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Age-related osteoporosis is a metabolic skeletal disorder caused by estrogen deficiency in postmenopausal women. Prolonged use of anti-osteoporotic drugs such as bisphosphonates and FDA-approved anti-resorptive selective estrogen receptor modulators (SERMs) has been associated with various clinical drawbacks. We recently discovered a low-molecular-weight biocompatible and osteoanabolic phytoprotein, called HKUOT-S2 protein (32 kDa), from Dioscorea opposita Thunb that can accelerate bone defect healing. Here, we demonstrated that the HKUOT-S2 protein treatment can enhance osteoblasts-induced ossification and suppress osteoporosis development by upregulating skeletal estrogen receptors (ERs) ERα, ERβ, and GPR30 expressions in vivo. Also, HKUOT-S2 protein estrogenic activities promoted hMSCs-osteoblasts differentiation and functions by increasing osteogenic markers, ALP, and RUNX2 expressions, ALP activity, and osteoblast biomineralization in vitro. Fulvestrant treatment impaired the HKUOT-S2 protein-induced ERs expressions, osteoblasts differentiation, and functions. Finally, we demonstrated that the HKUOT-S2 protein could bind to ERs to exert osteogenic and osteoanabolic properties. Our results showed that the biocompatible HKUOT-S2 protein can exert estrogenic and osteoanabolic properties by positively modulating skeletal estrogen receptor signaling to promote ossification and suppress osteoporosis. Currently, there is no or limited data if any, on osteoanabolic SERMs. The HKUOT-S2 protein can be applied as a new osteoanabolic SERM for osteoporosis treatment.

Abstract Background The prognosis of surgically treated subjects with early onset scoliosis (EOS) into adulthood has been lacking. We aimed to investigate the patients’ perspectives on satisfaction with surgical treatment. Methodology We included all surgical candidates with EOS who had undergone index spinal surgery for scoliosis correction between 2009 and 2013. The minimum duration of postoperative follow-up was 10 years at the time of survey completion. Three questionnaires were used in this study, comprising the revised Scoliosis Research Society questionnaire (SRS-22r), the Patient-Reported Outcomes Measurement Information System (PROMIS-29), and the World Health Organization Quality of Life (WHOQOL-BREF). Measures of treatment satisfaction were retrieved from SRS-22r. Results There were 29 participants who completed the survey, and thereby included in the study (i.e., a response rate of 43% and a dropout rate of 6%). Amongst them, 14, 11, and 4 individuals received posterior spinal fusion (PSF), magnetically controlled growing rods (MCGR), and traditional growing rods, respectively. The average duration after the index spinal surgery was 12.6 ± 2.2 years. Our findings revealed that self-image (across all treatment groups), sleep disruption (only in PSF), and social aspects (in both PSF and MCGR) were significantly worse when compared to the normative values. According to the multivariable linear regression model (R-square = 0.690, p

Abstract 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.

Delayed bone defect repairs lead to severe health and socioeconomic impacts on patients. Hence, there are increasing demands for medical interventions to promote bone defect healing. Recombinant proteins such as BMP-2 have been recognized as one of the powerful osteogenic substances that promote mesenchymal stem cells (MSCs) to osteoblast differentiation and are widely applied clinically for bone defect repairs. However, recent reports show that BMP-2 treatment has been associated with clinical adverse side effects such as ectopic bone formation, osteolysis and stimulation of inflammation. Here, we have identified one new osteogenic protein, named ‘HKUOT-S2’ protein, from Dioscorea opposita Thunb. Using the bone defect model, we have shown that the HKUOT-S2 protein can accelerate bone defect repair by activating the mTOR signaling axis of MSCs-derived osteoblasts and increasing osteoblastic biomineralization. The HKUOT-S2 protein can also modulate the transcriptomic changes of macrophages, stem cells, and osteoblasts, thereby enhancing the crosstalk between the polarized macrophages and MSCs-osteoblast differentiation to facilitate osteogenesis. Furthermore, this protein had no toxic effects in vivo. We have also identified HKUOT-S2 peptide sequence TKSSLPGQTK as a functional osteogenic unit that can promote osteoblast differentiation in vitro. The HKUOT-S2 protein with robust osteogenic activity could be a potential alternative osteoanabolic agent for promoting osteogenesis and bone defect repairs. We believe that the HKUOT-S2 protein may potentially be applied clinically as a new class of osteogenic agent for bone defect healing.

Compact, low‐inertia, and soft compliant robotic joint mechanisms are in great demand for ensuring safe interactions in human–robot collaborative tasks. Tensegrity, of which the structural integrity is constrained by tension, does not involve static/sliding friction among the rigid components. However, this mechanical stability is very susceptible to actuation errors. It requires complex kinematics modeling and sophisticated control model with sensing feedback. Herein, a low‐inertia tensegrity joint that is covered/protected by a fiber Bragg grating (FBG)‐embedded silicone sheath is proposed, with the aim to reinforce the joint motion stability and enable self‐contained sensing feedback. A learning‐based closed‐loop controller is also designed and trained with the proper joint configurations selected by a two‐step sampling method. Both the kinematics and static equilibriums of such configurations can be well satisfied. The experiments demonstrate that the joint can follow paths accurately in 2D by compensating manipulation error shortly under the closed‐loop control. The joint stiffness can also be varied against the external/impulsive disturbances. It can be foreseen that this primitive robot joint component with 2 degrees of freedom (DoFs) can provide safe, compliant interaction with human, for which a simple test of maneuvering a portable ultrasound probe (≈210 g) for abdominal imaging is demonstrated.

Summary: Background: Adolescent idiopathic scoliosis (AIS) affects up to 5% of the population. The efficacy of school-aged screening remains controversial since it is uncertain which curvatures will progress following diagnosis and require treatment. Patient demographics, vertebral morphology, skeletal maturity, and bone quality represent individual risk factors for progression but have yet to be integrated towards accurate prognostication. The objective of this work was to develop composite machine learning-based prediction model to accurately predict AIS curves at-risk of progression. Methods: 1870 AIS patients with remaining growth potential were identified. Curve progression was defined by a Cobb angle increase in the major curve of ≥6° between first visit and skeletal maturity in curves that exceeded 25°. Separate prediction modules were developed for i) clinical data, ii) global/regional spine X-rays, and iii) hand X-rays. The hand X-ray module performed automated image classification and segmentation tasks towards estimation of skeletal maturity and bone mineral density. A late fusion strategy integrated these domains towards the prediction of progressive curves at first clinic visit. Findings: Composite model performance was assessed on a validation cohort and achieved an accuracy of 83.2% (79.3–83.6%, 95% confidence interval), sensitivity of 80.9% (78.2–81.9%), specificity of 83.6% (78.8–84.1%) and an AUC of 0.84 (0.81–0.85), outperforming single modality prediction models (AUC 0.65–0.78). Interpretation: The composite prediction model achieved a high degree of accuracy. Upon incorporation into school-aged screening programs, patients at-risk of progression may be prioritized to receive urgent specialist attention, more frequent follow-up, and pre-emptive treatment. Funding: Funding from The Society for the Relief of Disabled Children was awarded to GKHS.

Silver nanoparticles (AgNPs) possess anti-inflammatory activities and have been widely deployed for promoting tissue repair. Here we explored the efficacy of AgNPs on functional recovery after spinal cord injury (SCI). Our data indicated that, in a SCI rat model, local AgNPs delivery could significantly recover locomotor function and exert neuroprotection through reducing of pro-inflammatory M1 survival. Furthermore, in comparison with Raw 264.7-derived M0 and M2, a higher level of AgNPs uptake and more pronounced cytotoxicity were detected in M1. RNA-seq analysis revealed the apoptotic genes in M1 were upregulated by AgNPs, whereas in M0 and M2, pro-apoptotic genes were downregulated and PI3k-Akt pathway signaling pathway was upregulated. Moreover, AgNPs treatment preferentially reduced cell viability of human monocyte-derived M1 comparing to M2, supporting its effect on M1 in human. Overall, our findings reveal AgNPs could suppress M1 activity and imply its therapeutic potential in promoting post-SCI motor recovery.

Abstract 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.

Although extrapulmonary complications of different organ systems are recognized in patients with severe COVID19 effects are less well studied. Here, Qiao et al. characterize the pathogenesis of SARS-CoV-2 on bone metabolism in Syrian hamster and find that bone loss is associated with virus-mediated cytokine dysregulation.

Purpose Over the past 12 years, vertebral body tethering (VBT) has been gradually promoted for treating scoliosis, but there are few published studies, with only short-term follow-up. This study aimed to systematically review VBT efficacy and safety for treating scoliosis. Methods PubMed, Web of Science, Embase, and the Cochrane Library were searched for studies on VBT treatment of scoliosis published up to November 2021. Two researchers independently screened the literature, extracted data, and assessed the risk of bias in included studies. Data on clinical efficacy, unplanned reoperations, and complications were extracted. The meta-analysis was performed with R 4.1.0. Results Twenty-six studies involving 1045 patients were included in the meta-analysis. The correction rate of major curve immediately post-operation was 46.6% ± 13.8% (16%–69%) and that at final follow-up was 53.2% ± 17.9% (16%–79%). The single-arm meta-analysis results of all included studies showed that VBT was effective in general. The overall clinical success rate was 73.02% (95% confidence interval [CI]: 68.31%–78.05%). The pooled overall unplanned reoperation rate was 8.66% (95% CI: 5.53%–13.31%). The overall incidence rate of complications was 36.8% (95% CI: 23.9%–49.7%). The subgroup analysis based on follow-up time indicated that patients with follow-up time >36 months had increased clinical success rate, unplanned reoperation rate, and incidence rate of complications compared with those with

IntroductionSpinal cord injury (SCI) causes significant and permanent disability affecting motor, sensory and autonomic functions. We conducted a survey on the priorities of functional recovery and preferences for community rehabilitation services in a cohort of Chinese individuals with SCI as well as the primary caregivers. The study also investigated their views on advanced technology and research.MethodsAn online platform with a self-administered questionnaire was used to collect the opinions of clients that received services from an SCI follow-up clinic, a self-help association, or a non-government organization from 1 September−31 December 2021.ResultsEighty-seven subjects (74 individuals with SCI−48 tetraplegic, 26 paraplegic, and 13 caregivers) responded to the survey. Recovery of arm/hand function was given the highest priority among tetraplegics, followed by upper trunk/body strength and balance, and bladder/bowel function. Sexual function had a significant lower ranking than all priority areas except normal sensation (p < 0.05). Paraplegics viewed bladder/bowel function as the most important area of functional recovery, followed by walking movement, upper trunk/body strength and balance, elimination of chronic pain, and regaining normal sensation. There was no statistically significant difference among the top priority areas (p > 0.05). In contrast to previous studies done in Western populations, the study revealed that sexual function was ranked as the lowest by all 3 groups of respondents (tetraplegics, paraplegics, and caregivers). The majority of participants thought community rehabilitation services were inadequate. Most of the respondents were interested to try advanced technology which would facilitate their daily life and rehabilitation. About half of the individuals with SCI thought advance in technology and research could bring significant improvement in their quality of life in the coming 10 years.ConclusionThis survey is the first study specifically looking into the recovery and rehabilitation priorities of a Chinese population of individuals with SCI. This is also the first study to investigate the priorities of the primary caregivers of SCI individuals. The findings are useful as a reference for planning of future research and provision of rehabilitation services for the SCI community locally and in other parts of China.

Abstract Background The first magnetically controlled growing rod (MCGR) was implanted in 2009. Since then multiple complications have been identified that have helped drive the development of the MCGR and its surgery. The aim of this report is to illustrate how identified complications in the first MCGR helped with developments in the past decade and to report a unique failure mechanism with stud fracture close to the barrel opening. Case presentation A 5-year old girl with a scoliosis of 58.5 degrees at T1–9 and 72.8 degrees at T9-L4 had a single MCGR inserted and anchored at T3–4 and L3–4. At postoperative 13 months the MCGR was noted to have lost of distraction between lengthening episodes due to unrestricted turning of the internal magnet. To prevent further loss of distraction, an external magnet was placed outside the skin to prevent the magnet from turning back. The overall balance was suboptimal and after the rod was fully distracted, proximal junctional kyphosis occurred. Subsequently, the MCGR was modified with an internal keeper plate to prevent loss of distraction and a dual set of these rods were implanted when the patient was 9 years old. Extension proximally to C7-T1 was done to manage the proximal junctional kyphosis. Her spinal balance improved and distractions continued. She subsequently developed add-on below and the piston rod was not aligned with the actuator. The lumbar spine was also observed to have autofusion. She subsequently had final fusion surgery performed at the age of 15 from C7-L4 leaving a residual tilt below to avoid fusion to the pelvis. The final extracted rod on the left side indicated the “crooked rod sign” on X-ray and rod dissections revealed a new failure mechanism of stud fracture close to the barrel opening. Body fluids and tissue may infiltrate the rod despite no obvious deformation or fractures resulting in hastened wearing of the threads. Conclusions There are various complications associated with MCGRs that are related to rod design and surgical inexperience. Repeated rod stalling is not recommended with potential stud fracture and “crooked rod sign”. Rotor stalling and thread wearing which indicates rod failure still require solutions.

Abstract Background There are no clear indicators for predicting return to work for patients with chronic low back pain (LBP). We aim to report the outcomes of a 14-week multidisciplinary programme targeting patients with chronic LBP who failed conventional physiotherapy to provide functional rehabilitation. Also, this study will identify factors predicting successful return to work (RTW). Methods A collected cohort of patients with chronic LBP was consecutively enrolled into the programme from 1996 to 2014. All recruited patients failed to RTW despite at least 3 months of conservative treatment. Patient underwent weekly multidisciplinary sessions with physiotherapists, occupational therapists and clinical psychologists. Patient perceived function was considered the primary outcome of the programme. Patients were assessed for their sitting, standing and walking tolerance. Oswestry Disability Index (ODI) and Spinal Function Sort Score (SFSS) were used to assess patient perceived disability. Results One hundred and fifty-eight patients were recruited. After the programme, statistically significant improvement was found in ODI (47.5 to 45.0, p = 0.01) and SFSS (98.0 to 109.5, p

Background: Prediction of curve progression risk in adolescent idiopathic scoliosis (AIS) remains elusive. Prior studies have revealed the potential for three-dimensional (3D) morphological parameters to prognosticate progression, but these require specialized biplanar imaging equipment and labor-intensive software reconstruction. This study aimed to formulate a deep learning model with standing posteroanterior (PA) X-rays at first clinic visit to differentiate between progressive (P) and non-progressive (NP) curves. Methods: For this retrospective cohort study, we identified patients presenting with AIS between October 2015 to April 2020 at our tertiary referral centre. Patients with mild curvatures (11 – 30o) who were skeletally immature (Risser sign of ≤2) were recruited. Patients receiving biplanar X-ray radiographs (EOS™) were divided between a training-cross-validation cohort (328 patients) and independent testing cohort (110 patients). Another 52 patients receiving standard PA spinal X-rays were recruited for cross-platform validation. Following 3D reconstruction, we designated the major curve apex upon PA X-rays as the region of interest (ROI) for machine learning. A self-attentive capsule network was constructed to differentiate between curves manifesting P and NP trajectories. A two-stage transfer learning strategy was introduced to pre-train and fine-tune the model. Model performance (accuracy, sensitivity, specificity) was compared to that of traditional convolutional neural networks (CNNs) and a clinical parameter-based logistic regression model. Findings: 3D reconstruction identified that apical rotation of the major curve and torsion were significantly different between P and NP curve trajectories. Our predictive model utilizing an ROI centered on the major curve apex achieved an accuracy of 76.6%, a sensitivity of 75.2% and a specificity of 80.2% upon independent testing. Cross-platform performance upon standard standing PA X-rays yielded an accuracy of 77.1%, a sensitivity of 73.5% and a specificity of 81.0%. Errors in prediction occurred when the degree of apical rotation / torsion was discrepant from that of the subsequent curve trajectory but could be rectified by considering serial X-rays. Performance was superior to that of traditional CNNs as well as clinical parameter-based regression models. Interpretation: This is the first report of automated prediction of AIS curve progression based on radiomics and deep learning, towards directing treatment strategy at first visit. Patients predicted to be at-risk of progression may be counselled to receive early bracing with enforcement of treatment compliance. Over-treatment may be avoided in curves deemed to be non-progressive. Results need to be consolidated in larger sample populations of different ethnicities. Funding: The Society for the Relief of Disabled Children (SRDC).

Purpose: To assess whether the magnitude of lengthening in magnetically controlled growing rod (MCGR) surgeries has an immediate or delayed effect on spinal off-loading. Methods: 9 whole porcine spines were instrumented using two standard MCGRs from T9 to L5. Static compression testing using a mechanical testing system (MTS) was performed at three MCGR lengthening stages (0 mm, 2 mm, and 6 mm) in each spine. At each stage, five cycles of compression at 175N with 25 min of relaxation was carried out. Off-loading was derived by comparing the load sustained by the spine with force applied by the MTS to the spine. Micro-CT imaging was subsequently performed. Results: The mean load sustained by the vertebral body before lengthening was 39.69N, and immediately after lengthening was 25.12N and 19.91N at 2 mm and 6 mm lengthening, respectively; decreasing to 10.07N, 8.31N, and 8.17N after 25 minutes of relaxation, at 0 mm, 2 mm, and 6 mm lengthening stages, respectively. There was no significant difference in off-loading between 2 mm and 6 mm lengthening stages, either instantaneously ( p = 0.395) or after viscoelastic relaxation ( p = 0.958). CT images showed fractures/separations at the level of pedicle screws in six spines and in the vertebral body’s growth zone in five spines after 6 mm MCGR lengthening. Conclusion: This study demonstrated MCGRs cause significant off-loading of the spine leading to stress shielding. 6 mm of lengthening caused tissue damage and microfractures in some spines. There was no significant difference in spine off-loading between 2 mm and 6 mm MCGR lengthening, either immediately after lengthening or after viscoelastic relaxation.

Magnetically controlled growing rods have been used to treat early-onset scoliosis for the last 9 years; however, few studies have been published, with only short-term follow-up. The aim of the present study is to systematically review the outcomes of magnetically controlled growing rods in the treatment of early-onset scoliosis with a minimum of 2-year follow-up. Studies were included if patients with early-onset scoliosis (scoliosis diagnosed before 10 years of age) underwent implantation of magnetically controlled growing rods with a minimum of 2-year follow-up. The literature review and data extraction followed the established preferred reporting items for systematic review and meta-analysis guidelines. Data of distraction frequency, number of distractions, distracted length, Cobb angle, kyphosis, T1–T12 length, and T1–S1 length preoperatively, postoperatively, and at final follow-up were collected. Data regarding complications and unplanned reoperations were also extracted. The mean values of these parameters were calculated, or pooled meta-analysis was performed if available. Ten articles were included in this systematic review, with a total of 116 patients and a follow-up period between 23 and 61 months. The mean preoperative Cobb angle and kyphosis angle were 60.1° and 38.0°, respectively, and improved to 35.4° and 26.1° postoperatively. At final follow-up, the Cobb and kyphosis angles were maintained at 36.9° and 36.0°, respectively. The average preoperative T1–T12 and T1–S1 lengths were 180.6 mm and 293.6 mm, respectively, and increased to 198.3 mm and 320.3 mm postoperatively. T1–T12 and T1–S1 lengths were 212.3 mm and 339.3 mm at final follow-up, respectively. The overall rate of patients with complications was 48% (95% confidence interval [CI], 0.38–0.58) and unplanned reoperation 44% (95% CI, 0.33–0.55) after sensitivity analysis. The current evidence from different countries with a minimum of a 2-year follow-up suggests that magnetically controlled growing rods are an effective technique to treat pediatric scoliosis and promote spine growth. However, nearly half of patients still developed complications or required unplanned reoperations.

Summary: Intervertebral disc degeneration might be amenable to stem cell therapy, but the required cells are scarce. Here, we report the development of a protocol for directed in vitro differentiation of human pluripotent stem cells (hPSCs) into notochord-like and nucleus pulposus (NP)-like cells of the disc. The first step combines enhancement of ACTIVIN/NODAL and WNT and inhibition of BMP pathways. By day 5 of differentiation, hPSC-derived cells express notochordal cell characteristic genes. After activating the TGF-β pathway for an additional 15 days, qPCR, immunostaining, and transcriptome data show that a wide array of NP markers are expressed. Transcriptomically, the in vitro-derived cells become more like in vivo adolescent human NP cells, driven by a set of influential genes enriched with motifs bound by BRACHYURY and FOXA2, consistent with an NP cell-like identity. Transplantation of these NP-like cells attenuates fibrotic changes in a rat disc injury model of disc degeneration. : Zhang et al. report notochord-like and nucleus pulposus (NP)-like cells can be derived from human pluripotent stem cells using a NOTO-eGFP reporter system and a compound-defined protocol. These derived NP-like cells share high similarities with adolescent human NP cells and attenuate injury-induced intervertebral disc degeneration after transplantation. Keywords: human induced pluripotent stem cells, intervertebral disc disease, nucleus pulposus (NP)-like cells, notochord-like cells (NCLs), directed differentiation

Study DesignA prospective genetic association study.PurposeThe etiology of Modic changes (MCs) is unclear. Recently, the role of genetic factors in the etiology of MCs has been evaluated. However, studies with a larger patient subset are lacking, and candidate genes involved in other disc degeneration phenotypes have not been evaluated. We studied the prevalence of MCs and genetic association of 41 candidate genes in a large Indian cohort.Overview of LiteratureMCs are vertebral endplate signal changes predominantly observed in the lumbar spine. A significant association between MCs and lumbar disc degeneration and nonspecific low back pain has been described, with the etiopathogenesis implicating various mechanical, infective, and biochemical factors.MethodsWe studied 809 patients using 1.5-T magnetic resonance imaging to determine the prevalence, patterns, distribution, and type of lumbar MCs. Genetic association analysis of 71 single nucleotide polymorphisms (SNPs) of 41 candidate genes was performed based on the presence or absence of MCs. SNPs were genotyped using the Sequenome platform, and an association test was performed using PLINK software.ResultsThe mean age of the study population (n=809) was 36.7±10.8 years. Based on the presence of MCs, the cohort was divided into 702 controls and 107 cases (prevalence, 13%). MCs were more commonly present in the lower (149/251, 59.4%) than in the upper (102/251, 40.6%) endplates. L4–5 endplates were the most commonly affected levels (30.7%). Type 2 MCs were the most commonly observed pattern (n=206, 82%). The rs2228570 SNP of VDR (p=0.02) and rs17099008 SNP of MMP20 (p=0.03) were significantly associated with MCs.ConclusionsGenetic polymorphisms of SNPs of VDR and MMP20 were significantly associated with MCs. Understanding the etiopathogenetic mechanisms of MCs is important for planning preventive and therapeutic strategies.

Study DesignRetrospective series.PurposeAssess results of decompression-only surgery for low-grade degenerative spondylolisthesis with consideration of instability.Overview of LiteratureThere is no consensus on whether fusion or decompression-only surgery leads to better outcomes for patients with low-grade degenerative spondylolisthesis. Current trends support fusion but many studies are flawed due to over-generalization without consideration of radiological instability and their variable presentations and natural history.MethodsPatients with surgically treated degenerative spondylolisthesis from 1990–2013 were included. Clinical and radiological instability measures were included. Any residual or recurrence of symptoms, revision surgery performed and functional outcome scores including the numerical global rate of change scale, visual analogue scale, and modified Barthel index were measured. Follow-up periods for patients were divided into short-term (10 years).ResultsA total of 64 patients were recruited. Mechanical low back pain was noted in 48 patients and most (85.4%) had relief of back pain postoperatively. Radiological instability was noted in 4 subjects by flexion-extension radiographs and 12 subjects with prone traction radiographs by increased disc height and reduction of olisthesis and slip angle. From the results of the short-term, mid-term and long-term follow-up, reoperation only occurred within the first 5-year follow-up period. All functional scores improved from preoperative to postoperative 1-year follow-up.ConclusionsDecompression-only for low-grade degenerative spondylolisthesis has good long-term results despite instability. Further higher-level studies should be performed on this patient group with radiological instability to suggest the superior surgical option.

Lumbar disc degeneration (LDD) is age-related break-down in the fibrocartilaginous joints between lumbar vertebrae. It is a major cause of low back pain and is conventionally assessed by magnetic resonance imaging (MRI). Like most other complex traits, LDD is likely polygenic and influenced by both genetic and environmental factors. However, genome-wide association studies (GWASs) of LDD have uncovered few susceptibility loci due to the limited sample size. Previous epidemiology studies of LDD also reported multiple heritable risk factors, including height, body mass index (BMI), bone mineral density (BMD), lipid levels, etc. Genetics can help elucidate causality between traits and suggest loci with pleiotropic effects. One such approach is polygenic score (PGS) which summarizes the effect of multiple variants by the summation of alleles weighted by estimated effects from GWAS. To investigate genetic overlaps of LDD and related heritable risk factors, we calculated the PGS of height, BMI, BMD and lipid levels in a Chinese population-based cohort with spine MRI examination and a Japanese case-control cohort of lumbar disc herniation (LDH) requiring surgery. Because most large-scale GWASs were done in European populations, PGS of corresponding traits were created using weights from European GWASs. We calibrated their prediction performance in independent Chinese samples, then tested associations with MRI-derived LDD scores and LDH affection status. The PGS of height, BMI, BMD and lipid levels were strongly associated with respective phenotypes in Chinese, but phenotype variances explained were lower than in Europeans which would reduce the power to detect genetic overlaps. Despite of this, the PGS of BMI and lumbar spine BMD were significantly associated with LDD scores; and the PGS of height was associated with the increased the liability of LDH. Furthermore, linkage disequilibrium score regression suggested that, osteoarthritis, another degenerative disorder that shares common features with LDD, also showed genetic correlations with height, BMI and BMD. The findings suggest a common key contribution of biomechanical stress to the pathogenesis of LDD and will direct the future search for pleiotropic genes.

Purpose: To compare the yearly cost involved per patient in the use of magnetically controlled growing rod (MCGR) and traditional growing rods (TGRs) in the treatment of early onset scoliosis (EOS) and to assess the overall cost burden of MCGR with reference to patient and health-care infrastructure. Methods: For a hypothetical case of a 5-year-old girl with a diagnosis of EOS, a decision-tree model using TreeAge Software was developed to simulate annual health state transitions and compare the 8-year accumulative direct, indirect, and total cost among the four groups: (1) dual MCGRs with exchange every 2 years, (2) dual MCGRs with exchange every 3 years, (3) TGR with surgical distraction every year, and (4) TGR with surgical distraction every 6 months. Base-case values and ranges of clinical parameters reflecting complication rate after each type of surgical distraction were determined from a review of literature and expert opinion. Government gazette and expert opinion provided cost estimation of growing rods, surgeries, surgical complications, and routine follow-up. Microsimulation of 1000 individuals was conducted to test the variation in total direct costs (in 2016 Hong Kong dollars (HKD)) between individuals, and estimated the standard deviations of total direct costs for each group. Results: Over the projected treatment period, indirect costs incurred by patients and family were higher for the MCGR as compared to the TGR. However, the total costs incurred by MCGR groups (group 1: HKD164k; group 2: HKD138k) were lower than those incurred by TGR groups (group 3: HKD191k; group 4: HKD290k). Although the accumulative costs of three groups (TGR with distraction every year and MCGR replacing every 2 and 3 years) were approaching each other in the first 2 years after initial implantation, at year 3 the accumulative cost of MCGR exchange every 2 years was HKD36k more than the yearly TGR surgery due to the cost of implant exchange. The cost incurred by both the MCGR groups was less than that incurred by the TGR groups from year 4 to skeletal maturity. Conclusions: The use of dual MCGRs, regardless of its 2- or 3-year exchange, was only cost saving and less expensive than the dual TGRs for EOS treatment from the fourth year of continuous treatment. Despite higher patient-related costs during MCGR treatment, it is important to consider the reduced risks and mental burden suffered by these children during repeat surgeries. With improved knowledge of the costs associated with long-term MCGR use, better constructed cost-effectiveness studies can be performed in the future.

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.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.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.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).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.

Purpose To assess the effect of frequent small distractions with a magnetically controlled growing rod (MCGR) on spinal length gain and achieved distraction length in children with early-onset scoliosis (EOS), and to determine whether the law of diminishing returns applies to this group of patients with MCGR. Methods A consecutive series of 3 males and 4 females with EOS who underwent MCGR implantation at a mean age of 10.2 years and were followed up for a mean of 3.8 years were reviewed. Distraction was aimed at 2 mm monthly. The coronal Cobb angle, T1-S1 length gain, and achieved distraction length were measured at 6-monthly intervals. Results The mean total number of distractions was 31. Four of the patients had problems that may have affected distractions. The mean coronal Cobb angle improved post-operatively and was maintained throughout the follow-up period. The mean T1-S1 length gain and achieved distraction length varied over the follow-up period and did not diminish with repeated lengthening. Conclusions Frequent small distractions with the MCGR for EOS enable T1-S1 and achieved distraction length gain without significant reduction in gain after repeated lengthening.

INTRODUCTION:High intensity zones (HIZ) of the lumbar spine are a phenotype of the intervertebral disc noted on MRI whose clinical relevance has been debated. Traditionally, T2-weighted (T2W) magnetic resonance imaging (MRI) has been utilized to identify HIZ of lumbar discs. However, controversy exists with regards to HIZ morphology, topography, and association with other MRI spinal phenotypes. Moreover, classification of HIZ has not been thoroughly defined in the past and the use of additional imaging parameters (e.g. T1W MRI) to assist in defining this phenotype has not been addressed. MATERIALS AND METHODS:A cross-sectional study of 814 (69.8% females) subjects with mean age of 63.6 years from a homogenous Japanese population was performed. T2W and T1W sagittal 1.5T MRI was obtained on all subjects to assess HIZ from L1-S1. We created a morphological and topographical HIZ classification based on disc level, shape type (round, fissure, vertical, rim, and enlarged), location within the disc (posterior, anterior), and signal type on T1W MRI (low, high and iso intensity) in comparison to the typical high intensity on T2W MRI. RESULTS:HIZ was noted in 38.0% of subjects. Of these, the prevalence of posterior, anterior, and both posterior/anterior HIZ in the overall lumbar spine were 47.3%, 42.4%, and 10.4%, respectively. Posterior HIZ was most common, occurring at L4/5 (32.5%) and L5/S1 (47.0%), whereas anterior HIZ was most common at L3/4 (41.8%). T1W iso-intensity type of HIZ was most prevalent (71.8%), followed by T1W high-intensity (21.4%) and T1W low-intensity (6.8%). Of all discs, round types were most prevalent (anterior: 3.6%, posterior: 3.7%) followed by vertical type (posterior: 1.6%). At all affected levels, there was a significant association between HIZ and disc degeneration, disc bulge/protrusion and Modic type II (p

Purpose. To evaluate the insertion torque and pullout strength of pedicle screws with or without repositioning. Methods. 20 fresh porcine lumbar vertebrae of similar size were used. The entry point was at the site just lateral and distal to the superior facet joint of the vertebra, and to a depth of 35 mm. A 6.2-mm-diameter, 35-mm-long pedicle screw was inserted parallel to the superior end plate on one side as control. On the other side, an identical screw was first inserted 10° caudal to the superior end plate, and then repositioned parallel to the superior end plate. The insertional torque and pullout strength were measured. Results. Three of the specimens were excluded owing to pedicle fractures during the pullout test. Repositioned pedicle screws were significantly weaker than controls in terms of the maximum insertional torque (3.20±0.28 vs. 2.04±0.28 Nm, 36% difference, p±0.01) and pullout strength (1664±378 vs. 1391±295 N, p±0.01). Conclusion. Repositioning pedicle screws should be avoided, especially when the pedicle wall is breached. If repositioning is deemed necessary, augmentation with polymethyl methacrylate or a screw with a larger diameter should be considered.

Purpose. To examine the effectiveness of a multidisciplinary rehabilitation programme for patients with chronic low back pain in Hong Kong, and to identify factors associated with work resumption. Methods. 57 men and 8 women aged 20 to 56 (mean, 39) years who had a >3-month history of low back pain and were unresponsive to >6 months of conventional treatment participated in a 14-week multidisciplinary rehabilitation programme involving physical conditioning, work conditioning, and work readiness. Training protocols entailed flexibility and endurance training, hydrotherapy, weight lifting, and work stimulation. Patients were assessed at baseline (week 1), week 7, week 14, and month 6 with regard to the intensity of low back pain, self-perceived disability, range of lumbar motion, isoinertial performance of the trunk muscles, and depression level. Patient demographics that influenced work resumption were identified using a prediction model. Patients who did and did not return to work were compared. Results. Of the 54 patients who completed all follow-up assessments, 28 returned to work and 26 did not. The latter was significantly older (37 vs. 42 years, p=0.038) and absent from work longer (11 vs. 22 months, p=0.029) than the former. The rehabilitation programme helped patients regain physical function and the ability to work. Patients who returned to work showed greater improvement in self-perceived disability and physical function. Conclusion. This rehabilitation programme facilitated regain of physical functioning and the ability to return to work. The pre-programme employment status, duration of absence from work, and patient age were the most important predictors for work resumption.

BackgroundThe Global Alignment and Proportion (GAP) score, based on pelvic incidence-based proportional parameters, was recently developed to predict mechanical complications after surgery for spinal deformities in adults. However, this score has not been validated in an independent external dataset.Questions/purposesAfter adult spinal deformity surgery, is a higher GAP score associated with (1) an increased risk of mechanical complications, defined as rod fractures, implant-related complications, proximal or distal junctional kyphosis or failure; (2) a higher likelihood of undergoing revision surgery to treat a mechanical complication; and (3) is a lower (more proportioned) GAP score category associated with better validated outcomes scores using the Oswestry Disability Index (ODI), Scoliosis Research Society-22 (SRS-22) and the Short Form-36 questionnaires?MethodsA total of 272 patients who had undergone corrective surgeries for complex spinal deformities were enrolled in the Scoli-RISK-1 prospective trial. Patients were included in this secondary analysis if they fulfilled the original inclusion criteria by Yilgor et al. From the original 272 patients, 14% (39) did not satisfy the radiographic inclusion criteria, the GAP score could not be calculated in 14% (37), and 24% (64) did not have radiographic assessment at postoperative 2 years, leaving 59% (159) for analysis in this review of data from the original trial. A total of 159 patients were included in this study,with a mean age of 58 ± 14 years at the time of surgery. Most patients were female (72%, 115 of 159), the mean number of levels involved in surgery was 12 ± 4, and three-column osteotomy was performed in 76% (120 of 159) of patients. The GAP score was calculated using parameters from early postoperative radiographs (between 3 and 12 weeks) including pelvic incidence, sacral slope, lumbar lordosis, lower arc lordosis and global tilt, which were independently obtained from a computer software based on centralized patient radiographs. The GAP score was categorized as proportional (scores of 0 to 2), moderately disproportional (scores of 3 to 6), or severely disproportional (scores higher than 7 to 13). Receiver operating characteristic area under curve (AUC) was used to assess associations between GAP score and risk of mechanical complications and risk of revision surgery. An AUC of 0.5 to 0.7 was classified as "no or low associative power", 0.7 to 0.9 as "moderate" and greater than 0.9 as "high". We analyzed differences in validated outcome scores between the GAP categories using Wilcoxon rank sum test.ResultsAt a minimum of 2 years' follow-up, a higher GAP score was not associated with increased risks of mechanical complications (AUC = 0.60 [95% CI 0.50 to 0.70]). A higher GAP score was not associated with a higher likelihood of undergoing a revision surgery to treat a mechanical complication (AUC = 0.66 [95% 0.53 to 0.78]). However, a moderately disproportioned GAP score category was associated with better SF-36 physical component summary score (36 ± 10 versus 40 ± 11; p = 0.047), better SF-36 mental component summary score (46 ± 13 versus 51 ± 12; p = 0.01), better SRS-22 total score (3.4 ± 0.8 versus 3.7 ± 0.7, p = 0.02) and better ODI score (35 ± 21 versus 25 ± 20; p = 0.003) than severely disproportioned GAP score category.ConclusionBased on the findings of this external validation study, we found that alignment targets based on the GAP score alone were not associated with increased risks of mechanical complications and mechanical revisions in patients with complex adult spinal disorders. Parameters not included in the original GAP score needed to be considered to reduce the likelihood of mechanical complications.Level of evidenceLevel III, diagnostic study.