry mouth-related taste dysfunction.

Facial Feminization Surgery under Insurance: The University of California Los Angeles Experience.

Despite improved insurance coverage for gender confirmation surgeries in the United States, coverage for facial feminization surgery (FFS) continues to be difficult. Here, we describe our institutional experience on navigation, time, and costs of the FFS insurance authorization process. METHODS: FFS consults (n = 40) at the University of California, Los Angeles (2018-2020) were reviewed for time and cost to definitive insurance authorization decision. Patients were stratified into 3 groups based on authorization process: Group A (standard approval, n = 26, 65.0%) including public and private insurances; Group B (extended approval, n = 10, 25.0%) consisting of private insurance plans that initially denied and required multi-level appeals for denial overturn; and Group C (denial, n = 4, 10.0%), including private insurance plans that denied even after multi-level appeals. RESULTS: An estimated 90% of all patient consults were approved for FFS under insurance. Group A averaged 1.1 months for approval, requiring 1.4 hours of administrative time translating to $38.18 per patient. The addition of multi-level appeals in Groups B and C increased the total time for a definitive decision (7.0 and 5.1 months, respectively) and required both surgeon and administrative time to navigate the process (10.8 and 12.0 hours, respectively). The time spent on the presurgical authorization process for Groups B and C translated to an over 20-fold increase in cost ($855.00 and $988.38, respectively) compared with Group A. CONCLUSION: Navigation of the insurance process for FFS is challenging and time-consuming; however, coverage is a reality in California provided that multi-level appeals are exhausted.

Stiffness of Nanoparticulate Mineralized Collagen Scaffolds Triggers Osteogenesis via Mechanotransduction and Canonical Wnt Signaling.

The ability of the extracellular matrix (ECM) to instruct progenitor cell differentiation has generated excitement for the development of materials-based regenerative solutions. Described a nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) material capable of inducing in vivo skull regeneration without exogenous growth factors or ex vivo progenitor cell-priming is described previously. Here, the contribution of titrating stiffness to osteogenicity is evaluated by comparing noncrosslinked (NX-MC) and crosslinked (MC) forms of MC-GAG. While both materials are osteogenic, MC demonstrates an increased expression of osteogenic markers and mineralization compared to NX-MC. Both materials are capable of autogenously activating the canonical BMPR signaling pathway with phosphorylation of Smad1/5. However, unlike NX-MC, human mesenchymal stem cells cultured on MC demonstrate significant elevations in the major mechanotransduction mediators YAP and TAZ expression, coincident with ß-catenin activation in the canonical Wnt signaling pathway. Inhibition of YAP/TAZ activation reduces osteogenic expression, mineralization, and ß-catenin activation in MC, with less of an effect on NX-MC. YAP/TAZ inhibition also results in a reciprocal increase in Smad1/5 phosphorylation and BMP2 expression. The results indicate that increasing MC-GAG stiffness induces osteogenic differentiation via the mechanotransduction mediators YAP/TAZ and the canonical Wnt signaling pathway, whereas the canonical BMPR signaling pathway is activated independent of stiffness.

Component Restoration in the Bilateral Intermediate Cleft Tip Rhinoplasty.

SUMMARY: The intermediate cleft tip rhinoplasty is frequently performed during childhood to address nasal tip anomalies in cleft patients before the most critical period of psychosocial development. The authors previously described the component restoration intermediate cleft tip rhinoplasty technique for the unilateral cleft nose, which was developed to systematically address the lining deficiency, cleft lower lateral cartilage malpositioning, and cleft lateral cartilage weakness using a combination of lower lateral cartilage release, lateral cartilage repositioning, and placement of an auricular composite chondrocutaneous graft. In this work, the authors evaluate the utility of this technique to the bilateral cleft nose. Preoperative and postoperative (mean ± SD, 18.6 ± 10.8 months) photographs of bilateral cleft patients treated with the component restoration intermediate cleft tip rhinoplasty (n = 7) were evaluated using photogrammetric measurements and aesthetic assessments. From preoperatively to postoperatively, the columella length-to-alar width ratio on basal photographs increased (0.19 ± 0.05 versus 0.28 ± 0.05; p = 0.001). On lateral view, the columella-labial angle decreased from preoperatively to postoperatively [138 degrees (interquartile range, 132 to 144 degrees) versus 123 degrees (interquartile range, 122 to 139 degrees); p = 0.04]. Aesthetic ratings performed by four blinded observers also improved from preoperatively to postoperatively (1.6 ± 0.8 versus 2.4 ± 0.7; p = 0.004). As a comparison, bilateral cleft nose patients who did not undergo intermediate cleft tip rhinoplasty (n = 3) of similar ages were subjected to the same photogrammetric and aesthetic analyses, which showed no differences from preoperatively to postoperatively. In combination, the current work suggests that the component restoration technique in the bilateral intermediate cleft tip rhinoplasty improves nasal tip support and aesthetic outcomes.