Predicting skin cancer risk from facial images with an explainable artificial intelligence (XAI) based approach: a proof-of-concept study.

Background: Efficient identification of individuals at high risk of skin cancer is crucial for implementing personalized screening strategies and subsequent care. While Artificial Intelligence holds promising potential for predictive analysis using image data, its application for skin cancer risk prediction utilizing facial images remains unexplored. We present a neural network-based explainable artificial intelligence (XAI) approach for skin cancer risk prediction based on 2D facial images and compare its efficacy to 18 established skin cancer risk factors using data from the Rotterdam Study. Methods: The study employed data from the Rotterdam population-based study in which both skin cancer risk factors and 2D facial images and the occurrence of skin cancer were collected from 2010 to 2018. We conducted a deep-learning survival analysis based on 2D facial images using our developed XAI approach. We subsequently compared these results with survival analysis based on skin cancer risk factors using cox proportional hazard regression. Findings: Among the 2810 participants (mean Age = 68.5 ± 9.3 years, average Follow-up = 5.0 years), 228 participants were diagnosed with skin cancer after photo acquisition. Our XAI approach achieved superior predictive accuracy based on 2D facial images (c-index = 0.72, 95% CI: 0.70-0.74), outperforming that of the known risk factors (c-index = 0.59, 95% CI 0.57-0.61). Interpretation: This proof-of-concept study underscores the high potential of harnessing facial images and a tailored XAI approach as an easily accessible alternative over known risk factors for identifying individuals at high risk of skin cancer. Funding: The Rotterdam Study is funded through unrestricted research grants from Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. G.V. Roshchupkin is supported by the ZonMw Veni grant (Veni, 549 1936320).

Bone health index in the assessment of bone health: The Generation R Study.

Bone Health Index (BHI) has been proposed as a useful instrument for assessing bone health in children. However, its relationship with fracture risk remains unknown. We aimed to investigate whether BHI is associated with bone mineral density (BMD) and prevalent fracture odds in children from the Generation R Study. We also implemented genome-wide association study (GWAS) and polygenic score (PGS) approaches to improve our understanding of BHI and its potential. In total, 4150 children (49.4 % boys; aged 9.8 years) with genotyped data and bone assessments were included in this study. BMD was measured across the total body (less head following ISCD guidelines) using a GE-Lunar iDXA densitometer; and BHI was determined from the hand DXA scans using BoneXpert®. Fractures were self-reported collected with home questionnaires. The association of BHI with BMD and fractures was evaluated using linear models corrected for age, sex, ethnicity, height, and weight. We observed a positive correlation between BHI and BMD (ρ = 0.32, p-value<0.0001). Further, every SD decrease in BHI was associated with an 11 % increased risk of prevalent fractures (OR:1.11, 95 % CI 1.00-1.24, p-value = 0.05). Our BHI GWAS identified variants (lead SNP rs1404264-A, p-value = 2.61 × 10-14) mapping to the ING3/CPED1/WNT16 locus. Children in the extreme tails of the BMD PGS presented a difference in BHI values of -0.10 standard deviations (95% CI -0.14 to -0.07; p-value<0.0001). On top of the demonstrated epidemiological association of BHI with both BMD and fracture risk, our results reveal a partially shared biological background between BHI and BMD. These findings highlight the potential value of using BHI to screen children at risk of fracture.

Personalizing dental screening and prevention protocols in dentulous patients with oropharyngeal cancer undergoing radiotherapy: A retrospective cohort study.

Objectives: Patients with head and neck cancer are routinely screened for dental foci prior to radiotherapy (RT) to prevent post- RT tooth extractions associated with an increased risk of osteoradionecrosis. We evaluated the risk factors for post-RT tooth extraction to personalise dental screening and prevention protocols prior to RT. Materials and methods: This retrospective cohort study included dentulous patients diagnosed with oropharyngeal cancer who had undergone radiation therapy at doses 60-70 Gy and achieved a disease-free survival of ≥ 1 year (N = 174). Risk factors were assessed using Cox regression models. Results: The cumulative incidence of post-RT tooth extraction was 30.7 % at 5 years. Main indications for extraction (n = 62) were radiation caries (n = 20) and periodontal disease (n = 27). Risk factors associated (p < 0.05) with radiation caries-related extractions included active smoking, alcohol abuse, poor oral hygiene, parotid gland irradiation, and mandibular irradiation. A high-dose volume in the mandible was associated with periodontal disease events. Conclusion: Post-RT extractions due to radiation caries were influenced by lifestyle factors and RT dose in the mandible and parotid glands. Periodontal disease-related extractions were primarily associated with the mandibular dose. During dental screening these post-RT risk factors should be taken into account to prevent osteoradionecrosis.

Developmental characteristics of the permanent upper lateral incisor in unilateral cleft lip and palate.

OBJECTIVES: This study aims to provide insights into the developmental characteristics of the upper lateral incisor in individuals with unilateral clefts. MATERIALS AND METHODS: Panoramic radiographs of a consistent group of Caucasian children taken over time (ages 6, 9, and 12) were extensively reviewed. The study assessed the distribution pattern, eruption path, tooth development, and crown size of the upper lateral incisor within the cleft region. RESULTS: The most commonly observed distribution pattern was the lateral incisor located distal to the cleft, accounting for 49.2% of cases. Furthermore, a significant delay in tooth development of the upper lateral incisor on the cleft side was noted at ages 6 and 9 (p > 0.001). Compared with the non-cleft side, these incisors often erupted along the alveolar cleft and exhibited microdontia (88.3%, p < 0.041). CONCLUSION: Lateral incisors on the cleft side display unique distribution patterns, microdontia, and delayed tooth development. Careful monitoring of the cuspid eruption is essential, as it can influence the eruption of the lateral incisor. CLINICAL RELEVANCE: A comprehensive understanding of the development of the upper lateral incisor relative to the cleft is vital for determining its prognosis over time. The position of the upper lateral incisor can also influence the timing and prognosis of secondary alveolar bone grafting. Preserving the upper lateral incisor favors arch length, perimeter, and symmetry in individuals with unilateral clefts.

Bone formation by human paediatric marrow stromal cells in a functional allogeneic immune system.

Allogeneic stem-cell based regenerative medicine is a promising approach for bone defect repair. The use of chondrogenically differentiated human marrow stromal cells (MSCs) has been shown to lead to bone formation by endochondral ossification in immunodeficient pre-clinical models. However, an insight into the interactions between the allogeneic immune system and the human MSC-derived bone grafts has not been fully achieved yet. The choice of a potent source of MSCs isolated from pediatric donors with consistent differentiation and high proliferation abilities, as well as low immunogenicity, could increase the chance of success for bone allografts. In this study, we employed an immunodeficient animal model humanised with allogeneic immune cells to study the immune responses towards chondrogenically differentiated human pediatric MSCs (ch-pMSCs). We show that ch-differentiated pMSCs remained non-immunogenic to allogeneic CD4 and CD8 T cells in an in vitro co-culture model. After subcutaneous implantation in mice, ch-pMSC-derived grafts were able to initiate bone mineralisation in the presence of an allogeneic immune system for 3 weeks without the onset of immune responses. Re-exposing the splenocytes of the humanised animals to pMSCs did not trigger further T cell proliferation, suggesting an absence of secondary immune responses. Moreover, ch-pMSCs generated mature bone after 8 weeks of implantation that persisted for up to 6 more weeks in the presence of an allogeneic immune system. These data collectively show that human allogeneic chondrogenically differentiated pediatric MSCs might be a safe and potent option for bone defect repair in the tissue engineering and regenerative medicine setting.

Non-Surgical Respiratory Management in Relation to Feeding and Growth in Patients with Robin Sequence; a Prospective Longitudinal Study.

OBJECTIVE: To reflect upon our non-surgical respiratory management by evaluating clinical outcomes regarding airway, feeding, and growth during the first year of life in patients with Robin Sequence. DESIGN: Prospective study. SETTING: Sophia Children's Hospital, Rotterdam, the Netherlands. PATIENTS/ PARTICIPANTS: 36 patients with Robin Sequence who were treated between 2011 and 2021. INTERVENTIONS: Positional therapy and respiratory support. MAIN OUTCOME MEASURE(S): Data on respiratory outcomes included polysomnography characteristics and capillary blood gas values. Feeding outcomes were based on the requirement of additional tube feeding. Outcomes on growth were expressed as standard-deviation-scores (SDS) for weight-for-age (WFA) and height-for-age (HFA). RESULTS: Twenty patients were treated with positional therapy (PT), whilst the other 16 patients required respiratory support. Twenty-two patients presented with non-isolated Robin Sequence (RS). During the first year of life, obstructive apnea hypopnea index decreased, oxygen levels enhanced, and capillary blood gas values improved. Eighty-six percent (31/36) experienced feeding difficulties, which completely resolved in 71% (22/31) during their first year of life. From start treatment, to stop treatment, to the age of 1 year, the SDS WFA worsened from -0.40 to -0.33 to -1.03, respectively. CONCLUSIONS: Non-surgical respiratory treatment resulted in an improvement of respiratory outcomes to near normal during the first year of life in patients with RS. These patients often experience feeding difficulties and endure impaired weight gain up to 1 year of age, despite near normalization of breathing. The high prevalence of feeding difficulties and impaired weight for age indicate the urgency for early recognition and adequate treatment to support optimal growth.

Adherence to dietary guidelines and dental caries among children: a longitudinal cohort study.

BACKGROUND: Even though dietary sugars are the most important nutrient for caries development, the disease process is dependent on other dietary practices. The intake of individual nutrient components cannot be evaluated separately from the overall diet which includes other nutrients, foods and habits. Therefore, the aim of this study was to investigate the association between adherence to dietary guidelines and dental caries. METHODS: This study was embedded in the Generation R Study, conducted in Rotterdam, the Netherlands. In total, 2911 children were included in the present analyses. Dietary intake at the age of 8 years was assessed using food-frequency questionnaires. Diet quality scores were estimated, reflecting adherence to Dutch dietary guidelines. Dental caries was assessed at the age of 13 years using intra-oral photographs. Associations were estimated using multinomial logistic regression analyses, adjusted for sociodemographic characteristics and oral hygiene practices. RESULTS: The prevalence of dental caries at the age of 13 years was 33% (n = 969). Better diet quality was associated with a lower occurrence of severe dental caries after adjustments for sociodemographic factors [e.g. highest vs. lowest quartile of diet quality: odds ratio (OR) 0.62, 95% confidence interval (CI) 0.39-0.98]. After additional adjustments for oral hygiene practices, this association was not statistically significant (OR 0.65, 95% CI 0.41-1.03). CONCLUSION: Adherence to dietary guidelines has the potential to reduce dental caries in children; however, with proper oral hygiene practices, this relationship might be attenuated. To understand the role of dietary patterns and dental caries, the contributing role of daily eating occasions needs to be studied further.

Three-dimensional dento-skeletal effects of mandibular midline distraction and surgically assisted rapid maxillary expansion: A retrospective study.

It was the aim of the study to provide a three-dimensional evaluation of dento-skeletal effects following bone-borne vs tooth-borne mandibular midline distraction (MMD) and tooth-borne surgically assisted rapid maxillary expansion (SARME). A retrospective observational study was conducted. Cone beam computed tomography (CBCT) records were taken pre-operatively (T1), immediately post-distraction (T2) and 1 year post-operatively (T3). All included 30 patients had undergone MMD (20 bone-borne MMD; 10 tooth-borne MMD). A total of 20 bone-borne MMD and 8 tooth-borne MMD patients had simultaneously undergone tooth-borne SARME. At T1 vs T3, canine (p = 0.007; 26.0 ± 2.09 vs 29.2 ± 2.02) and first premolar (p = 0.005; 33.8 ± 2.70 vs 37.0 ± 2.43) showed significant expansion on the tip level for tooth-borne MMD. This was no significant on the apex level, indicating tipping. Bone-borne MMD showed a parallel distraction gap, whereas tooth-borne MMD showed a V-shape. There was a significant (p = 0.017; 138 ± 17.8 vs 141 ± 18.2) inter-condylar axes increase for bone-borne MMD. In conclusion, bone-borne vs tooth-borne MMD and tooth-borne SARME showed stable dento-skeletal effects at 1 year post-operatively. Bone-borne and tooth-borne MMD seemed not to be superior to each other. The choice of distractor type therefore depends more on anatomical and comfort factors.

Oral and craniofacial research in the Generation R study: an executive summary.

OBJECTIVES: Oral conditions are of high prevalence and chronic character within the general population. Identifying the risk factors and determinants of oral disease is important, not only to reduce the burden of oral diseases, but also to improve (equal access to) oral health care systems, and to develop effective oral health promotion programs. Longitudinal population-based (birth-)cohort studies are very suitable to study risk factors on common oral diseases and have the potential to emphasize the importance of a healthy start for oral health. In this paper, we provide an overview of the comprehensive oral and craniofacial dataset that has been collected in the Generation R study: a population-based prospective birth cohort in the Netherlands that was designed to identify causes of health from fetal life until adulthood. METHODS: Within the multidisciplinary context of the Generation R study, oral and craniofacial data has been collected from the age of 3 years onwards, and continued at the age of six, nine, and thirteen. Data collection is continuing in 17-year-old participants. RESEARCH OUTCOMES: In total, the cohort population comprised 9749 children at birth, and 7405 eligible participants at the age of seventeen. Based on questionnaires, the dataset contains information on oral hygiene, dental visits, oral habits, oral health-related quality of life, orthodontic treatment, and obstructive sleep apnea. Based on direct measurements, the dataset contains information on dental caries, developmental defects of enamel, objective orthodontic treatment need, dental development, craniofacial characteristics, mandibular cortical thickness, and 3D facial measurements. CONCLUSIONS: Several research lines have been set up using the oral and craniofacial data linked with the extensive data collection that exists within the Generation R study. CLINICAL RELEVANCE: Being embedded in a multidisciplinary and longitudinal birth cohort study allows researchers to study several determinants of oral and craniofacial health, and to provide answers and insight into unknown etiologies and oral health problems in the general population.

Evaluation of AR visualization approaches for catheter insertion into the ventricle cavity.

Augmented reality (AR) has shown potential in computer-aided surgery. It allows for the visualization of hidden anatomical structures as well as assists in navigating and locating surgical instruments at the surgical site. Various modalities (devices and/or visualizations) have been used in the literature, but few studies investigated the adequacy/superiority of one modality over the other. For instance, the use of optical see-through (OST) HMDs has not always been scientifically justified. Our goal is to compare various visualization modalities for catheter insertion in external ventricular drain and ventricular shunt procedures. We investigate two AR approaches: (1) 2D approaches consisting of a smartphone and a 2D window visualized through an OST (Microsoft HoloLens 2), and (2) 3D approaches consisting of a fully aligned patient model and a model that is adjacent to the patient and is rotationally aligned using an OST. 32 participants joined this study. For each visualization approach, participants were asked to perform five insertions after which they filled NASA-TLX and SUS forms. Moreover, the position and orientation of the needle with respect to the planning during the insertion task were collected. The results show that participants achieved a better insertion performance significantly under 3D visualizations, and the NASA-TLX and SUS forms reflected the preference of participants for these approaches compared to 2D approaches.

Optimizing the Psychosocial Function Measures in the International Consortium for Health Outcomes Measurement Standard Set for Cleft.

BACKGROUND: To ensure the feasibility of implementing PROMs in clinical practice, they must be continually appraised for undue burden placed on patients and clinicians and their usefulness for decision-making. This study assesses correlations between the CLEFT-Q psychosocial scales in the International Consortium for Health Outcomes Measurement Standard Set for cleft and explores their associations with patient characteristics and psychosocial care referral. METHODS: Spearman correlation coefficients were calculated for CLEFT-Q psychological function, social function, school function, face, speech function, and speech-related distress scales. Logistic regressions were used to assess the association of cleft phenotype, syndrome, sex, and adoption status on scale scores and clinical referral to psychosocial care for further evaluation and management. RESULTS: Data were obtained from 3067 patients with cleft lip and/or palate at three centers. Strong correlations were observed between social function and psychological function (r > 0.69) and school function (r > 0.78) scales. Correlation between school function and psychological function scales was lower (r = 0.59 to 0.68). Genetic syndrome (OR, 2.37; 95% CI, 1.04 to 5.41), psychological function (OR, 0.92; 95% CI, 0.88 to 0.97), school function (OR, 0.94; 95% CI, 0.90 to 0.98), and face (OR, 0.96; 95% CI, 0.94 to 0.98) were significant predictors for referral to psychosocial care. CONCLUSIONS: Because social function as measured by the CLEFT-Q showed strong correlations with both school and psychological function, its additional value for measuring psychosocial function within the Standard Set is limited, and it is reasonable to consider removing this scale from the International Consortium for Health Outcomes Measurement Standard Set for cleft.

Orofacial abnormalities in mucopolysaccharidosis and mucolipidosis type II and III: A systematic review.

Mucopolysaccharidoses (MPSs) and mucolipidosis II and III (ML II and III) often manifest with orofacial (progressive) abnormalities, which may have a major impact on quality of life. However, because these patients have multiple somatic health issues, orofacial problems are easily overlooked in clinical practice and available literature on this topic solely consists of case reports, small case series, and small cohort studies. The aim of this systematic review was to gain more insight in the nature and extent of orofacial abnormalities in MPS, ML II, and III. A systematic review of all previously published articles addressing orofacial abnormalities in MPS, ML II, and III was performed. Both clinical studies and case reports were included. Outcome was the described orofacial abnormalities, subdivided into abnormalities of the face, maxilla, mandible, soft tissues, teeth, and occlusion. The search resulted in 57 articles, describing orofacial features in 340 patients. Orofacial abnormalities were present in all subtypes of MPS, ML II, and III, and consisted of thickened lips, a hypoplastic midface, a high-arched palate, hypoplastic condyles, coronoid hyperplasia, macroglossia, gingival hyperplasia, thick dental follicles, dentigerous cysts, misshapen teeth, enamel defects, and open bite. Orofacial abnormalities are present in all subtypes of MPS, ML II, and III. As orofacial abnormalities may cause complaints, evaluation of orofacial health should be part of routine clinical care.

Current Practice for Transverse Mandibular and Maxillary Discrepancies in the Netherlands: A Web-Based Survey Among Orthodontists and Oral and Maxillofacial Surgeons.

The main objective of this study was to provide an overview of the current practice for transverse mandibular and maxillary discrepancies in the Netherlands using a web-based survey. Orthodontists (ORTHO) and Oral and Maxillofacial Surgeons (OMFS) in the Netherlands were invited to the web-based survey via their professional association. Three cases were presented which could be treated non-surgically and surgically. Participants were asked what treatment they preferred: no treatment, orthodontic treatment with optional extractions or surgically assisted orthodontic treatment. The web-based survey ended with questions on various technical aspects and any experienced complication. Invitation was sent to all 303 members of professional association for ORTHO and to all 379 members of professional association for OMFS. Overall response number was 276 (response rate of 40.5%), including 127 incomplete responses. Generally, ORTHO prefer orthodontic treatment with optional extractions and OMFS lean towards surgically assisted orthodontic treatment. Mandibular Midline Distraction appears to be less preferred, possibly due to lack of clinical experience or knowledge by both professions despite being proven clinical stable surgical technique with stable long-term outcomes. There seems to be consensus on technical aspects by both professions, however, there are various thoughts on duration of consolidation period. Complications are mostly minor and manageable.

Osteoradionecrosis after postoperative radiotherapy for oral cavity cancer: A retrospective cohort study.

OBJECTIVE: Osteoradionecrosis (ORN) is a severe late complication after radiotherapy but current knowledge on ORN risks in the setting of postoperative radiotherapy (PORT) is limited. We studied the incidence and risk factors of ORN in patients with oral cavity cancers (OCC, treated with PORT. PATIENTS AND METHODS: A retrospective cohort study was conducted including OCC patients (mainly squamous cell) treated with postoperative intensity modulated radiotherapy between 2010 and 2018 with > 1 year disease-free survival. Cumulative incidences of ORN were computed using the Kaplan Meier method. Clinical and dosimetric risk factors for mandibular ORN were evaluated using Cox regression models. RESULTS: Within our cohort (N = 227, median follow-up 49 months) we observed 46 cases of ORN, mainly in the mandible (n = 41). The cumulative incidence of mandibular ORN was 15.9 % (SE 2.5 %) at three years and 19.8 % (SE 3.0 %) at five years. At univariable analysis, smoking, mandibular mandibulotomy or segment resection, mean dose to the mandible, and mandible volume (%) ≥ 60 Gy (V60) were significantly associated with increased ORN risks. At multivariable analysis, smoking (HR 2.13, 95 %CI 1.12-4.06) and V60 (HR 1.02 per 1 % increase, 95 %CI 1.01-1.04) remained predictive factors. For active smokers with a high V60 ≥ 40 % we observed rapid ORN development with a 1-year incidence of 29 % vs 6 % for others (p < 0.01). CONCLUSION: OCC Patients treated with PORT are at high risk for mandibular ORN. We identified the mandibular volume receiving ≥ 60 Gy as the dominant risk factor, especially in active smokers. Limiting high-dose volumes at treatment planning may decrease ORN risks.

Augmented reality navigation for minimally invasive craniosynostosis surgery: a phantom study.

PURPOSE: In minimally invasive spring-assisted craniectomy, surgeons plan the surgery by manually locating the cranial sutures. However, this approach is prone to error. Augmented reality (AR) could be used to visualize the cranial sutures and assist in the surgery planning. The purpose of our work is to develop an AR-based system to visualize cranial sutures, and to assess the accuracy and usability of using AR-based navigation for surgical guidance in minimally invasive spring-assisted craniectomy. METHODS: An AR system was developed that consists of an electromagnetic tracking system linked with a Microsoft HoloLens. The system was used to conduct a study with two skull phantoms. For each phantom, five sutures were annotated and visualized on the skull surface. Twelve participants assessed the system. For each participant, model alignment using six anatomical landmarks was performed, followed by the participant delineation of the visualized sutures. At the end, the participants filled a system usability scale (SUS) questionnaire. For evaluation, an independent optical tracking system was used and the delineated sutures were digitized and compared to the CT-annotated sutures. RESULTS: For a total of 120 delineated sutures, the distance of the annotated sutures to the planning reference was [Formula: see text] mm. The average delineation time per suture was [Formula: see text] s. For the system usability questionnaire, an average SUS score of 73 was obtained. CONCLUSION: The developed AR-system has good accuracy (average 2.4 mm distance) and could be used in the OR. The system can assist in the pre-planning of minimally invasive craniosynostosis surgeries to locate cranial sutures accurately instead of the traditional approach of manual palpation. Although the conducted phantom study was designed to closely reflect the clinical setup in the OR, further clinical validation of the developed system is needed and will be addressed in a future work.

Mandibular distraction to correct severe non-isolated mandibular hypoplasia: The role of drug-induced sleep endoscopy (DISE) in decision making.

OBJECTIVES: In patients with mandibular hypoplasia, mandibular distraction osteogenesis (MDO) aims to relieve tongue-based airway obstruction. Drug-induced sleep endoscopy (DISE) provides a dynamic assessment of the upper airway and visualizes anatomical site and cause of airway obstruction. The aim of this study was to evaluate the effect of MDO on tongue-based airway obstruction found by DISE within a non-isolated patient population with severe upper airway obstruction (UAO). Furthermore, we aimed to assess the additional value of DISE in clinical decision making by correlating DISE findings to functional airway outcomes after MDO. METHODS: Findings on DISE in children who underwent MDO were retrospectively gathered and evaluated. According to DISE findings, severity of tongue-based obstruction was scored using a 4-step classification similar to the one that is used by Bravo et al.. Intubation conditions were scored according to the Cormack Lehane score (CLS). Pre-and postoperative DISE findings were compared and correlated with functional airway outcomes following MDO. RESULTS: In 19 out of 28 MDO procedures, both a pre-and postoperative DISE was available. Tongue-based obstruction scores improved in 13 procedures, which correlated to a functional improvement in seven. Postoperative tongue-based obstruction differed significantly between patients with successful MDO and patients treated unsuccessfully (2.00 ((Interquartile range (IQR) 1.00-2.00) vs. 3.00 (IQR 2.00-4.00), p = 0.028), whereas this difference was not significant for the CLS (1.00 (IQR 1.00-1.50) vs. 2.00 (IQR 1.00-4.00), p = 0.066). If no improvement of tongue-based obstruction was seen, MDO is very unlikely to be successful on the functional airway. CONCLUSIONS: DISE provides information on the site and nature of airway obstruction and can visualize the effect of MDO on the severity of tongue-based airway obstruction. Therefore, it can be of additional value in understanding the differences in functional airway outcomes after MDO and aids in deciding appropriate and targeted treatment. Hence, standardized use of DISE, in addition to the clinical assessment of mandibular position and a polysomnography, during MDO management is highly recommended.

Evaluation of dental maturity in Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis.

OBJECTIVES: To determine whether dental maturity (dental development) was delayed in patients with Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis, compared with a Dutch control group without syndromes. MATERIALS AND METHODS: This study included 60 patients (38 patients with Muenke syndrome, 17 patients with Saethre-Chotzen syndrome, and 5 with TCF12-related craniosynostosis), aged 5.8-16.8 years that were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care, and Orthodontics, in Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands. Dental age was calculated according to Demirjian's index of dental maturity. The control group included 451 children without a syndrome. RESULTS: Compared with the control group, dental development was delayed by an average of one year in 5- to 8-year-old patients with Muenke syndrome (P = 0.007) and in 8- to 10-year-old patients with Saethre-Chotzen syndrome (P = 0.044), but not in patients with TCF12-related craniosynostosis. CONCLUSIONS: Our results indicated that dental development was delayed by one year, on average, in patients with Muenke syndrome and Saethre-Chotzen syndrome, compared with a Dutch control group without syndromes. IMPLICATIONS: Our findings have improved the understanding of dental development in patients with Muenke and Saethre-Chotzen syndrome. These results can provide guidance on whether the orthodontist needs to consider growth disturbances related to dental development.

CYP11B1 variants influence skeletal maturation via alternative splicing.

We performed genome-wide association study meta-analysis to identify genetic determinants of skeletal age (SA) deviating in multiple growth disorders. The joint meta-analysis (N = 4557) in two multiethnic cohorts of school-aged children identified one locus, CYP11B1 (expression confined to the adrenal gland), robustly associated with SA (rs6471570-A; ß = 0.14; P = 6.2 × 10-12). rs6410 (a synonymous variant in the first exon of CYP11B1 in high LD with rs6471570), was prioritized for functional follow-up being second most significant and the one closest to the first intron-exon boundary. In 208 adrenal RNA-seq samples from GTEx, C-allele of rs6410 was associated with intron 3 retention (P = 8.11 × 10-40), exon 4 inclusion (P = 4.29 × 10-34), and decreased exon 3 and 5 splicing (P = 7.85 × 10-43), replicated using RT-PCR in 15 adrenal samples. As CYP11B1 encodes 11-ß-hydroxylase, involved in adrenal glucocorticoid and mineralocorticoid biosynthesis, our findings highlight the role of adrenal steroidogenesis in SA in healthy children, suggesting alternative splicing as a likely underlying mechanism.

Chondrogenically Primed Human Mesenchymal Stem Cells Persist and Undergo Early Stages of Endochondral Ossification in an Immunocompetent Xenogeneic Model.

Tissue engineering approaches using progenitor cells such as mesenchymal stromal cells (MSCs) represent a promising strategy to regenerate bone. Previous work has demonstrated the potential of chondrogenically primed human MSCs to recapitulate the process of endochondral ossification and form mature bone in vivo, using immunodeficient xenogeneic models. To further the translation of such MSC-based approaches, additional investigation is required to understand the impact of interactions between human MSC constructs and host immune cells upon the success of MSC-mediated bone formation. Although human MSCs are considered hypoimmunogenic, the potential of chondrogenically primed human MSCs to induce immunogenic responses in vivo, as well as the efficacy of MSC-mediated ectopic bone formation in the presence of fully competent immune system, requires further elucidation. Therefore, the aim of this study was to investigate the capacity of chondrogenically primed human MSC constructs to persist and undergo the process of endochondral ossification in an immune competent xenogeneic model. Chondrogenically differentiated human MSC pellets were subcutaneously implanted to wild-type BALB/c mice and retrieved at 2 and 12 weeks post-implantation. The percentages of CD4+ and CD8+ T cells, B cells, and classical/non-classical monocyte subsets were not altered in the peripheral blood of mice that received chondrogenic MSC constructs compared to sham-operated controls at 2 weeks post-surgery. However, MSC-implanted mice had significantly higher levels of serum total IgG compared to sham-operated mice at this timepoint. Flow cytometric analysis of retrieved MSC constructs identified the presence of T cells and macrophages at 2 and 12 weeks post-implantation, with low levels of immune cell infiltration to implanted MSC constructs detected by CD45 and CD3 immunohistochemical staining. Despite the presence of immune cells in the tissue, MSC constructs persisted in vivo and were not degraded/resorbed. Furthermore, constructs became mineralised, with longitudinal micro-computed tomography imaging revealing an increase in mineralised tissue volume from 4 weeks post-implantation until the experimental endpoint at 12 weeks. These findings indicate that chondrogenically differentiated human MSC pellets can persist and undergo early stages of endochondral ossification following subcutaneous implantation in an immunocompetent xenogeneic model. This scaffold-free model may be further extrapolated to provide mechanistic insight to osteoimmunological processes regulating bone regeneration and homeostasis.

Virtual extensions improve perception-based instrument alignment using optical see-through devices.

Instrument alignment is a common task in various surgical interventions using navigation. The goal of the task is to position and orient an instrument as it has been planned preoperatively. To this end, surgeons rely on patient-specific data visualized on screens alongside preplanned trajectories. The purpose of this manuscript is to investigate the effect of instrument visualization/non visualization on alignment tasks, and to compare it with virtual extensions approach which augments the realistic representation of the instrument with simple 3D objects. 18 volunteers performed six alignment tasks under each of the following conditions: no visualization on the instrument; realistic visualization of the instrument; realistic visualization extended with virtual elements (Virtual extensions). The first condition represents an egocentric-based alignment while the two other conditions additionally make use of exocentric depth estimation to perform the alignment. The device used was a see-through device (Microsoft HoloLens 2). The positions of the head and the instrument were acquired during the experiment. Additionally, the users were asked to fill NASA-TLX and SUS forms for each condition. The results show that instrument visualization is essential for a good alignment using see-through devices. Moreover, virtual extensions helped achieve the best performance compared to the other conditions with medians of 2 mm and 2° positional and angular error respectively. Furthermore, the virtual extensions decreased the average head velocity while similarly reducing the frustration levels. Therefore, making use of virtual extensions could facilitate alignment tasks in augmented and virtual reality (AR/VR) environments, specifically in AR navigated surgical procedures when using optical see-through devices.