Correction objectives have higher impact than screw pattern and density on the optimal 3D correction of thoracic AIS: a biomechanical study

Study design Assessment of screw pattern, implant density (ID), and optimization of 3D correction through computer-based biomechanical models. Objective To investigate how screw pattern and ID affect intraoperative 3D correction of thoracic curves in adolescent idiopathic scoliosis, and how different correction objectives impact the optimal screw pattern. Summary of background data Screw pattern, ID, correction objectives and surgical strategies for posterior fusion of AIS are highly variable among experienced surgeons. The “optimal” instrumentation remains not well defined. Methods 10 patient-specific multibody models of representative adolescent idiopathic scoliosis Lenke 1A cases were built and used to compare alternative virtual correction surgeries. Five screw patterns and IDs (average: 1.6 screws/instrumented level, range: 1.2–2) were simulated, considering concave rod rotation, en bloc derotation, and compression/distraction as primary correction maneuvers. 3D correction descriptors were quantified in the coronal, sagittal and transverse planes. An objective function weighting the contribution of intraoperative 3D correction and mobility allowed rating of the outcomes of the virtual surgeries. Based on surgeon-dependent correction objectives, the optimal result among the simulated constructs was identified. Results Low-density (ID ≤ 1.4) constructs provided equivalent 3D correction compared to higher (ID ≥ 1.8) densities (average differences ranging between 2° and 3°). The optimal screw pattern varied from case to case, falling within the low-density screw category in 14% of considered scenarios, 73% in the mid-density (1.4 < ID < 1.8) and 13% in the high-density. The optimal screw pattern was unique in five cases; multiple optima were found in other cases depending on the considered correction objectives. Conclusions Low-density screw patterns provided equivalent intraoperative 3D correction to higher-density patterns. Simulated surgeon’s choice of correction objectives had the greatest impact on the selection of the optimal construct for 3D correction, while screw density and ID had a limited impact

Impact of Pregnancy on Loss of Deformity Correction After Pedicle Screw Instrumentation for Adolescent Idiopathic Scoliosis

OBJECTIVE: A retrospective multicenter comparative study was carried out to evaluate whether pregnancy leads to the loss of deformity correction (LOC) in female patients surgically treated for idiopathic scoliosis. METHODS: A total of 128 female patients who underwent segmental spinal instrumentation and fusion for adolescent idiopathic scoliosis (AIS) between 1999 and 2014 were reviewed. Of these patients, 62 became pregnant (surgery-pregnancy group [SPG]), whereas 66 did not (surgery-nonpregnancy [SNP] group). Radiographic parameters were analyzed before surgery, after surgery, before pregnancy, up to 1 year after delivery, and at final follow-up (FFU). Health-related quality of life was analyzed using the Scoliosis Research Society outcome questionnaire (SRS-22r). RESULTS: The mean age at the time of surgery was 16 years in both groups. The mean preoperative major curves were 65 degrees (standard deviation [SD], 12 degrees) versus 67 degrees (SD, 11 degrees), 18 degrees (SD, 9 degrees) versus 17 degrees (SD, 9 degrees) immediately after surgery, and 20 degrees (SD, 8 degrees) versus 20 degrees (SD, 8 degrees) at FFU in the SPG and SNP groups, respectively (P > 0.10 for all comparisons). The mean loss of correction was 3.5 degrees (SD, 3 degrees) in the SPG and 4.5 (SD, 3 degrees) for SNP groups, respectively (P = 0.379). The mean preoperative thoracic kyphosis (T5-T12) was 26.5 degrees (SD, 11.9 degrees) for SPG and 24.7 degrees (SD, 14.5 degrees) for SNP, after surgery 19.2 degrees (SD, 9.5 degrees) for SPG, 18.8 (SD, 8.9 degrees) for SNP and at FFU, 20.3 degrees (SD, 9 degrees) for SPG and 21.3 degrees (SD, 8.5 degrees) for SNP. CONCLUSIONS: Women who have undergone pedicle screw instrumentation and fusion who have had >= 1 pregnancies do not have curve progression or deterioration in the longer-term outcomes compared with patients who have not become pregnant.Peer reviewe

Assessment of stability during gait in patients with spinal deformity-A preliminary analysis using the dynamic stability margin.

Daily living activities are dynamic, requiring spinal motion through space. Current assessment of spinal deformities is based on static measurements from full-spine standing radiographs. Tools to assess dynamic stability during gait might be useful to enhance the standard evaluation. The aim of this study was to evaluate gait dynamic imbalance in patients with spinal deformity using the dynamic stability margin (DSM). Twelve normal subjects and 17 patients with spinal deformity were prospectively recruited. A kinematic 3D gait analysis was performed for the control group (CG) and the spinal deformity group (SDG). The DSM (distance between the extrapolated center of mass and the base of support) and time-distance parameters were calculated for the right and left side during gait. The relationship between DSM and step length was assessed using three variables: gait stability, symmetry, and consistency. Variables’ accuracy was validated by a discriminant analysis. Patients with spinal deformity exhibited gait instability according to the DSM (0.25 m versus 0.31 m) with decreased velocity (1.1 m s−1 versus 1.3 m s−1) and decreased step length (0.32 m versus 0.38 m). According to the discriminant analysis, gait stability was the more accurate variable (area under the curve AUC =0.98) followed by gait symmetry and consistency. However, gait consistency showed 100% of specificity, sensitivity, and accuracy of precision. The DSM showed that patients with spinal malalignment exhibit decreased gait stability, symmetry, and consistency besides gait time-distance parameter changes. Additional work is required to determine how to apply the DSM for preoperative and postoperative spinal deformity management.There is no financial or personal relationship to disclose, nor any other conflicts of interest, that may bias or influence this stud

Biomechanical effect of pedicle screw distribution in AIS instrumentation using a segmental translation technique: computer modeling and simulation

BACKGROUND: Efforts to select the appropriate number of implants in adolescent idiopathic scoliosis (AIS) instrumentation are hampered by a lack of biomechanical studies. The objective was to biomechanically evaluate screw density at different regions in the curve for AIS correction to test the hypothesis that alternative screw patterns do not compromise anticipated correction in AIS when using a segmental translation technique. METHODS: Instrumentation simulations were computationally performed for 10 AIS cases. We simulated simultaneous concave and convex segmental translation for a reference screw pattern (bilateral polyaxial pedicle screws with dorsal height adjustability at every level fused) and four alternative patterns; screws were dropped respectively on convex or concave side at alternate levels or at the periapical levels (21 to 25% fewer screws). Predicted deformity correction and screw forces were compared. RESULTS: Final simulated Cobb angle differences with the alternative screw patterns varied between 1 degrees to 5 degrees (39 simulations) and 8 degrees (1 simulation) compared to the reference maximal density screw pattern. Thoracic kyphosis and apical vertebral rotation were within 2 degrees of the reference screw pattern. Screw forces were 76 +/- 43 N, 96 +/- 58 N, 90 +/- 54 N, 82 +/- 33 N, and 79 +/- 42 N, respectively, for the reference screw pattern and screw dropouts at convex alternate levels, concave alternate levels, convex periapical levels, and concave periapical levels. Bone-screw forces for the alternative patterns were higher than the reference pattern (p 0.28). Alternate dropout screw forces were higher than periapical dropouts (p < 0.05). CONCLUSIONS: Using a simultaneous segmental translation technique, deformity correction can be achieved with 23% fewer screws than maximal density screw pattern, but resulted in 25% higher bone-screw forces. Screw dropouts could be either on the convex side or on the concave side at alternate levels or at periapical levels. Periapical screw dropouts may more likely result in lower bone-screw force increase than alternate level screw dropouts

Bovine Colostrum Supplementation and Bone Health: a Pilot Study

Research has shown the positive effects of some bovine colostrum components in bone cells; for instance, lactoferrin is reported to stimulate osteoblast proliferation and inhibit osteoclast activity in cell cultures. However, whether bovine colostrum as a whole can induce bone mass gains in osteoporotic bones is relatively unclear. The aim of this study was to investigate the effects of bovine colostrum supplementation in ovariectomized-induced bone loss (OVX) rats. Methods: Twenty-seven-month-old female Wister rats (n=16) were randomly assigned to the following two groups: 1) a healthy control (non-OVX) with no supplementation, and 2) a OVX with bovine colostrum supplementation (0.5g/day; oral consumption). After 5 months supplementation, bone microstructure was scanned using micro-CT (right tibia). Bone formation markers (serum: pre-and post supplementation) were analysed (alkaline phosphatase and osteocalcin) by ECLIA. The study was approved by the National Ethics Committee for the Use of Animals in Research (ORBEA). Results: No significant differences were found between groups in serum alkaline phosphatase either before or after supplementation (p>0.05). Serum osteocalcin significantly increased post-supple-mentation in the OVX compared to pre-supplementation (pre: 11.32+/-1.61; post: 12.45+/-1.21μg/L, p0.05). Trabecular bone mineral content (BMC), trabecular thickness, cortical bone mineral density (BMD) and cortical BMC were similar between groups after supplementation (p>0.05). However, OVX group revealed significantly higher trabecular porosity (5.6%, p<0.01), trabecular separation (36.3%, p<0.01), and cortical porosity (8.0%, p<0.01) compared to the healthy control post-supplementation. Conclusion: Bovine colostrum seems to preserve bone mass of OVX by stimulating bone formation. However, these positive effects seem not to be sufficient to restore bone micro-architecture in the OVX group, possibly because the administrated dose of bovine colostrum was not sufficient for OVX to catch-up healthy rats in terms of trabecular and cortical porosity. The potential therapeutic use of bovine colostrum for osteoporosis deserves further investigation

Identification and validation of multiple cell surface markers of clinical-grade adipose-derived mesenchymal stromal cells as novel release criteria for good manufacturing practice-compliant production

Background: Clinical translation of mesenchymal stromal cells (MSCs) necessitates basic characterization of the cell product since variability in biological source and processing of MSCs may impact therapeutic outcomes. Although expression of classical cell surface markers (e.g., CD90, CD73, CD105, and CD44) is used to define MSCs, identification of functionally relevant cell surface markers would provide more robust release criteria and options for quality control. In addition, cell surface expression may distinguish between MSCs from different sources, including bone marrow-derived MSCs and clinical-grade adipose-derived MSCs (AMSCs) grown in human platelet lysate (hPL). Methods: In this work we utilized quantitative PCR, flow cytometry, and RNA-sequencing to characterize AMSCs grown in hPL and validated non-classical markers in 15 clinical-grade donors. Results: We characterized the surface marker transcriptome of AMSCs, validated the expression of classical markers, and identified nine non-classical markers (i.e., CD36, CD163, CD271, CD200, CD273, CD274, CD146, CD248, and CD140B) that may potentially discriminate AMSCs from other cell types. More importantly, these markers exhibit variability in cell surface expression among different cell isolates from a diverse cohort of donors, including freshly prepared, previously frozen, or proliferative state AMSCs and may be informative when manufacturing cells. Conclusions: Our study establishes that clinical-grade AMSCs expanded in hPL represent a homogeneous cell culture population according to classical markers,. Additionally, we validated new biomarkers for further AMSC characterization that may provide novel information guiding the development of new release criteria

Loss of histone methyltransferase Ezh2 stimulates an osteogenic transcriptional program in chondrocytes but does not affectcartilage development

Ezh2 is a histone methyltransferase that suppresses osteoblast maturation and skeletal development. We evaluated the roleof Ezh2 in chondrocyte lineage differentiation and endochondral ossification. Ezh2 was genetically inactivated in the mesenchymal, osteoblastic, and chondrocytic lineages in mice using the Prrx1-Cre,Osx1-Cre, and Col2a1-Cre drivers, respectively. Wild-type and conditional knockout mice were phenotypically assessed by grossmorphology, histology, and micro-CT imaging. Ezh2-deficient chondrocytes in micromass culture models were evaluated usingRNA-sequencing, histologic evaluation, and western blotting. Aged mice with Ezh2 deficiency were also evaluated for prematuredevelopment of osteoarthritis using radiographic analysis. Ezh2 deficiency in murine chondrocytes reduced bone density at 4 weeks of age, although caused no other gross developmentaleffects. Knockdown of Ezh2 in chondrocyte micromass cultures resulted in a global reduction in trimethylation of histone 3lysine 27 (H3K27me3) and altered differentiation in vitro. RNA-seq analysis revealed enrichment of an osteogenic gene expressionprofile in Ezh2 deficient chondrocytes. Joint development proceeded normally in the absence of Ezh2 in chondrocytes withoutinducing excessive hypertrophy or premature osteoarthritis in vivo. In summary, loss of Ezh2 reduced H3K27me3 levels, increased expression of osteogenic genes in chondrocytes, and resulted ina transient post-natal bone phenotype. Remarkably, Ezh2 activity is dispensable for normal chondrocyte maturation and endochondralossification in vivo, even though it appears to have a critical role during early stages of mesenchymal lineage-commitment

Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome:Results from The GALA Study

BACKGROUND: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international, cohort of children with ALGS.METHODS: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS.RESULTS: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (&gt;6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and &lt;10.0 mg/dL had a 4.1-fold (95% CI 1.6 - 10.8) and those ≥10.0 mg/dL had an 8.0-fold (95% CI 3.4 - 18.4) increased risk of developing CEPH compared with those &lt;5.0 mg/dL. Median TB levels between ≥5.0 and &lt;10.0 mg/dL and &gt;10.0 mg/dL were associated with a 4.8 (95% CI 2.4 - 9.7) and 15.6 (95% CI 8.7 - 28.2) increased risk of transplantation relative to &lt;5.0 mg/dL. Median TB &lt;5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p&lt;0.001).CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB &lt;5.0 mg/dL between 6-and-12-months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of novel therapies.</p