Suppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1.

Apoptosis occurs during development when a separation of tissues is needed. Synovial joint formation is initiated at the presumptive site (interzone) within a cartilage anlagen, with changes in cellular differentiation leading to cavitation and tissue separation. Apoptosis has been detected in phalangeal joints during development, but its role and regulation have not been defined. Here, we use a mouse model of brachydactyly type A1 (BDA1) with an IhhE95K mutation, to show that a missing middle phalangeal bone is due to the failure of the developing joint to cavitate, associated with reduced apoptosis, and a joint is not formed. We showed an intricate relationship between IHH and interacting partners, CDON and GAS1, in the interzone that regulates apoptosis. We propose a model in which CDON/GAS1 may act as dependence receptors in this context. Normally, the IHH level is low at the center of the interzone, enabling the "ligand-free" CDON/GAS1 to activate cell death for cavitation. In BDA1, a high concentration of IHH suppresses apoptosis. Our findings provided new insights into the role of IHH and CDON in joint formation, with relevance to hedgehog signaling in developmental biology and diseases.

Virtual reality-based surgical planning simulator for tumorous resection in FreeForm Modeling: an illustrative case of clinical teaching.

The importance of virtual reality (VR) has been emphasized by many medical studies, yet it has been relatively under-applied to surgical operation. This study characterized how VR has been applied in clinical education and evaluated its tutorial utility by designing a surgical model of tumorous resection as a simulator for preoperative planning and medical tutorial. A 36-year-old male patient with a femoral tumor who was admitted to the Affiliated Jiangmen Traditional Chinese Medicine Hospital was randomly selected and scanned by computed tomography (CT). The data in digital imaging and communications in medicine (*.DICOM) format were imported into Mimics to reconstruct a femoral model, and were generated to the format of *.stl executing in the computer-aided design (CAD) software SenSable FreeForm Modeling (SFM). A bony tumor was simulated by adding clay to the femur, the procedure of tumorous resection was virtually performed with a toolkit called Phantom, and its bony defect was filled with virtual cement. A 3D workspace was created to enable the individual multimodality manipulation, and a virtual operation of tumorous excision was successfully carried out with indefinitely repeated running. The precise delineation of surgical margins was shown to be achieved with expert proficiency and inexperienced hands among 43 of 50 participants. This simulative educator presented an imitation of high definition, those trained by VR models achieved a higher success rate of 86% than the rate of 74% achieved by those trained by conventional methods. This tumorous resection was repeatably handled by SFM, including the establishment of surgical strategy, whereby participants felt that respondent force feedback was beneficial to surgical teaching programs, enabling engagement of learning experiences by immersive events which mimic real-world circumstances to reinforce didactic and clinical concepts.

Electromyographic Discrepancy in Paravertebral Muscle Activity Predicts Early Curve Progression of Untreated Adolescent Idiopathic Scoliosis.

STUDY DESIGN: This study adopted a prospective cohort study design. PURPOSE: This study aimed to examine electromyogram (EMG) discrepancy in paravertebral muscle activity and scoliosis progression, determine how vertebral morphology and EMG discrepancy evolve during scoliosis progression, and identify differences in EMG activity between individuals with and without adolescent idiopathic scoliosis (AIS). OVERVIEW OF LITERATURE: Higher EMG activity is observed in the convex side of scoliotic curves, but not in populations without scoliosis, suggesting that higher EMG activity is a causative factor for curve progression. METHODS: In this study, 267 matched pairs of AIS and controls were recruited. The participants underwent EMG measurements at their first presentation and did not receive any treatment for 6 months at which point they underwent EMG and radiographs. Early curve progression was defined as >5° in Cobb angle at 6 months. The root mean square of the EMG (rms-EMG) signal was recorded with the participants in sitting and back extension. The rms-EMG ratio at the upper end vertebrae, apical vertebrae (AV), and lower end vertebrae (LEV) of the major curve was calculated. RESULTS: The rms-EMG ratio in the scoliosis cohort was high compared with that in the controls (sitting: 1.2±0.3 vs. 1.0±0.1, p<0.01; back extension: 1.1±0.2 vs. 1.0±0.1, p<0.01). An AV rms-EMG ratio in back extension, with a cutoff threshold of ≥1.5 in the major thoracic curve and ≥1.3 in the major lumbar curve, was a risk factor for early curve progression after 6 months without treatment (odds ratio, 4.1; 95% confidence interval, 2.8-5.9; p<0.01). Increases in side deviation (SD) (distance between the AV and the central sacral line) were related to a higher rms-EMG ratio in LEV of the major thoracic curve (baseline: rs=0.2, p=0.03; 6 months: rs=0.3, p<0.01). CONCLUSIONS: An EMG discrepancy was detected in the scoliosis cohort, which was related to increases in SD in the major thoracic curve. The AV rms-EMG ratio in back extension was correlated with curve progression after 6 months of no treatment.

Scoliosis in osteogenesis imperfecta: identifying the genetic and non-genetic factors affecting severity and progression from longitudinal data of 290 patients.

BACKGROUND: Scoliosis is widely prevalent among osteogenesis imperfecta (OI) patients, and is progressive with age. However, factors affecting scoliosis in OI are not well known. METHODS: We retrospectively retrieved longitudinal radiographic and clinical records of consecutive OI patients seeking treatments at our hospital from 2014 to 2022, graded their pre-operative spinal conditions into four outcome groups, estimated their progression rates, and descriptively and inferentially analyzed the genetic and non-genetic factors that may affect the outcomes and progression rates. RESULTS: In all, 290 OI patients met the inclusion criteria, where 221 had genetic records. Of these 221, about 2/3 had mutations in COL1A1 or COL1A2, followed by mutations in WNT1 (9.0%), IFITM5 (9.0%) and other OI risk genes. With an average age of 12.0 years (interquartile range [IQR] 6.9-16.1), 70.7% of the cohort had scoliosis (Cobb angle > 10°), including 106 (36.5%) mild (10°-25°), 40 (13.8%) moderate (25°-50°), and 59 (20.3%) severe (> 50°) scoliosis patients. Patients with either COL1A1 and COL1A2 were strongly biased toward having mild or no scoliosis, whereas patients with mutations in IFITM5, WNT1 and other recessive genes were more evenly distributed among the four outcome grades. Lower-limb discrepancy, bone mineral density (BMD) and age of first drug used were all significantly correlated with severity outcomes. Using multivariate logistic regression, we estimated that each year older adds an odds ratio of 1.13 (95% confidence interval [CI] 1.07-1.2) in progression into advanced stages of scoliosis. We estimated a cohort-wide progression rate of 2.7 degrees per year (95% CI 2.4-3.0). Early-onset patients experienced fast progressions during both infantile and adolescent stages. Twenty-five of the 59 (42.8%) patients with severe scoliosis underwent spinal surgeries, enjoying an average Cobb angle reduction of 33° (IQR 23-40) postoperatively. CONCLUSION: The severity and progression of scoliosis in osteogenesis imperfecta were affected by genetic factors including genotypes and mutation types, and non-genetic factors including age and BMD. As compared with COL1A1, mutations in COL1A2 were less damaging while those on IFITM5 and other recessive genes conferred damaging effects. Progression rates were the fastest in the adolescent adult age-group.

Virtual operation for hip joint replacement implemented by Sensable_FreeForm_Modelling: A surgical drill.

OBJECTIVE: To design a virtual operation of joint replacement for surgical drills using a haptic device, SenSable_FreeForm_Modelling (SFM), to enhance surgeons' efficiency and enable "Virtual tutorial without reality" for interns. METHOD: A patient with hip joint osteoarthritis is randomly selected to perform Total Hip Replacement (THR). The hip images were input into Mimics in the format of *.dicom after CT scan and then exported to SFM using the stereolithographic (*.stl) format. A surgical toolkit can be created virtually with Computer Aided Design software such as Pro-E or Ghost SDK and a visual drill scenario of THR directed by a force-respondent stick, namely Phantom. RESULT: 3D models of the hip joint were rebuilt illustrating clearly that the geometrical shapes of the surgical equipment created are similar to real instruments, and the THR operation is emulated distinctly in novelty. CONCLUSION: In obedience to an ancient maxim, so called 'genuine knowledge originated from practice', this simulative operation offers hands-on experience for students in the orthopaedics field with remarkable effects, contributing not only teaching cases for medical courses but also a planning basis for physical surgery.

Percutaneous endoscopic lumbar discectomy in lumbar disc herniation with posterior ring apophysis fracture: A case report in a 15-year-old child.

RATIONALE: Lumbar disc herniation (LDH) with posterior ring apophysis fracture (PRAF) is rather rare in children, and in all age-stratified LDH patients, the incidence of RAF was 5.3% to 7.5%. Interestingly, the incidence of LDH with RAF in children (15%-32%) is several times higher than in adults, the mis-diagnosis of which may lead to delayed treatment. PATIENT CONCERNS: Here, we report a 15-year-old schoolboy who suffered from sudden low back pain and radiating pain in both lower limbs after sport activities. Symptoms persisted after 3 months of conservative treatment. Computer radiography and magnetic resonance imaging indicated central disc herniation with PRAF at L4-5. DIAGNOSIS: LDH with PRAF. INTERVENTIONS: The herniated disc and epiphyseal fragments were successfully excised by the percutaneous endoscopic lumbar discectomy minimal-invasive technique. OUTCOMES: Surgery was successful. Symptoms were immediately relieved postoperatively with a wound of only about 7.0 mm. Discharged on the next day. No perioperative complications occurred. Moreover, the imaging and clinical outcomes were also more satisfactory during the post-operative 15 months outpatient follow-up. LESSONS: Pediatric LDH with PRAF is extremely uncommon, and there is a lack of training among physicians for such cases, which may lead to delayed diagnosis and treatment. Once a diagnosis for LDH with PRAF is established, percutaneous endoscopic lumbar discectomy is a safe and effective minimally invasive treatment to be considered, and we hope that this technique can provide more assistance in the future.

Patient-reported outcomes in a Chinese cohort of osteogenesis imperfecta unveil psycho-physical stratifications associated with clinical manifestations.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare congenital disorder of the skeletal system, inflicting debilitating physical and psychological distress on patients and caregivers. Over the decades, much effort has been channeled towards understanding molecular mechanisms and developing new treatments. It has recently become more apparent that patient-reported outcome measurements (PROM) during treatment, healing and rehabilitation are helpful in facilitating smoother communication, refining intervention strategies and achieving higher quality of life. To date, systematic analyses of PROM in OI patients remain scarce. RESULTS: Here, utilizing a PROM Information System, we report a cross-sectional and longitudinal study in a southern Chinese cohort of 90 OI patients, covering both the child and adult age-groups. In the child group where both self and parental surveys were obtained, we identified two clusters of comparable sizes showing different outlooks in physical mobility and emotional experiences. One cluster (Cluster 1) is more negative about themselves than the other (Cluster 2). A concordance of 84.7% between self and parental assessments was recorded, suggesting the stability and validity of PROM-based stratification. Clinical subtyping, deformity, leg length discrepancy, and limited joint mobility were significantly associated with this stratification, with Cluster 1 showing higher percentages of severe phenotypes than Cluster 2. Since OI is a genetic disorder, we performed genetic testing on 72 of the 90 patients, but found no obvious association between genotypes and the PROM stratification. Analyses of longitudinal data suggested that patients tended to stay in the same psychological state, in both clusters. Adult patients also showed a continuous spectrum of self-evaluation that matches their clinical manifestations. CONCLUSION: By systematically analyzing patient-reported outcomes, our study demonstrated the link between the sociopsychological wellbeing of OI patients, and their clinical manifestations, which may serve as the basis for evaluating clinical interventions and help achieve better patient-centric medical practices. The lack of genotype-PROM association may be due to the diverse mutational spectrum in OI, which warrants further investigation when a larger sample size is available.

Comprehensive risk assessments and anesthetic management for children with osteogenesis imperfecta: A retrospective review of 252 orthopedic procedures over 5 years.

BACKGROUND: Major anesthetic risks arise in orthopedic surgeries for children with osteogenesis imperfecta, a rare genetically inherited condition presenting diverse skeletal issues. AIM: We aimed to investigate anesthetic risks, including difficult airway, hypo- and hyperthermia, blood loss, and pain, in connection with patient, anesthetic, and surgical factors. METHODS: Both descriptive and inferential statistics were employed to study the anesthetic risks and their predictors. Data of 252 surgeries for 132 Chinese osteogenesis imperfecta patients aged 18 or below were retrieved from the authors' hospital between 2015 and 2019. RESULTS: Two thirds of the cohort were Sillence type IV patients, with types I, III, and V accounting for 7.6%, 14.4%, and 11.4%, respectively. Video and direct laryngoscopy were used. No case of difficult airway was identified. Due to a careful management strategy, intraoperative temperature varied on average between -0.38°C and +0.89°C from the initial temperature. Fifty-two and 18 cases of hyper- and hypothermia were encountered, respectively. The use of sevoflurane for maintenance resulted in a mean increase of +0.24°C [95% CI 0.05 ~ 0.42] in the maximum temperature. Massive blood losses (>20% of estimated total blood volume) were observed in 18.3% of the cases. Neither intraoperative temperature changes nor blood loss was found to be related to Sillence classification. Regional anesthesia techniques were applied to 72.6% of the cases. Ultrasound guidance was used per the judgment of anesthesiologists or when in case of difficult landmarks. The incidence of difficult regional anesthesia was low (4 out of 252). For postoperative analgesia, 154 neuraxial blocks (including 77 caudal and 77 lumbar epidural) and 29 peripheral nerve blocks were performed. CONCLUSION: Anesthesia for children with osteogenesis imperfecta undergoing complex orthopedic procedures was challenging. Proper anesthesia planning was essential for both intraoperative management and postoperative analgesia. Age, surgical duration, and use of sevoflurane for maintenance impacted the intraoperative temperature most, and massive blood loss was not uncommon. The risks for airway or regional anesthesia difficulties were low. Pain scores could be controlled to be ≤3 via multiple techniques.

PRIMUS: Comprehensive proteomics of mouse intervertebral discs that inform novel biology and relevance to human disease modelling.

Mice are commonly used to study intervertebral disc (IVD) biology and related diseases such as IVD degeneration. Discs from both the lumbar and tail regions are used. However, little is known about compartmental characteristics in the different regions, nor their relevance to the human setting, where a functional IVD unit depends on a homeostatic proteome. Here, we address these major gaps through comprehensive proteomic profiling and in-depth analyses of 8-week-old healthy murine discs, followed by comparisons with human. Leveraging on a dataset of over 2,700 proteins from 31 proteomic profiles, we identified key molecular and cellular differences between disc compartments and spine levels, but not gender. The nucleus pulposus (NP) and annulus fibrosus (AF) compartments differ the most, both in matrisome and cellularity contents. Differences in the matrisome are consistent with the fibrous nature required for tensile strength in the AF and hydration property in the NP. Novel findings for the NP cells included an enrichment in cell junction proteins for cell-cell communication (Cdh2, Dsp and Gja1) and osmoregulation (Slc12a2 and Wnk1). In NP cells, we detected heterogeneity of vacuolar organelles; where about half have potential lysosomal function (Vamp3, Copb2, Lamp1/2, Lamtor1), some contain lipid droplets and others with undefined contents. The AF is enriched in proteins for the oxidative stress responses (Sod3 and Clu). Interestingly, mitochondrial proteins are elevated in the lumbar than tail IVDs that may reflect differences in metabolic requirement. Relative to the human, cellular and structural information are conserved for the AF. Even though the NP is more divergent between mouse and human, there are similarities at the level of cell biology. Further, common cross-species markers were identified for both NP (KRT8/19, CD109) and AF (COL12A1). Overall, mouse is a relevant model to study IVD biology, and an understanding of the limitation will facilitate research planning and data interpretation, maximizing the translation of research findings to human IVDs.

Significance of recumbent curvature in prediction of in-orthosis correction for adolescent idiopathic scoliosis.

BACKGROUND:: Prediction of in-orthosis curvature at pre-orthosis stage is valuable for the treatment planning for adolescent idiopathic scoliosis, while the position of spinal curvature assessment that is effective for this prediction is still unknown. OBJECTIVES:: To compare the spinal curvatures in different body positions for predicting the spinal curvature rendered by orthosis. STUDY DESIGN:: A prospective cohort study. METHODS:: Twenty-two patients with adolescent idiopathic scoliosis (mean Cobb angle: 28.1°± 7.3°) underwent ultrasound assessment of spinal curvature in five positions (standing, supine, prone, sitting bending, prone bending positions) and that within orthosis. Differences and correlations were analyzed between the spinal curvatures in the five positions and that within orthosis. RESULTS:: The mean in-orthosis curvature was 11.2° while the mean curvatures in five studied positions were 18.7° (standing), 10.7° (supine), 10.7° (prone), -3.5° (prone bending), and -6.5° (sitting bending). The correlation coefficients of the in-orthosis curvature and that in five studied positions were r = 0.65 (standing), r = 0.76 (supine), r = 0.87 (prone), r = 0.41 (prone bending), and r = 0.36 (sitting bending). CONCLUSION:: The curvature in recumbent positions (supine and prone) is highly correlated to the initial in-orthosis curvature without significant difference. Thus, the initial effect of spinal orthosis could be predicted by the curvature in the recumbent positions (especially prone position) at the pre-orthosis stage. CLINICAL RELEVANCE: Prediction of in-orthosis correction at pre-orthosis stage is valuable for spinal orthosis design. This study suggests assessing the spinal curvature in recumbent position (especially prone position) to predict the initial in-orthosis correction for optimizing the orthosis design.

An effective assessment method of spinal flexibility to predict the initial in-orthosis correction on the patients with adolescent idiopathic scoliosis (AIS).

BACKGROUND: Spinal flexibility is an essential parameter for clinical decision making on the patients with adolescent idiopathic scoliosis (AIS). Various methods are proposed to assess spinal flexibility, but which assessment method is more effective to predict the effect of orthotic treatment is unclear. OBJECTIVE: To investigate an effective assessment method of spinal flexibility to predict the initial in-orthosis correction, among the supine, prone, sitting with lateral bending and prone with lateral bending positions. METHODS: Thirty-five patients with AIS (mean Cobb angle: 28° ± 7°; mean age: 12 ± 2 years; Risser sign: 0-2) were recruited. Before orthosis fitting, spinal flexibility was assessed by an ultrasound system in 4 positions (apart from standing) including supine, prone, sitting with lateral bending and prone with lateral bending. After orthosis fitting, the initial in-orthosis correction was routinely assessed by whole spine standing radiograph. Comparisons and correlation analyses were performed between the spinal flexibility in the 4 positions and the initial in-orthosis correction. RESULTS: The mean in-orthosis correction was 41% while the mean curve correction (spinal flexibility) in the 4 studied positions were 40% (supine), 42% (prone), 127% (prone with lateral bending) and 143% (sitting with lateral bending). The correlation coefficients between initial in-orthosis correction and curve correction (spinal flexibility) in the 4 studied positions were r = 0.66 (supine), r = 0.75 (prone), r = 0.03 (prone with lateral bending) and r = 0.04 (sitting with lateral bending). CONCLUSIONS: The spinal flexibility in the prone position is the closest to and most correlated with the initial in-orthosis correction among the 4 studied positions. Thus, the prone position could be an effective method to predict the initial effect of orthotic treatment on the patients with AIS.