Residual velopharyngeal insufficiency (VPI) after primary cleft palate repair continues to impair speech, psychosocial functioning, and overall quality of life (QOL). Although VPI surgery is a standard intervention, further evidence is needed regarding its impact on patient-reported outcomes (PROMs) and the clinical factors associated with postoperative quality-of-life improvement. This study evaluated changes in VPI-related QOL before and after secondary VPI surgery using the validated Velopharyngeal Insufficiency Effects on Life Outcomes (VELO) instrument, contextualized these findings using a reference group with velopharyngeal competence (VPC), and identified key clinical determinants of postoperative QOL. A retrospective study was conducted on 170 participants, including 85 patients with residual VPI undergoing secondary palatoplasty and 85 participants with established VPC. Certified cleft specialists assessed speech and functional outcomes, while QOL was measured using the validated Chinese version of the VELO instrument. Postoperative speech and VELO assessments were conducted at a mean follow-up of 5.7 ± 4.0 years after surgery. Statistical analyses included Chi-square, Wilcoxon rank, and Mann–Whitney U tests; multivariate logistic regression identified predictors of inadequate postoperative QOL. At baseline, VPI patients demonstrated significantly poorer speech performance, higher oronasal fistula (ONF) rates, and lower VELO scores than the reference group (all P < 0.001). Following surgery, ONF rates declined from 27.1

This study aimed to compare the outcomes of different muscle reconstruction techniques with or without primary rhinoplasty (PR) in unilateral incomplete cleft lip repair patients. The study included 73 patients, with 36 patients undergoing traditional reconstruction techniques and 37 patients receiving the novel reconstruction technique. All patients wore nasal molds for 1 year after the primary surgery. Nasal and labial symmetry was evaluated using 12 indicators, based on two-dimensional photographs taken preoperatively, at 7 days postoperatively, and at 3-year follow-ups. The results at 7 days postoperatively indicated that the novel reconstruction method showed superior nasal symmetry in terms of nostril width ratio (p < 0.001) and nasal base ratio (p = 0.010) compared with the traditional reconstruction method. The 3-year follow-up results demonstrated that the novel reconstruction method also achieved better nasal symmetry in terms of nostril height ratio (p = 0.045), nostril width ratio (p = 0.023), nasal base ratio (p = 0.012), and columellar angle (p = 0.038) than the traditional reconstruction method. Both techniques performed equally well in terms of labial symmetry. In conclusion, although without PR, the novel muscle reconstruction technique showed better long-term outcomes and more significant improvements in nasal symmetry compared with traditional repair using the Tajima technique.

OBJECTIVES:We evaluated the long-term impact of a two-stage bone grafting technique on nasal morphology in patients with unilateral cleft lip and palate (UCLP) who missed the optimal timing for alveolar bone grafting. METHODS:We retrospectively analyzed 148 patients with UCLP (≥12 years) who underwent secondary nasolabial repair between 2018 and 2022. Patients were categorized into three groups: non-grafting repair (n=50), conventional secondary alveolar bone grafting (SABG, n=50), and two-stage bone grafting (n=48). Nasal morphology was assessed using standardized two-dimensional photogrammetry at baseline and at least 3 years postoperatively. RESULTS:At 3 years, the two-stage grafting group exhibited superior outcomes in nasal morphology. In terms of nasal symmetry, the columellar angle improved to a mean of 86.99° (vs. 84.43° in conventional SABG, p<0.05). Key indicators for alar base form also showed improvement: the nasal alar base internal angle was 133.52° (vs. 137.04°, p<0.05) and nasal alar base angle was 1.58° (vs. 2.10°, p<0.05). No significant differences existed between the conventional SABG and non-grafting groups (all p>0.05). Safety was excellent across all the groups. CONCLUSIONS:For late-presenting patients with UCLP, two-stage bone grafting offers more effective and lasting correction of secondary nasal deformities than conventional SABG or non-grafting methods.

During the development of oral squamous cell carcinoma (OSCC), multiple danger signals can initiate chronic oral mucosal inflammation, which then gives rise to precancerous and cancerous lesions. Modulation of immune homeostasis is essential to intercept inflammation-driven OSCC. In this study, we aimed to identify key inflammatory danger signals involved in precancerous oral mucosal inflammation and to develop a locally applicable immunomodulatory strategy to prevent this precancerous inflammation. We first identified that saliva cell-free DNA (cfDNA) levels and cfDNA-induced TLR9 activation were linked to OSCC development and progression. Hypothesizing that removing cfDNA would be beneficial for OSCC prevention, we created a cationic nanoparticles-enabled mouthwash that regulates precancerous inflammation via removing negatively charged cfDNA. Both cationic nanoparticles and polymers inhibited the in vitro cellular proinflammatory response induced by plasma from OSCC patients and suppressed OSCC patient plasma-induced tumor cell migration and stemness. In the precancerous mouse model, cationic nanoparticles-enabled mouthwash alleviated oral mucosal inflammation via inhibiting TLR9 activation. Overall, our study highlights the role of cfDNA in OSCC progression and the potential of cationic nanoparticle-enabled mouthwash for treating OSCC-related precancerous oral mucosal inflammation.

This retrospective study analyzed clinical characteristics and surgical outcome predictors in 676 patients with submucous cleft palate (SMCP) treated between 2008 and 2025. Patients were stratified by palatal morphology to evaluate velopharyngeal function and articulation. Among 183 patients surgically treated for velopharyngeal insufficiency (VPI), postoperative cure rates were assessed using regression analysis. Preoperatively, 52.96% of the cohort presented with VPI. Palatal morphology significantly correlated with function; the bifid uvula subtype exhibited the highest rate of velopharyngeal competence (49.60%), while the palatal fistula subtype had the lowest (16.67%). Crucially, analysis of surgical outcomes identified younger age as the sole significant predictor of achieving competence (median age 5.83 years for cured versus 10.00 for non-cured patients; P = 0.002). The odds of an unfavorable outcome increased by approximately 9% for each additional year of age. While specific morphologies, such as the translucent zone with bifid uvula, and severe hypernasality impacted prognosis, surgical timing proved paramount. These findings emphasize that while morphology and articulation status aid initial assessment, early diagnosis and timely intervention are the most critical factors for optimizing speech outcomes in SMCP patients.

ObjectiveTo compare speech outcomes following primary cleft palate repair using modified Sommerlad palatoplasty (MSP) versus Sommerlad-Furlow modified palatoplasty (SFP).DesignRetrospective cohort study.SettingA high-volume tertiary cleft center.PatientsPatients who underwent primary cleft palate repair before 5 years of age between 2011 and 2021 were retrospectively reviewed.ParticipantsPatients treated with MSP or SFP and with complete follow-up records were included. Participants were stratified by age at surgery as younger than 1.5 years or 1.5 years and older.InterventionsPrimary cleft palate repair with MSP or SFP.Main Outcome Measure(s)Postoperative speech outcomes, particularly velopharyngeal competence (VPC), and factors associated with speech performance.ResultsA total of 1265 patients were included, of whom 874 underwent surgery before 1.5 years of age and 391 at 1.5 years or older. In the younger group, surgical technique and cleft type were significantly associated with speech outcomes. After adjustment for baseline differences, SFP achieved a significantly higher VPC rate than MSP in patients with Veau III cleft palate (84.4% vs 73.0%, P = .027). In the older group, sex, cleft type, and surgical technique were not significantly associated with speech outcomes.ConclusionsIn this cohort, speech outcomes after primary palatoplasty were influenced by surgical technique and cleft type. For patients with Veau III cleft palate who underwent repair before 1.5 years of age, SFP was associated with superior speech outcomes compared with MSP.

Background:Despite the global popularity of minimally invasive thread lifts, the absence of standardized protocols has led to significant variations in outcomes. This study establishes China's first expert consensus (T/CAPA 009-2023) on facial thread lift techniques, addressing critical gaps in operator training, material selection, and anatomical precision. Methods:A multidisciplinary panel analyzed 2,143 PPDO thread procedures (2018-2022) across 35 institutions. The consensus framework integrates: 1) Graded facility/operator requirements (Grade III device management), 2) Anatomical stratification (SMAS, fat layers, ligament anchoring), and 3) Region-specific protocols (upper/mid/lower face, neck) with 14 illustrated surgical designs. Conclusion:Multicenter data and anatomical studies demonstrate that this consensus framework improves thread lift safety and efficacy, though further RCTs are warranted to confirm long-term outcomes The hierarchical protocol serves as a global benchmark for aesthetic training programs, particularly in Asian facial anatomy.

ObjectiveTo investigate the association between Wnt signaling pathway genes and non-syndromic orofacial cleft (NSOC) in the Han Chinese population.DesignBased on a previously published genome-wide association study (GWAS), we performed a discovery phase analysis on 635 QC-passed SNPs (out of 7054 initially extracted from 59 Wnt pathway genes). Significant loci were then validated in an independent replication cohort.SettingA specialized craniofacial surgery center within a tertiary care institution.Patients/ParticipantsIn the discovery phase, we extracted the genotype data of 2512 NSOC cases and 2255 controls from two previous published GWASs. The independent replication cohort included 2724 patients with NSOC and 1263 healthy controls, all of Han Chinese descent.InterventionsNo clinical interventions were applied; the study involved genetic data analysis only.Main Outcome MeasuresSNPs associated with NSOC and its subtypes were identified through allelic and genotypic association analyses, with odds ratios (ORs), 95% confidence intervals (CIs), and P-values calculated.ResultsIn the independent replication cohort, rs4821611 in RAC2 was significantly associated with NSOC (P = 5.8 × 10-7, OR = 0.77, 95% CI: 0.70-0.85), NSCL/P (P = 4.4 × 10-11, OR = 0.68, 95%CI: 0.61-0.77), and NSCLO (P = 3.27 × 10-15, OR = 0.6, 95% CI: 0.53-0.68). Genotypic analysis confirmed these associations. rs757190 in WNT3 was also associated with NSCLP (P = 0.00056, OR = 0.78, 95% CI: 0.67-0.90).Conclusionsrs4821611 in RAC2 and rs757190 in WNT3 are associated with NSOC and its subtypes in the Han Chinese population, supporting a role for Wnt signaling in cleft pathogenesis.

Secondary narrow nostril deformity after unilateral cleft lip repair remains a stubborn clinical challenge, with an incidence of approximately 84%. It compromises both nasal airway function and facial esthetics. The etiology is multifactorial, involving congenital tissue deficiencies, abnormal orbicularis oris insertion, and iatrogenic deformities resulting from primary repair. Current reconstructive approaches can be broadly categorized into tissue augmentation, structural reinforcement, and contour-modifying strategies, with postoperative nasal retainers serving as a key adjunct device. Although studies have suggested benefits in improving nasal symmetry and airway patency, variability in surgical indications and outcomes has hindered the establishment of a unified consensus. The authors provide an overview of current surgical strategies and postoperative management for secondary narrow nostril deformity, aiming to support more precise treatment planning and improved surgical results.

OBJECTIVES:This study aims to evaluate the healing process and identify risk factors associated with delayed healing and outcomes. METHODS:1355 consecutive participants with nonsyndromic cleft palate, treated with the Sommerlad-Furlow modified palatoplasty. Sixteen variables were recorded including sex, age, cleft type (Veau class), surgeons' qualification, antibiotics, relaxing incision (RI), postoperative upper respiratory tract infection (PURI), preoperative leukocyte count, preoperative hemoglobin (HGB), the cleft width, inter maxillary tuberosity width, the cleft ratio, operation duration, the initial time of poor healing wound observed after surgery, depth and location of the poor healing wound. RESULTS:In total, 1148 patients demonstrated normal healing (84.7%, 1148/1355), while 207 patients exhibited delayed wound healing issues (15.3%, 207/1355), among whom 131 healed within 3 months (9.7%, 131/1355; 63.3%, 131/207), 15 healed after 3 months and within 6 months (1.1%, 15/1355; 7.2%, 15/207), and fistula remained after 6 months in 61 patients (4.5%, 61/1355; 29.5%, 61/207). A total of 1294 (95.5%, 1294/1355) of the participants had healed palatal wounds after 6 months postoperatively. Surgeons' qualifications, PURI, the cleft width, cleft ratio, and operation duration were significantly different in the delayed healing group. CONCLUSIONS:Preoperative measurement of the cleft ratio might help the cleft surgeons to predict the palate healing outcome. Surgeons' improved operation skills, shortened operation duration, and prevention of PURI were supposed to reduce the occurrence of poor wound healing. Moreover, focusing on delayed wound depth and location is critical for estimating the process and outcomes of delayed healing. LEVEL OF EVIDENCE: 2:

ObjectiveTo investigate Aristaless-like homeobox 4 (ALX4), a paired-like homeodomain transcription factor essential for craniofacial morphogenesis, as a susceptibility gene for non-syndromic orofacial cleft (NSOC) and to explore its potential regulatory mechanisms in the Han Chinese population.DesignA two-stage case-control genetic association study complemented by exploratory RNA sequencing (RNA-seq) and functional validation.SettingTertiary medical center for orofacial cleft treatment in western China.Patients, ParticipantsDiscovery phase: 2512 NSOC patients and 2255 controls. Replication phase: 2724 NSOC patients and 1263 controls. RNA-seq: 6 patients with non-syndromic cleft lip only (NSCLO) and 2 lip trauma controls. Real-time quantitative PCR (RT-qPCR) validation: 5 NSCLO patients and 5 controls.Interventions: Genotyping of 76 tag single-nucleotide polymorphisms (SNPs) within the ALX4 gene region using the SNPscan method, with three SNPs selected for independent replication. Exploratory RNA-seq of lip tissues, RT-qPCR validation, and dual-luciferase reporter assays.Main Outcome Measure(s)Allelic and genotypic associations between ALX4 variants and NSOC subtypes; differential expression of ALX4 and hsa-miR-455-3p in NSCLO tissues; functional validation of microRNA-target interactions.ResultsMultiple ALX4 SNPs showed significant associations with NSOC subtypes after Bonferroni correction (P < 6.58 × 10-4). rs3861063 demonstrated consistent protective effects for microform cleft lip across both phases. ALX4 and hsa-miR-455-3p were upregulated in NSCLO tissues, confirmed by RT-qPCR. Dual-luciferase assays confirmed that hsa-miR-455-3p directly targets the ALX4 3'UTR (untranslated region), though paradoxical co-upregulation suggests complex regulatory mechanisms.ConclusionsALX4 is a novel NSOC susceptibility gene in Han Chinese, with subtype-specific genetic associations and a complex regulatory interaction involving hsa-miR-455-3p, expanding our understanding of NSOC genetic architecture.

OBJECTIVES:Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect influenced by genetic and environmental factors, with genetic factors playing a major role. This study aims to investigate the association between the dystrophin (DMD) gene and NSCL/P in a Chinese Han population. METHODS:Four tag single nucleotide polymorphisms (SNPs) in the DMD gene were selected and allelic and genotype-based association analyses were performed on 1 780 patients with NSCL/P and 1 823 normal controls. RESULTS:Comparison with the controls showed that patients with NSCL/P presented three SNPs (rs5971698, rs5928208, and rs5972815) with significant associations with NSCL/P or its subphenotypes. Allelic association analysis revealed that rs5971698 was associated with NSCL/P, unilateral cleft lip with or without cleft palate (UCL/P), left cleft lip with or without cleft palate (LCL/P), unilateral cleft lip and cleft palate (UCLP), left cleft lip and cleft palate (LCLP), unilateral cleft lip (UCL), and left cleft lip only (LCL) (P<0.05); rs5928208 was associated with non-syndromic cleft lip and cleft palate (NSCLP), bilateral cleft lip with or without cleft palate (BCL/P), LCL/P, bilateral cleft lip and cleft palate (BCLP), and LCL (P<0.05); and rs5972815 was associated with UCLP, UCL, and right cleft lip only (RCL)(P<0.05), exhibiting significant laterality bias. Genotype analysis further confirmed these associations. Functional predictions suggested that different alleles at rs5928208 and rs5972815 may influence transcription factor binding affinity. CONCLUSIONS:This study identified associations between SNPs in the DMD gene and NSCL/P in a Western Chinese Han population, providing new evidence for distinct genetic susceptibility loci among NSCL/P subtypes.

ObjectiveGenome-wide association studies have identified over 80 loci associated with nonsyndromic orofacial cleft (NSOC), yet substantial heritability remains unexplained. Insights from syndromic orofacial cleft (SOC) implicated genes could help bridge this gap.DesignA case-control association study in a Han Chinese cohort was conducted to evaluate the association between SOC-implicated genes and NSOC subtypes using association, linkage disequilibrium (LD), and haplotype analyses.SettingTertiary medical center.Patients, ParticipantsThe study included 1626 cases of non-syndromic cleft lip with or without cleft palate, 930 cases of non-syndromic cleft palate only, and 2255 controls.InterventionsPeripheral blood (cases) and umbilical cord blood (controls) were collected for DNA extraction.Main Outcome MeasuresAllelic (Pearson' s χ2, 1 df) and genotypic (Pearson' s χ2, 2 df) associations between SNPs and NSOC subtypes were evaluated, with odds ratios (ORs) and 95% confidence intervals (CIs). LD and sliding-window haplotype association analyses were performed in Haploview. SNPs with minor allele frequency (MAF) >0.05 and in Hardy-Weinberg equilibrium in controls were analyzed. The significance threshold was P < 1.27 × 10-5 after Bonferroni correction.ResultsAllelic analysis identified 23 SNPs that were significantly associated with NSOC subtypes (lowest P = 2.02 × 10-22). Genotypic analysis identified 39 significant SNPs (lowest P = 1.09 × 10-36). Signals mapped to 7 genes. Haplotype analyses revealed a shared causal variant block at MYMK and TWIST2, and allelic heterogeneity at NEDD4L.ConclusionsWe identified MYMK, TWIST2, and NEDD4L as NSOC-associated genes. Using SOC genes as prior knowledge reveals loci missed by standard GWAS, offering key insights into NSOC pathogenesis.

ObjectiveTo systematically characterize anatomical, histopathological and ultrastructural alterations of perioral and velopharyngeal muscles in patients with nonsyndromic cleft lip and/or palate (CL/P).DesignSystematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines.SettingSystematic literature search of PubMed, EMBASE, Scopus, CNKI, Cochrane Database of Systematic Reviews, and gray literature sources (ClinicalTrials.gov, International Clinical Trials Registry Platform, Conference Proceedings Citation Index-Science, ProQuest Dissertations and Theses, GreyNet International) from January 1980 to June 2025, supplemented by manual reference screening.PatientsPatients with nonsyndromic CL/P of any age, sex, or cleft severity. Comparator groups included individuals without CL/P or nonaffected contralateral sides.Interventions:Not applicable. This review synthesized observational evidence from cohort, case-control, and cross-sectional studies.Main Outcome(s)Morphological characteristics (imaging and cadaveric dissection), and histopathological features (light microscopy and histochemical staining) of cleft-affected perioral and velopharyngeal muscles.ResultsA total of 21 studies were included. Anatomical investigations consistently demonstrated ectopic muscle insertions, aberrant fiber orientation, and muscle hypoplasia in both the lip and velopharyngeal musculature. Histopathological analyses revealed fiber disorganization, increased myofiber diameter variability, extensive interstitial fibrosis, mitochondrial dysfunction, and, in some studies, a shift toward type II fiber predominance. But the ultrastructural findings are limited to a small number of studies with inconsistent results, yielding low confidence. Methodological heterogeneity and risk of bias precluded meta-analysis. Confidence in findings, assessed using CERQual, was high for anatomical outcomes and moderate for histopathological features.ConclusionsPerioral and velopharyngeal muscles in patients with CL/P exhibit distinct but incompletely characterized pathological alterations. Future research should clarify muscle-specific pathology, regenerative dynamics, and clinically relevant strategies that may improve long-term functional recovery after cleft repair.RegistrationPROSPERO CRD420251115465.

OBJECTIVE:Lithium chloride (LiCl) induces cleft palate by disrupting palatal shelf elevation, but the underlying metabolic mechanisms remain unclear. This study aims to investigate these mechanisms using an integrated multi-omics approach. DESIGN:A LiCl-induced cleft palate mouse model was established by intraperitoneal injection of LiCl (0.4 mg/g/day) from embryonic day (E) 10.5 to E13.5. Palatal shelves were collected at E16.5 for targeted metabolomics using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and transcriptome sequencing. Integrated pathway analysis was performed to identify key pathways. Immunofluorescence, reverse transcription quantitative PCR (RT-qPCR), and Hydroxyproline assay validated findings in vivo and in human embryonic palatal mesenchymal (HEPM) cells. Further temporal analysis was conducted at E13.5, E14.0, and E14.5 to identify the key stage. RESULTS:In LiCl-induced cleft palate mice, multi-omics identified 24 differentially abundant metabolites and 595 differentially expressed genes, with arginine and proline metabolism as the most enriched pathway. Within this pathway, 4-Hydroxyproline was downregulated, proline was upregulated, accompanied by downregulation of P4HA3, a key enzyme for 4-Hydroxyproline synthesis. Immunofluorescence revealed increased β-catenin and decreased P4HA3 in cleft palate tissues, with partial colocalization. Temporal analysis showed these changes became significant at E14.0, coinciding with disrupted palatal elevation. In vitro, LiCl simultaneously upregulated β-catenin and downregulated P4HA3 in HEPM cells. CONCLUSION:LiCl-induced cleft palate in mice involves β-catenin-associated downregulation of P4HA3, which contributes to a reduction in 4-Hydroxyproline and impaired palatal elevation. These findings reveal a novel metabolic mechanism in cleft palate pathogenesis.