Atypical mandibulofacial dysostosis with microcephaly diagnosed through the identification of a novel pathogenic mutation in EFTUD2.

BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain containing 2 gene (EFTUD2, OMIM* 603892). It is characterized by mandibulofacial dysplasia, microcephaly, malformed ears, cleft palate, growth and intellectual disability. MFDM can be easily misdiagnosed due to its phenotypic overlap with other craniofacial dysostosis syndromes. The clinical presentation of MFDM is highly variable among patients. METHODS: A patient with craniofacial anomalies was enrolled and evaluated by a multidisciplinary team. To make a definitive diagnosis, whole-exome sequencing was performed, followed by validation by Sanger sequencing. RESULTS: The patient presented with extensive facial bone dysostosis, upward slanting palpebral fissures, outer and middle ear malformation, a previously unreported orbit anomaly, and spina bifida occulta. A novel, pathogenic insertion mutation (c.215_216insT: p.Tyr73Valfs*4) in EFTUD2 was identified as the likely cause of the disease. CONCLUSIONS: We diagnosed this atypical case of MFDM by the detection of a novel pathogenetic mutation in EFTUD2. We also observed previously unreported features. These findings enrich both the genotypic and phenotypic spectrum of MFDM.

Profiling of Long Non-Coding RNAs in Auricular Cartilage of Patients with Isolated Microtia.

Introduction: Microtia is the second most common maxillofacial birth defect worldwide. However, the involvement of long non-coding RNAs (lncRNAs) in isolated microtia is not well understood. This study aimed at identifying lncRNAs that regulate the expression of genes associated with isolated microtia. Methods: We used our microarray data to analyze the expression pattern of lncRNA in the auricular cartilage tissues from 10 patients diagnosed with isolated microtia, alongside 15 control subjects. Five lncRNAs were chosen for validation using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results: We identified 4651 differentially expressed lncRNAs in the auricular cartilage from patients with isolated microtia. By Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathway (GO/KEGG) analysis, we identified 27 differentially expressed genes enriched in pathways associated with microtia. In addition, we predicted 9 differentially expressed genes as potential cis-acting targets of 12 differentially expressed lncRNAs. Our findings by qRT-PCR demonstrate significantly elevated expression levels of ZFAS1 and DAB1-AS1, whereas ADIRF-AS1, HOTAIRM1, and EPB41L4A-AS1 exhibited significantly reduced expression levels in the auricular cartilage tissues of patients with isolated microtia. Conclusions: Our study sheds light on the potential involvement of lncRNAs in microtia and provides a basis for further investigation into their functional roles and underlying mechanisms.

A publicly available newborn ear shape dataset for medical diagnosis of auricular deformities.

Early and accurate diagnosis of ear deformities in newborns is crucial for an effective non-surgical correction treatment, since this commonly seen ear anomalies would affect aesthetics and cause mental problems if untreated. It is not easy even for experienced physicians to diagnose the auricular deformities of newborns and the classification of the sub-types, because of the rich bio-metric features embedded in the ear shape. Machine learning has already been introduced to analyze the auricular shape. However, there is little publicly available datasets of ear images from newborns. We released a dataset that contains quality-controlled photos of 3,852 ears from 1,926 newborns. The dataset also contains medical diagnosis of the ear shape, and the health data of each newborn and its mother. Our aim is to provide a freely accessible dataset, which would facilitate researches related with ear anatomies, such as the AI-aided detection and classification of auricular deformities and medical risk analysis.

Quantitative Framework Fabrication with Autogenous Costal Cartilage in Microtia Reconstruction.

Hearing improvement is another basic requirement for microtia patients in addition to aesthetic needs. This quantitative framework fabrication method can reduce the learning curve, obtain satisfactory aesthetic results with few complications, and reserve a certain space for future canalplasty. Laryngoscope, 134:148-153, 2024.

Long-Term Effectiveness of Ear Molding and Factors Affecting Outcomes.

BACKGROUND: The EarWell System offers a correction opportunity for infants born with ear anomalies. However, the long-term effectiveness of ear molding remains unclear. This study aimed to explore the long-term effectiveness of this novel technique and to determine the risk factors for recurrence. METHODS: This retrospective, population-based cohort study was performed from 2017 through 2021. Infants who completed ear molding therapy and were followed up for longer than 6 months were enrolled. The main outcomes were immediate and long-term efficacy, which were graded by two blinded plastic surgeons. RESULTS: A total of 226 infants (334 ears) were recruited. The most common anomalies were helical deformities [113 ears (33.8%)], and the rarest were cryptotia [five ears (1.5%)] and conchal crus [five ears (1.5%)]. The age at initiation of treatment was a factor affecting both immediate ( P = 0.004) and long-term effectiveness ( P = 0.009). The type of anomaly also influenced long-term molding outcomes. For cup ears, the success rate of long-term outcomes (76.0%) was significantly lower than that of immediate outcomes (98.7%) ( P < 0.001). Prominent ear, cup ear, and microtia were found to be the most likely to relapse during long-term follow-up. The results of logistic regression also demonstrated age, duration time, and the type of anomaly to be risk factors of ear molding effects. CONCLUSIONS: The EarWell System was shown to be a secure and effective method for treatment of congenital ear anomalies. Some infants' ear anomalies recurred after successful immediate results. The age at initiation of treatment and the type of anomaly were predictors of long-term outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

The circular RNA expression profile of human auricle cartilage and the role of circCOL1A2 in isolated microtia.

Microtia is one of the most common craniofacial birth defects worldwide, and its primary clinical manifestation is auricle deformity. Epigenetic factors are known to contribute to the etiology of microtia, yet the involvement of circular RNAs (circRNAs) in human auricle development and their association with microtia remains poorly understood. In this study, we aimed to analyze differentially expressed circRNAs and explore their functional implications in isolated microtia. By employing circRNA microarray analysis and bioinformatics approaches, we identified 340 differentially expressed circRNAs in auricle cartilage of patients with isolated microtia, comprising 152 upregulated and 188 downregulated circRNAs. A circRNA-mRNA co-expression network was constructed, followed by gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Subsequently, we selected four significantly upregulated circRNAs from the co-expression network based on their association with cartilage development and validated their expressions in 30 isolated microtia and 30 control clinical auricle cartilage samples. Among these circRNAs, circCOL1A2, the most significantly upregulated circRNA, was selected as a representative circRNA for investigating its role in isolated microtia. Overexpression of circCOL1A2 significantly inhibited chondrocyte proliferation and chondrogenic differentiation of human mesenchymal stem cells. Additionally, circCOL1A2 upregulated Dermatan Sulfate Epimerase Like (DSEL) expression by sponging miR-637 through the competing endogenous RNA (ceRNA) mechanism. Notably, the downregulation of DSEL attenuated the inhibitory effect of circCOL1A2 overexpression on cell proliferation and chondrogenic differentiation. Collectively, these findings highlight the involvement of circCOL1A2 in the pathogenesis of isolated microtia and emphasize the potential significance of dysregulated circRNAs in disease development.

The Effects of BCDs in Unilateral Conductive Hearing Loss: A Systematic Review.

Bone conduction devices (BCDs) are widely used in the treatment of conductive hearing loss (CHL), but their applications on unilateral CHL (UCHL) patients remain controversial. To evaluate the effects of BCDs in UCHL, a systematic search was undertaken until May 2023 following the PRISMA guidelines. Among the 391 references, 21 studies met the inclusion criteria and were ultimately selected for review. Data on hearing thresholds, speech recognition, sound localization, and subjective questionnaire outcomes were collected and summarized. Moderate hearing threshold improvements were found in UCHL patients aided with BCDs. Their speech recognition abilities improved significantly. However, sound localization results showed wide individual variations. According to subjective questionnaires, BCDs had an overall positive influence on the daily life of UCHL patients, although several unfavorable experiences were reported by some of them. We concluded that the positive audiological benefits and subjective questionnaire results have made BCDs a credible intervention for UCHL patients. Before final implantations, UCHL patients should first go through a period of time when they were fitted with non-implantable BCDs as a trial.

Crystal structure of LRG1 and the functional significance of LRG1 glycan for LPHN2 activation.

The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1), primarily produced by hepatocytes and neutrophils, is a multifunctional protein that modulates various signaling cascades, mainly TGFß signaling. Serum LRG1 and neutrophil-derived LRG1 have different molecular weights due to differences in glycosylation, but the impact of the differential glycan composition in LRG1 on its cellular function is largely unknown. We previously reported that LRG1 can promote both angiogenic and neurotrophic processes under hyperglycemic conditions by interacting with LPHN2. Here, we determined the crystal structure of LRG1, identifying the horseshoe-like solenoid structure of LRG1 and its four N-glycosylation sites. In addition, our biochemical and cell-biological analyses found that the deglycosylation of LRG1, particularly the removal of glycans on N325, is critical for the high-affinity binding of LRG1 to LPHN2 and thus promotes LRG1/LPHN2-mediated angiogenic and neurotrophic processes in mouse tissue explants, even under normal glucose conditions. Moreover, the intracavernous administration of deglycosylated LRG1 in a diabetic mouse model ameliorated vascular and neurological abnormalities and restored erectile function. Collectively, these data indicate a novel role of LRG1 glycans as molecular switches that can tune the range of LRG1's cellular functions, particularly the LRG1/LPHN2 signaling axis.

The Effect of Fixation Materials on the Long-Term Stability of Cartilage Framework for Microtia Reconstruction.

Objective: To observe the effect of fixation materials on the long-term stability of the cartilage framework in auricular reconstruction. Methods: Consecutive patients who underwent the first stage of auricular reconstruction by the same surgical team from September 2018 to March 2021 were included. Those with braided absorbable suture, polypropylene suture, and titanium wire were defined as Groups A, B, and C, respectively. Six months later, when the patients underwent the second stage of surgery, absorption and deformation of the framework were assessed. Results: A total of 604 patients (622 ears) were included. The most common occurrence was spot absorption in the antihelix and was observed in 34.7%, 17.4%, and 22.8% ears in the A, B, and C groups, respectively (p < 0.05). There were also significant differences regarding severe absorption and severe deformation. The histological examination suggested that those in Group A had more T cells and macrophages around the suture than those in Groups B and C. Conclusion: Absorbable suture seems to correlate with higher risk of cartilage absorption and helix displacement. Titanium wire had the lowest rate of helix pop-out or fracture, which means the best stability.

Changes of Age-related Auricular Cartilage Plasticity and Biomechanical Property in a Rabbit Model.

OBJECTIVES: Ear molding is an emerging technique that can correct auricular deformities. Treatment initiation time is the most important prognostic determinant of ear molding. Here, we aimed to examine why auricular cartilage plasticity appeared to diminish with age. Thus, we characterized age-related changes in the biomechanical, biochemical, and morphological properties of auricular cartilage. METHODS: New Zealand rabbits were used as the experimental animal. We examined immature [postnatal 0 day (P0), 5 days (P5), 15 days (P15)], young [2 months (2M)], and mature [6 months (6M)] rabbits. Rabbits' ears were splinted and folded using adhesive fixation strips. Folding duration ranged from 1 day to 5 days to 10 days. Photographs were taken to calculate the retained fold angle. Cartilage morphology and extracellular matrix (ECM) content were examined histologically (using hematoxylin-eosin, Safranin O, elastic Van Gieson, and Masson's trichrome). Water content, DNA content, and cell density were also analyzed. Biomechanical properties were measured using a Nano indenter. RESULTS: Immature ears had smaller angles after strip removal, and the angled deformation lasted a longer time. Cartilage matrix compositions, including glycosaminoglycan (GAG), elastin fiber, and collagen, increased over development. The water content, DNA content, and cell density decreased with age. Young's modulus was significantly higher in mature cartilage. CONCLUSIONS: Here, we successfully established an animal model of ear molding and demonstrated that immature cartilage was associated with better plasticity. We also found that the cartilage's biomechanical property increased with the accumulation of ECM. The biomechanical change could underlie age-related shape plasticity. LEVEL OF EVIDENCE: NA Laryngoscope, 133:88-94, 2023.

Decidual macrophages in recurrent spontaneous abortion.

Recurrent spontaneous abortion (RSA) is defined as two or more pregnancy loss, affecting the happiness index of fertility couples. The mechanisms involved in the occurrence of RSA are not clear to date. The primary problem for the maternal immune system is how to establish and maintain the immune tolerance to the semi-allogeneic fetuses. During the pregnancy, decidual macrophages mainly play an important role in the immunologic dialogue. The purpose of this study is to explore decidual macrophages, and to understand whether there is a connection between these cells and RSA by analyzing their phenotypes and functions. Pubmed, Web of Science and Embase were searched. The eligibility criterion for this review was evaluating the literature about the pregnancy and macrophages. Any disagreement between the authors was resolved upon discussion and if required by the judgment of the corresponding author. We summarized the latest views on the phenotype, function and dysfunction of decidual macrophages to illuminate its relationship with RSA.

Surface astigmatism correction using segmented freeform surfaces for a progressive addition lens.

The undesired distribution of irregular surface astigmatism (SA) on the freeform surface has been the major concern of progressive addition lens (PAL) design. Herein, we proposed a segmented freeform surface (SFS) construction method, which relies on the lines of curvature to rule the surface segmentation and then eliminates the difference between principal curvatures to correct the SA. Based on ray tracing and numerical simulation results, the SFS-PAL design has superior performance in image quality within a dynamic field of view over the conventional freeform PAL. To verify the feasibility and the real performance of the new design, we used the diamond turning method with a fast tool servo to realize the rapid prototyping, and then used injection molding for the mass production of the high-quality SFS-PALs.

Using ear molding to correct auricular helix adhesion deformity.

Objectives: This study examined the effectiveness of Byrd's EarWell system for the treatment of auricular helix adhesion. Methods: The newborns with helix adhesion were treated with ear molding. The photos of pinna were taken before, during, and after the treatment. The immediate and long-term outcomes, as well as the complications, were assessed by two independent plastic surgeons. Study design: A retrospective study. Data on family history, neonatal weight, gestational age, delivery method, laterality, gender, age of initiating treatment, medical comorbidities, duration of treatment, and follow-up time were collected. Study site and period: From 2019 to 2021, infants treated with the EarWell System in the Eye and ENT Hospital of Fudan University were enrolled in this study. Results: A total of 46 newborns (66 ears) with helix adhesion were included. The average onset time of treatment was 4.57 ± 3.63 weeks. The average duration of treatment was 7.40 ± 2.05 weeks. 97.0% ears' (64/66) immediate results were excellent or good. During long-term follow-up, 95.5% ears achieved excellent or good outcomes. Age of initiation treatment significantly affected immediate (p = 0.001) and long-term (p = 0.004) outcomes. Conclusions: EarWell System was an effective method to correct auricular helix adhesion. Using this approach, patients with helix adhesion could avoid surgeries. Age of initiation treatment was the predictor of successful correction.

Structural basis for assembly and disassembly of the IGF/IGFBP/ALS ternary complex.

Insulin-like growth factors (IGFs) have pleiotropic roles in embryonic and postnatal growth and differentiation. Most serum IGFs are bound in a ternary complex with IGF-binding protein 3 (IGFBP3) and acid-labile subunit (ALS), extending the serum half-life of IGFs and regulating their availability. Here, we report cryo-EM structure of the human IGF1/IGFBP3/ALS ternary complex, revealing the detailed architecture of a parachute-like ternary complex and crucial determinants for their sequential and specific assembly. In vitro biochemical studies show that proteolysis at the central linker domain of IGFBP3 induces release of its C-terminal domain rather than IGF1 release from the ternary complex, yielding an intermediate complex that enhances IGF1 bioavailability. Our results provide mechanistic insight into IGF/IGFBP3/ALS ternary complex assembly and its disassembly upon proteolysis for IGF bioavailability, suggesting a structural basis for human diseases associated with IGF1 and IGFALS gene mutations such as complete ALS deficiency (ACLSD) and IGF1 deficiency.

Key Genes Identified in Nonsyndromic Microtia by the Analysis of Transcriptomics and Proteomics.

As one of the common birth defects worldwide, nonsyndromic microtia is a complex disease that results from interactions between environmental and genetic factors. However, the underlying causes of nonsyndromic microtia are currently not well understood. The present study determined transcriptomic and proteomic profiles of auricular cartilage tissues in 10 patients with third-degree nonsyndromic microtia and five control subjects by RNA microarray and tandem mass tag-based quantitative proteomics technology. Relative mRNA and protein abundances were compared and evaluated for their function and putative involvement in nonsyndromic microtia. A total of 3971 differentially expressed genes and 256 differentially expressed proteins were identified. Bioinformatics analysis demonstrated that some of these genes and proteins showed potential associations with nonsyndromic microtia. Thirteen proteins with the same trend at the mRNA level obtained by the integrated analysis were validated by parallel reaction monitoring analysis. Several key genes, namely, LAMB2, COMP, APOA2, APOC2, APOC3, and A2M, were found to be dysregulated, which could contribute to nonsyndromic microtia. The present study is the first report on the transcriptomic and proteomic integrated analysis of nonsyndromic microtia using the same auricular cartilage sample. Additional studies are required to clarify the roles of potential key genes in nonsyndromic microtia.

The Impact of Occupational Stigma on Gig Workers' Workplace Well-being: A Cross-sectional Study Based on the Platform-Based Food-Delivery Sector in China.

OBJECTIVE: In this article, the influence of occupational stigma on workplace well-being of platform-based food-delivery workers is examined. The mediation effect of work-contingent self-esteem and the moderating effect of job control are also assessed. METHODS: Questionnaire data from 362 platform-based food-delivery workers were gathered at three time points, and multiple regression analyses were used to test each hypothesis. RESULTS: Occupational stigma reduces workplace well-being of platform-based food-delivery workers, and this relationship is mediated by work-contingent self-esteem. Job control exerts a negative moderating effect on the relationship between occupational stigma and platform-based food-delivery workers' work-contingent self-esteem. CONCLUSIONS: Strategies for reducing occupational stigma should be prioritized to increase workplace well-being in gig workers. Giving them more control over their work will likely alleviate the detrimental effect of occupational stigma on work-contingent self-esteem.

The Course of Superficial Temporal Artery in Patients with Microtia and its Relationship with the Remnant.

OBJECTIVE: Temporoparietal fascia is important for auricular reconstruction or repair after auricular reconstruction. Thus, the course of the superficial temporal artery (STA) is of vital importance to prevent destruction of the artery. The purpose of this study was to evaluate the course of the superficial temporal artery in patients with congenital microtia and its relationship with remnants. METHODS: This was a prospective study. Patients with microtia who underwent auricular reconstruction in our hospital from January 2021 to July 2021 underwent ultrasound examination of the STA. Under the guidance of ultrasound, the superficial temporal artery and its branches were located and marked on the body surface before the operation, ranging from the zygomatic arch plane to the temporal parietal artery. In addition, the hemodynamics of the STAs were recorded. RESULTS: A total of 108 patients with microtia were collected, including 106 patients with unilateral microtia and 2 patients with bilateral microtia. There were 82 cases of lobule type, 21 cases of small concha type, and 7 cases of large concha type. The superficial temporal artery in 103 ears was divided into two branches: the parietal branch and the frontal branch, but there was only one branch in 7 ears. The parietal branch was absent in 5 cases, and the frontal branch was absent in 2 cases. In most of the ears, the bifurcation was located above the zygomatic arch plane. Only in 2 ears was the bifurcation located below the zygomatic arch, and the most common bifurcation position was the eyebrow arch level (43.7%). Regarding the shortest distances between the STA and the remnant, they were less than 0.5 cm in 47 ears, more than 1 cm in 30 ears, and 0.5 cm to 1 cm in 33 ears. CONCLUSION: The course of STA varied greatly and there were occasional single branches. The distances between the STA and remnant were often near 0.5 cm by ultrasonography. Therefore, when removing the remnant and separating the pocket, care should be taken to avoid arterial injury. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Removal of anti-nutritional factors of rapeseed protein isolate (RPI) and toxicity assessment of RPI.

We prepared a detoxified rapeseed protein isolate (RPI) by phytase/ethanol treatment based on alkaline extraction and acidic precipitation. Contents of protein, fat, ash, moisture, crude fiber, glucosinolates, phytic acid, and phenolics and color were determined. To evaluate the safety of detoxified RPI, five groups of C57 mice (detoxified RPI [10 and 20 g kg-1]; commercial soybean protein isolate (SPI) [10 g kg-1]; non-detoxified RPI [10 g kg-1]; control) were used in the acute-toxicity test. Bodyweight and pathology parameters were recorded at different time points, followed by macroscopic examination, organ-weight measurement and microstructure examination. After pretreatment of rapeseed meals with phytase (enzyme : substrate ratio, 1 : 5 mg g-1) for 1.5 h and two-time ethanol extraction for precipitated protein, the chemical characteristics in RPI were protein (88.26%), fat (0.57%), ash (2.72%), moisture (1.90%), crude fiber (0.77%), glucosinolates (0 µmol g-1), phytic acid (0.17%), phenolics (0.36%) and whiteness (73.38). Treatment resulted in significant removal of anti-nutritional factors (ANFs) and increased whiteness in detoxified RPI compared with non-detoxified RPI, and lower than in cruciferin-rich canola protein isolate (Puratein®). Experimental-related effects on bodyweight, clinical observations, or clinicopathology, in mice treated with detoxified RPI were not observed except for a decreased thyroid gland/parathyroid gland index in mice treated with non-detoxified RPI. Furthermore, the no-observed-effect level (NOEL) was 10 g kg-1 of detoxified RPI, whereas the no-observed-adverse-effect-level (NOAEL) was the highest fed level of 20 g kg-1 of detoxified RPI. Overall, detoxified RPI prepared by the combined treatment of phytase and ethanol was considered safe under the conditions tested, in which the contents of the main ANFs were reduced significantly.