Long-term Safety and Effectiveness of Hyaluronic Acid Fillers Correcting Nasolabial Folds in Chinese Patients.

Background: Soft-tissue fillers, specifically hyaluronic acid fillers, can reduce many signs of aging by treating the associated loss of subcutaneous fat and midfacial contour deficiencies. The objective of this study was to investigate whether the effectiveness and safety of Belotero Volume Lidocaine (BVL) compared with Restylane (RES, control) is noninferior in the treatment of severe nasolabial folds (NLFs) in Chinese patients. Methods: This was a prospective, randomized, controlled, split-face clinical study. Overall, 220 Chinese patients of both sexes with symmetrical NLFs of severe intensity (grade 4) on the Wrinkle Severity Rating Scale (WSRS) were treated with both fillers. Treatment outcomes were assessed by the WSRS, and other scales, at multiple time points up to 18 months postinjection. The co-primary effectiveness outcomes were based on the blinded evaluator ratings of NLFs according to the WSRS scale after 6 and 12 months. Adverse events were assessed during the whole study and patients' pain sensation at three time points after injection. Results: Noninferiority of BVL versus control based on the WSRS was demonstrated at month 6 and month 12. Response rates were slightly higher for BVL than control at all time points, and BVL had a sustained effect until month 18. Pain sensation scores were significantly lower for BVL compared with control. The incidence rates of treatment-related AEs were low and very similar for both treatments. Conclusions: This study demonstrates that BVL is a safe, long-lasting, and effective treatment to correct severe NLFs in Chinese patients while being noninferior to the control device.

Multi-target landmark detection with incomplete images via reinforcement learning and shape prior embedding.

Medical images are generally acquired with limited field-of-view (FOV), which could lead to incomplete regions of interest (ROI), and thus impose a great challenge on medical image analysis. This is particularly evident for the learning-based multi-target landmark detection, where algorithms could be misleading to learn primarily the variation of background due to the varying FOV, failing the detection of targets. Based on learning a navigation policy, instead of predicting targets directly, reinforcement learning (RL)-based methods have the potential to tackle this challenge in an efficient manner. Inspired by this, in this work we propose a multi-agent RL framework for simultaneous multi-target landmark detection. This framework is aimed to learn from incomplete or (and) complete images to form an implicit knowledge of global structure, which is consolidated during the training stage for the detection of targets from either complete or incomplete test images. To further explicitly exploit the global structural information from incomplete images, we propose to embed a shape model into the RL process. With this prior knowledge, the proposed RL model can not only localize dozens of targets simultaneously, but also work effectively and robustly in the presence of incomplete images. We validated the applicability and efficacy of the proposed method on various multi-target detection tasks with incomplete images from practical clinics, using body dual-energy X-ray absorptiometry (DXA), cardiac MRI and head CT datasets. Results showed that our method could predict whole set of landmarks with incomplete training images up to 80% missing proportion (average distance error 2.29 cm on body DXA), and could detect unseen landmarks in regions with missing image information outside FOV of target images (average distance error 6.84 mm on 3D half-head CT). Our code will be released via https://zmiclab.github.io/projects.html.

An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort.

Craniosynostosis (CRS) is a disease with prematurely fused cranial sutures. In the last decade, the whole-exome sequencing (WES) was widely used in Caucasian populations. The WES largely contributed in genetic diagnosis and exploration on new genetic mechanisms of CRS. In this study, we enrolled 264 CRS patients in China. After a 17-gene-panel sequencing designed in the previous study, 139 patients were identified with pathogenic/likely pathogenic (P/LP) variants according to the ACMG guideline as positive genetic diagnosis. WES was then performed on 102 patients with negative genetic diagnosis by panel. Ten P/LP variants were additionally identified in ten patients, increasing the genetic diagnostic yield by 3.8% (10/264). The novel variants in ANKH, H1-4, EIF5A, SOX6, and ARID1B expanded the mutation spectra of CRS. Then we designed a compatible research pipeline (RP) for further exploration. The RP could detect all seven P/LP SNVs and InDels identified above, in addition to 15 candidate variants found in 13 patients with worthy of further study. In sum, the 17-gene panel and WES identified positive genetic diagnosis for 56.4% patients (149/264) in 16 genes. At last, in our estimation, the genetic testing strategy of "Panel-first" saves 24.3% of the cost compared with "WES only", suggesting the "Panel-first" is an economical strategy.

Lifting the midface using a hyaluronic acid filler with lidocaine: A randomized multi-center study in a Chinese population.

BACKGROUND: Soft-tissue augmentation of the midface is increasingly requested by patients, and hyaluronic acid (HA) fillers are frequently used in treatment. AIMS: To evaluate the efficacy and safety of treatment of midface volume/contour deficit with a firm HA filler including lidocaine (HARL ). PATIENTS/METHODS: This was a 12-month, randomized, evaluator-blinded, controlled study. Chinese adults with mild to substantial volume loss were randomly assigned in a 3:1 ratio to treatment or untreated control groups. RESULTS: A total of 148 subjects were enrolled. The primary objective was met; results of the midface volume scale (MMVS) rated by a blinded evaluator were in favor of HARL at Month 6 (p < 0.0001 vs. the untreated control group). Similar to the MMVS improvement, improved midface fullness and aesthetic appearance was observed based on the Global Aesthetic Improvement Scale (GAIS) up to 12 months by both treating investigators and subjects (at least 96% at Week 4 and 65% at Month 12). Subject satisfaction was high, and the majority of subjects considered the results to look natural (>97%). The study product was well tolerated. CONCLUSIONS: Midfacial treatment using HARL was effective, well tolerated, and led to high levels of satisfaction in a Chinese population for up to 12 months. GOV IDENTIFIER: NCT03097783.

Genetic evidence for facial variation being a composite phenotype of cranial variation and facial soft tissue thickness.

Facial and cranial variation represent a multidimensional set of highly correlated and heritable phenotypes. Little is known about the genetic basis explaining this correlation. We develop a software package ALoSFL for simultaneous localization of facial and cranial landmarks from head computed tomography (CT) images, apply it in the analysis of head CT images of 777 Han Chinese women, and obtain a set of phenotypes representing variation in face, skull and facial soft tissue thickness (FSTT). Association analysis of 301 single nucleotide polymorphisms (SNPs) from 191 distinct genomic loci previously associated with facial variation reveals an unexpected larger number of loci showing significant associations (P < 1e-3) with cranial phenotypes than expected under the null (O/E = 3.39), suggesting facial and cranial phenotypes share a substantial proportion of genetic components. Adding FSTT to a SNP-only model shows a large impact in explaining facial variance. A gene ontology analysis reveals that bone morphogenesis and osteoblast differentiation likely underlie our cranial-significant findings. Overall, this study simultaneously investigates the genetic effects on both facial and cranial variation of the same sample, supporting that facial variation is a composite phenotype of cranial variation and FSTT.

Postoperative Complications of Box-Shift Osteotomy for Orbital Hypertelorism.

OBJECTIVE: To summarize and analyze the postoperative complications of box-shift osteotomy performed at our center for Chinese orbital hypertelorism patients from 2008 to 2017. METHOD: This retrospective study reviews the records of 78 patients with complete medical records and at least 2 years of postoperative follow-up data. Both radiologic and anthropometric assessments were conducted before, 1 month after and 2 years after surgery to evaluate the bony and soft-tissue alterations. Postoperative complications were recorded during hospitalization and at each follow-up visit and divided into 3 groups: acute complications that occurred within 1 month after surgery; early complications that occurred within 6 months after surgery; and long-term complications that occurred within 2 years after surgery. RESULTS: Both bony and soft-tissue alterations were significant at 1 month after surgery. The acute complications that occurred in our center included infection (12.8%), cerebrospinal fluid leakage (29.5%), epilepsy (2.6%), and nasal tip skin necrosis (1.3%). The early complications included strabismus (11.5%) and nasolacrimal duct obstruction (3.8%). The long-term complications included insufficient correction (55.1%), palpable metal implants (92.3%) and a drooping nasal tip (33.9%). Due to the insufficient correction and the continued growth of rib graft, the difference in the hypertelorism index and nasal length, between one month and 2 years postoperatively were statistically significant (P < 0.01). Other radiographic and anthropometric measurements changed with growth without a significance difference between 1 month and 2 years after surgery. CONCLUSION: In this study, we recorded all postoperative complications of box-shift osteotomy. The challenge of our future work is to identify methods for decreasing the incidence of these complications.

[The development and recent status of the craniomaxillofacial surgery in China during past three decades].

The authors made a profound review on the development and the recent status of craniomaxillofacial surgery in China during past three decades. The emphases were placed on the following aspects: the modifications of the reconstructive procedure and minimal invasive mode, the researches on molecular genetic characteristics of the congenital craniofacial malformations, the clinical applications of three-dimensional digital computer-aided techniques (including three-dimensional printing and prefabricated template for precious osteotomies), the craniomaxillofacial defects reconstructing by using the distraction osteogenesis and osseous integrated titanium implant and prothesis, etc. Finally, the authors outlooked prospectively the future trends of the craniomaxillofacial surgery.

iTRAQ-Based Proteomic Analysis reveals possible target-related proteins and signal networks in human osteoblasts overexpressing FGFR2.

BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) play a vital role in skeletogenesis. However, the molecular mechanisms triggered by FGFR2 in osteoblasts are still not fully understood. In this study, proteomics and bioinformatics analysis were performed to investigate changes in the protein profiles regulated by FGFR2, with the goal of characterizing the molecular mechanisms of FGFR2 function in osteoblasts. METHODS: In this study, FGFR2-overexpression cell line was established using the lentivirus-packaging vector in human osteoblasts (hFOB1.19). Next, the isobaric tags for relative and absolute quantitation (iTRAQ) in combination with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to compare the proteomic changes between control and FGFR2-overexpression cells. Thresholds (fold-change of ≥ 1.5 and a P-value of < 0.05) were selected to determine differentially expressed proteins (DEPs). The bioinformatics analysis including GO and pathway analysis were done to identify the key pathways underlying the molecular mechanism. RESULTS: A Total of 149 DEPs was identified. The DEPs mainly located within organelles and involved in protein binding and extracellular regulation of signal transduction. ColI, TNC, FN1 and CDKN1A were strikingly downregulated while UBE2E3, ADNP2 and HSP70 were significantly upregulated in FGFR2-overexpression cells. KEEG analysis suggested the key pathways included cell death, PI3K-Akt signaling, focal adhesion and cell cycle. CONCLUSIONS: To our knowledge, this is the first protomic research to investigate alterations in protein levels and affected pathways in FGFR2-overexpression osteoblasts. Thus, this study not only provides a comprehensive dataset on overall protein changes regulated by FGFR2, but also shed light on its potential molecular mechanism in human osteoblasts.

Overexpression of Glypican 3 Promotes Proliferation, Regulates Cell Cycle Progression, and Inhibits Apoptosis of Human Fetal Osteoblastic Cell Line 1.19.

Craniosynostosis is a complex disease condition, which involves premature fusion of cranial vault sutures and lacks desirable treatment. Previous studies have demonstrated decreased proliferation rate of osteoblasts and downregulated expression of glypican 3 (GPC3) in syndromic craniosynostosis patients. In this study, quantitative and qualitative analysis were utilized to assess the effect of GPC3 in human fetal osteoblastic cell line, hFOB 1.19. Lentiviral transfection efficiency with green fluorescent protein images was obtained after 72 hours. Western Blot and quantitative real-time polymerase chain reaction analysis results indicated that GPC3 was overexpressed in hFOB 1.19 cells transfected with recombinant lentivirus LV-GPC3-GFP. Cell proliferation was assessed by CCK-8 assay and cell cycle progression and apoptosis were analyzed by flow cytometric assay. Results revealed that GPC3 promoted cell viability, induced cell cycle entry into S phase, and inhibited cell apoptosis. These findings provide novel ideas in understanding the pathogenesis of craniosynostosis. It also provides novel insights in the treatment of craniosynostosis by targeting GPC3.

Value of Osteoblast-Derived Exosomes in Bone Diseases.

PURPOSE: The authors' purpose is to reveal the value of osteoblast-derived exosomes in bone diseases. METHODS: Microvesicles from supernatants of mouse Mc3t3 were isolated by ultracentrifugation and then the authors presented the protein profile by proteomics analysis. RESULTS: The authors detected a total number of 1536 proteins by mass spectrometry and found 172 proteins overlap with bone database. The Ingenuity Pathway Analysis shows network of "Skeletal and Muscular System Development and Function, Developmental Disorder, Hereditary Disorder" and pathway about osteogenesis. EFNB1 and transforming growth factor beta receptor 3 in the network, LRP6, bone morphogenetic protein receptor type-1, and SMURF1 in the pathway seemed to be valuable in the exosome research of related bone disease. CONCLUSIONS: The authors' study unveiled the content of osteoblast-derived exosome and discussed valuable protein in it which might provide novel prospective in bone diseases research.

Early Complications and Associated Perioperative Factors in Nonsyndromic Craniosynostosis.

This is the first Eastern center-based retrospective report on early complications and associated perioperative factors of nonsyndromic craniosynostosis (NSC). The authors' purpose is to tailor preoperative counseling, convey objective perioperative data, and determinants for early complications in NSC so as to enhance exchanges with international center. Inclusion criteria required a diagnosis of NSC confirmed by 3-dimentional computed tomography scans and complete medical record. Genetic evidence of syndromic craniosynostosis was excluded. Study population was divided into 4 groups based on the suture involvement, which were compared with respect to demographics, perioperative factors, and the occurrence of complications. Demographic data were analyzed using descriptive statistics. Categorical variables were analyzed using the Fisher exact test. Continuous variables were analyzed using the Kruskal-Wallis test. To better study key determinants for early complications, regression analysis was performed. It revealed a predominance of sagittal (n = 36) throughout the time period studied. Eastern China (n = 33) and Southwest China (n = 13) were the top 2 districts where patients came. The authors also reported an overall rate of early complication of 80% (n = 52). The most common were pyrexia (n = 50). Blood loss was a risk (P = 0.041; OR, 1.102); meanwhile, transfusion of concentrated red blood cells was a higher risk (P = 0.035; OR, 2.033). This study represents the authors' initial 4 years practice in NSC. The authors are endeavoring to enhance exchanges with Western centers.

"Well Digging" Subcraniotomy Strategy with Navigation for Optic Nerve Decompression in Frontoorbital Fibrous Dysplasia: Preliminary Experience.

BACKGROUND: During the past decades, surgical intervention has been the primary treatment modality for frontoorbital fibrous dysplasia involving optic nerve. However, controversy has surrounded the role of optic nerve decompression in a number of ways. Herein, we describe 3 patients with frontoorbital fibrous dysplasia involving optic nerve, who underwent a "well digging" subcraniotomy strategy with navigation for intraorbital unit optic nerve decompression. METHODS: From 2013 to 2015, 3 patients with frontoorbital fibrous dysplasia were investigated in a retrospective manner. They underwent unilateral intraorbital optic nerve decompression with the help of "well digging" strategy and navigation. The key procedures comprise preoperative software simulation, frontoorbital subcraniotomy (like digging a well), expanding cone-shaped surgical field, intraorbital unit optic nerve decompression with navigation, correcting frontal-orbital dystopias, and deformities. RESULTS: Both at the immediate postoperative period and during the 3-12 months follow-up, 2 cases showed improvement of visual acuity in the affected eye and 1 case showed no deterioration. Other ocular examinations including eye movement were stable. Subsequent reconstruction yielded a satisfactory cosmetic result. No postoperative complications happened. CONCLUSIONS: In our philosophy, surgical management should be tailored to each patient, which is based on the most possible potential etiology. We consider that the intraorbital optic nerve decompression may be more feasible and safer with the help of "well digging" strategy and navigation, especially for those with exophthalmos, orbital volume decreasing, and nonacute visual loss.

Identification and proteomic analysis of osteoblast-derived exosomes.

Exosomes are nanometer-sized vesicles with the function of intercellular communication, and they are released by various cell types. To reveal the knowledge about the exosomes from osteoblast, and explore the potential functions of osteogenesis, we isolated microvesicles from supernatants of mouse Mc3t3 by ultracentrifugation, characterized exosomes by electron microscopy and immunoblotting and presented the protein profile by proteomic analysis. The result demonstrated that microvesicles were between 30 and 100 nm in diameter, round shape with cup-like concavity and expressed exosomal marker tumor susceptibility gene (TSG) 101 and flotillin (Flot) 1. We identified a total number of 1069 proteins among which 786 proteins overlap with ExoCarta database. Gene Oncology analysis indicated that exosomes mostly derived from plasma membrane and mainly involved in protein localization and intracellular signaling. The Ingenuity Pathway Analysis showed pathways are mostly involved in exosome biogenesis, formation, uptake and osteogenesis. Among the pathways, eukaryotic initiation factor 2 pathways played an important role in osteogenesis. Our study identified osteoblast-derived exosomes, unveiled the content of them, presented potential osteogenesis-related proteins and pathways and provided a rich proteomics data resource that will be valuable for further studies of the functions of individual proteins in bone diseases.

Skeleton first in surgical treatment of facial disharmony.

PURPOSE: The aim of this study was to correct facial disharmony with or without occlusal dysfunction. METHODS: Based on computed tomography and presurgical design, restoration of normal skeleton relationship is a priority for selected facial deformities. Combination of different osteotomies for facial skeleton was chosen in 1-stage operation such as orthognathic surgery, zygomatic reduction, and mandibular angle reduction. Supplementary surgeries was considered in some cases as substitute implantation or autologous fat graft. RESULTS: All the 50 patients (hemifacial microsomia, Romberg syndrome, mandibular condyle hyperplasia, secondary cleft palate, and Crouzon syndrome) received surgeries, and their facial appearance improved significantly. Yearly follow-up shows that the symmetry and balance of the facial proportion approach normal, whereas most of their occlusal relationship has been significantly improved after the first stage of surgery. CONCLUSIONS: For most facial disharmony with or without occlusal dysfunction, skeleton-first surgery is a feasible strategy.

The C342R mutation in FGFR2 causes Crouzon syndrome with elbow deformity.

Crouzon syndrome is an autosomal dominant craniosynostosis syndrome caused by mutation in the fibroblast growth factor receptor 2 (FGFR-2). Numerous findings from animal studies imply a critical role for FGFRs in the regulation of skeletal development. Here, we report 2 unrelated patients with Crouzon syndrome accompanied by elbow deformity. Subsequently, we analyzed the sequence of the FGFR2 gene and found that both of the patients carried the Cys342Arg mutation. The findings suggest that the C342R mutation in FGFR2 may cause Crouzon syndrome and elbow deformity in Chinese patients.

S267P mutation in FGFR2: first report in a patient with Crouzon syndrome.

It has been known for several years that mutations in the fibroblast growth factor receptor (FGFR2) result in syndromic craniosynostosis including Apert, Crouzon, or Pfeiffer syndromes. Here, we report on a child with a clinically diagnosed Crouzon syndrome that shows the missense point mutation S267P in FGFR2 gene. The mutation is firstly identified in Crouzon syndrome. Our observations expand the molecular spectrum of FGFR2 mutations in the syndrome.

Analysis of alar balance in secondary cleft lip with Z-plasty technique of nasal cartilage.

The cleft nasal deformity is a prevailing problem of complex challenge for plastic surgery, especially in the secondary correction. We mainly chose 40 patients with unilateral secondary cleft lip nasal deformity with alar collapse. Based on biomechanics and anatomy of nasal cartilage, we adapt a Z-plasty with cartilage mucosa using the deformed lateral crus of the upper lateral cartilage to support the collapse of lower lateral cartilage. All of our patients were satisfied with the aesthetic morphology after surgery, so we are confident that this method should be considered as an auxiliary treatment to rhinoplasty.

Edge locked stitching between nostril ala and lateral cartilages with a mucochondrial Z-plasty in correction of unilateral cleft nasal deformity in secondary rhinoplasty.

BACKGROUND: Ala and nostril collapse are most raised complaints in secondary deformity of unilateral cleft patients. While a lot of techniques have been introduced so far, the purpose of this study was to evaluate the effectiveness of edge locked stitching between nostril ala and lateral cartilages with mucochondrial Z-plasty to correct the collapse in lower lateral cartilage in the ala and nostril shaping. METHODS: Fifty-seven patients with unilateral cleft nasal deformities were recruited. They all had primary surgery before and were left with nasal deformities. Based on the anatomic understanding, we operated on all the patients using edge locked stitching between nostril ala and lateral cartilages with a mucochondrial Z-plasty to correct the abnormal lateral collapse of nostril deformities. RESULTS: All the patients had an improvement in the shape of the ala and nostril immediately after the surgery. Follow-up at 6 months (or later) showed no severe relapse. CONCLUSION: The edge locked stitching between nostril ala and lateral cartilages with mucochondrial Z-plasty is effective to correct ala and nostril deformities in unilateral cleft.

Severe meningeal calcification in a Crouzon patient carrying a mutant C342W FGFR2.

Crouzon is an autosomal dominant craniosynostosis syndrome caused by mutation in the fibroblast growth factor receptor (FGFR)-2 gene. Recent findings from animal studies imply a critical role for FGFs in the regulation of mineralization. Here, we presented a 5-year-old girl with severe meningeal calcification. Subsequently, we analyzed FGFR2 mutation and identified a mutation of Cys342Tyr. The findings suggest that abnormal calcification was atypical phenotype of Crouzon patients with Cys342Tyr mutation in FGFR2.