Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse.

Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction-related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 (Igf2) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.

Gut Microbiota Alterations in Adolescent Idiopathic Scoliosis Are Associated with Aberrant Bone Homeostasis.

OBJECTIVE: Low bone mineral density is the major prognostic factor for adolescent idiopathic scoliosis (AIS), but the underlying mechanisms remain unclear. Accumulating evidence suggests that gut microbiota (GM) have the potential to affect bone development, and the GM signatures are altered in AIS patients. However, the effect of GM alterations on aberrant bone homeostasis in AIS remains unclear. This study aims to investigate the GM profile in AIS patients with different bone mineral density (BMD) and explore the association between GM, osteopenia, and aberrant bone turnover. METHODS: A total of 126 patients with AIS who received surgical treatment were retrospectively included in this study. We analyzed the composition of the GM by 16S rRNA sequencing and BMD by dual X-ray absorptiometry. Based on the BMD of the femur neck, the patients were divided into the osteopenia group (OPN) if the Z score < -1, and the normal (NOR) group if the Z score ≥ -1 SD compared to the healthy control. For the 16S rRNA sequencing, the raw reads were filtered to remove low-quality reads, and operational taxonomic units were identified with the Uparse program. Weighted UniFrac distance matrix for the beta-diversity metrics and principal coordinate analysis (PCoA) was performed, and the statistical comparisons were made with permutational multivariate analysis of variance (PERMANOVA) and analysis of similarity (ANONISM). Linear discriminant analysis effect size (LEfSe) was used to identify the enriched species in two groups. The "Random forest" was applied to determine the optimal biomarker for OPN according to the mean decrease in Gini value. The metabolic function was predicted by the Tax4Fun analysis. The Pearson correlation coefficient was used to evaluate the associations between GM species, bone turnover markers, and BMD. RESULTS: The serum ß-CTX was increased in the OPN group (n = 67) compared to the NOR group (n = 59). Patients in OPN groups showed significantly decreased α diversity indicated by the Shannon index. Principal coordinate analysis (PCoA) analysis showed significant clustering of GM between OPN and NOR groups. At genus level, the Escherichia-Shigella and Faecalibacterium were significantly enriched in the OPN group compared to that in the NOR group (p < 0.05), whereas the abundance of Prevotella was significantly decreased (p = 0.0012). The relative abundance of Megamonas and Prevotella was positively correlated with the femur BMD. The abundance of Escherichia-Shigella was negatively correlated with femur BMD and positively correlated with serum ß-CTX levels. Functional analysis revealed significant differences in starch and sucrose metabolism, pyruvate and cysteine, and methionine metabolism between NOR and OPN groups. CONCLUSION: The alterations of GM in AIS patients are correlated with osteopenia. The association between enriched species, BMD, and bone turnover markers provides novel diagnostic and therapeutic targets for the clinical management of AIS.

Development of ethnicity-adjusted global alignment and proportion score to predict the risk of mechanical complications following corrective surgery for adult spinal deformity.

BACKGROUND CONTEXT: Surgery for degenerative scoliosis (DS) is a complex procedure with high complication and revision rates. Based on the concept that pelvic incidence (PI) is a constant parameter, the global alignment and proportional (GAP) score was developed from sagittal alignment data collected in the Caucasian populations to predict mechanical complications. However, the PI varies among different ethnic groups, and the GAP score may not apply to Chinese populations. Thus, this study aims to assess the predictability of the GAP score for mechanical complications in the Chinese populations and develop an ethnicity-adjusted GAP score. PURPOSE: To test the predictability of the original GAP score in the Chinese population and develop a Chinese ethnicity-tailored GAP scoring system. STUDY DESIGN/SETTINGS: Retrospective cohort study. PATIENT SAMPLE: A total of 560 asymptomatic healthy volunteers were enrolled to develop Chinese ethnicity-tailored GAP (C-GAP) score and a total of 114 DS patients were enrolled to test the predictability of original GAP score and C-GAP score. OUTCOME MEASURES: Demographic information, sagittal spinopelvic parameters of healthy volunteers and DS patients were collected. Mechanical complications were recorded at a minimum of 2-year follow-up after corrective surgery for DS patients. METHODS: A total of 560 asymptomatic healthy volunteers with a mean age of 61.9±14.1 years were enrolled to develop ethnicity-adjusted GAP score. Besides, 114 surgically trated DS patients (M/F=10/104) with a mean age of 60.7±7.1 years were retrospectively reviewed. Demographic data and radiological parameters of both groups, including PI, lumbar lordosis (LL), sacral slope (SS), the sagittal vertical axis (SVA), and global tilt (GT) were collected. Ideal LL, SS, and GT were obtained by calculating their correlation with PI of healthy volunteers using linear regression analysis. Relative pelvic version (RPV), relative lumbar lordosis (RLL), lordosis distribution index (LDI), and relative spinopelvic alignment (RSA) were obtained using the ideal parameters, and the Chinese population adjusted GAP score (C-GAP) was developed based on these values. The predictability of original and C-GAP for mechanical failure was evaluated using clinical and radiological data of DS patients by evaluating the area under the curve (AUC) using receiver operating characteristic curve. This study was supported the National Natural Science Foundation of China (NSFC) (No. 82272545), ($ 8,000-10,000) and the Jiangsu Provincial Key Medical Center, and the China Postdoctoral Science Foundation (2021M701677), Level B ($ 5,000-7,000). RESULTS: Ideal SS=0.53×PI+9 (p=.002), ideal LL=0.48×PI+22 (p=.023) and ideal GT=0.46 × PI-9 (p=.011). were obtained by correlation analysis using sagittal parameters from those healthy volunteers, and RPV, RLL, RSA, and LDI were calculated accordingly. Then, the ethnicity-adjusted C-GAP score was developed by summing up the numeric value of calculated RPV, RLL, RSA, and LDI. The AUC was classified as ''no or low discriminatory power'' for the original GAP score in predicting mechanical complications (AUC=0.592, p=.078). Similarly, the original GAP score did not correlate with mechanical complications in DS patients. According to the C-GAP score, the sagittal parameters were proportional in 25 (21.9%) cases, moderately disproportional in 68 (59.6%), and severely disproportional in 21% (18.5%) cases. The incidence of mechanical complications was statistically different among proportioned and moderately disproportional and severely disproportional portions of the C-GAP score (p=.03). The predictability of the C-GAP score is high with an AUC=0.773 (p<.001). In addition, there is a linear correlation between mechanical complication rate and C-GAP score (χ=0.102, p=.02). CONCLUSION: The Ethnicity-adjusted C-GAP score system developed in the current study provided a more accurate and reliable for predicting the risk of mechanical complications after corrective surgery for adult spinal deformity.

FNIP1 abrogation promotes functional revascularization of ischemic skeletal muscle by driving macrophage recruitment.

Ischaemia of the heart and limbs attributable to compromised blood supply is a major cause of mortality and morbidity. The mechanisms of functional angiogenesis remain poorly understood, however. Here we show that FNIP1 plays a critical role in controlling skeletal muscle functional angiogenesis, a process pivotal for muscle revascularization during ischemia. Muscle FNIP1 expression is down-regulated by exercise. Genetic overexpression of FNIP1 in myofiber causes limited angiogenesis in mice, whereas its myofiber-specific ablation markedly promotes the formation of functional blood vessels. Interestingly, the increased muscle angiogenesis is independent of AMPK but due to enhanced macrophage recruitment in FNIP1-depleted muscles. Mechanistically, myofiber FNIP1 deficiency induces PGC-1α to activate chemokine gene transcription, thereby driving macrophage recruitment and muscle angiogenesis program. Furthermore, in a mouse hindlimb ischemia model of peripheral artery disease, the loss of myofiber FNIP1 significantly improved the recovery of blood flow. Thus, these results reveal a pivotal role of FNIP1 as a negative regulator of functional angiogenesis in muscle, offering insight into potential therapeutic strategies for ischemic diseases.

Selecting the Vertebra above Sagittal Stable Vertebra as the Distal Fusion Level in Scheuermann's Kyphosis: A Prospective Study with a Minimum of 2-Year Follow-Up.

OBJECTIVE: The proper selection of the lower instrumented vertebra (LIV) remains controversial in the surgical treatment of Scheuermann's disease and there is a paucity of studies investigating the clinical outcomes of fusion surgery when selecting the vertebra one level proximal to the sagittal stable vertebra (SSV-1) as LIV. The purpose of this study is to investigate whether SSV-1 could be a valid LIV for Scheuermann kyphosis (SK) patients with different curve patterns. METHODS: This was a prospective study on consecutive SK patients treated with posterior surgery between January 2018 and September 2020, in which the distal fusion level ended at SSV-1. The LIV was selected at SSV-1 only in patients with Risser >2 and with LIV translation less than 40 mm. All of the patients had a minimum of 2-year follow-up. Patients were further grouped based on the sagittal curve pattern as thoracic kyphosis (TK, n = 23) and thoracolumbar kyphosis (TLK, n = 13). Radiographic parameters including global kyphosis (GK), lumbar lordosis (LL), sagittal vertical axis (SVA), LIV translation, pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) were measured preoperatively, postoperatively, and at the latest follow-up. The intraoperative and postoperative complications were recorded. The Scoliosis Research Society (SRS)-22 scores were performed to evaluate clinical outcomes. RESULTS: A total of 36 patients were recruited in this study, with 23 in the TK group and 13 in the TLK group. In TK group, the GK was significantly decreased from 80.8° ± 10.1° to 45.4° ± 7.7° after surgery, and was maintained at 45.3° ± 8.6° at the final follow-up. While in the TLK group, GK was significantly decreased from 70.7° ± 9.2° to 39.1° ± 5.4° after surgery (p < 0.001) and to 39.3° ± 4.5° at the final follow-up. Meanwhile, despite presenting with different sagittal alignment, significant improvement was observed in LL, SVA, and LIV translation for both TK and TLK groups (p < 0.05). Self-reported scores of pain and self-image in TK group and scores of self-image and function in TLK group showed significant improvement at the final follow-up (all p < 0.05). Distal junctional kyphosis (DJK) was observed in two patients (8.7%) in TK group, and one patient (7.7%) in TLK group. No revision surgery was performed. CONCLUSION: Selecting SSV-1 as LIV can achieve satisfactory radiographic and clinical outcomes for SK patients with different curve patterns without increasing the risk of DJK. This selection strategy could be a favorable option for SK patients with Risser sign >2 and LIV translation less than 40 mm.

Clinical outcomes of selecting the vertebra above sagittal stable vertebra as distal fusion level for Scheuermann's thoracic kyphosis / 中华骨科杂志

Objective:To investigate the clinical outcome and complications associated with utilizing sagittal plane stable vertebra-1 (SSV-1) as the distal instrumented vertebra (LIV) in posterior fusion of thoracic kyphosis with Scheuermann's Disease kyphosis (STK).Methods:A longitudinal study on patients with STK who underwent posterior correction and fusion surgery from January 2018 to June 2021 were conducted. All participants had a follow-up duration over two years. Patients were divided into two groups according to the segment of LIV: the SSV group, where LIV was located in SSV; and the SSV-1 group, where LIV was located in the vertebral body above SSV. The radiographic parameters, including global kyphosis (GK), lumbar lordosis (LL), and sagittal plane (SVA), LIV offset distance (LIV translation), pelvic incidence (PI), pelvic tilt (PT) and sacral slope (SS), were compared between the two groups. The SRS-22 scale was used to evaluate health-related quality of life at pre-operation and last follow-up, and the incidence of postoperative distal junctional kyphosis (DJK) was also recorded. Analytical techniques, such as Analysis of Variance and Mann-Whitney tests, were employed to compare inter-group differences.Results:A total of 57 patients were included in the study, 36 in the SSV group and 21 in the SSV-1 group. The average age for patients were 16.1±2.3 years (range 13-20 years), and the average follow-up time was 32.8±6.8 months (range 24-53 months). There were no statistically significant differences between the two groups in terms of gender, age, follow-up time, surgical time, intraoperative bleeding volume, and fusion level. Before surgery, the LIV deviation distance in the SSV group was significantly lower than that in the SSV-1 group (-7.9±11.0 mm vs. 31.5±11.5 mm, t=7.64, P<0.001). In the SSV group, the preoperative GK was 79.3°±10.5°, and the last follow-up GK was 44.4°±8.5°, which was significantly improved compared to preoperative value ( t=28.28, P<0.001); in the SSV-1 group, the preoperative GK was 81.1°±10.6°, and the value at 1-week post-operative was 44.9°±7.8°, which was significantly improved compared to pre-operative value ( t=22.23, P<0.001). At the last follow-up, it was 45.1°±8.7°, with a correction rate of 44.3%±8.5%. No significant difference was observed between the two groups in terms of GK, LL, SVA, PI, PT and SS at pre-operative, 1-week post-operative and last follow-up ( P>0.05). All patients had no intraoperative complications of nerve injury. During the follow-up period, one patient (1/21, 4.8%) developed DJK without complications such as proximal kyphosis, pseudarthrosis, or failed internal fixation. At the last follow-up, the functional score of SRS-22 in SSV-1 group improved from preoperative (3.5±0.54) to postoperative (4.1±0.62), with an average improvement rate of 19.2%±3.2%, and the difference was statistically significant ( t=3.74, P=0.001). These results indicating that the surgical treatment was effective in relieving the symptoms of the patients. Conclusion:Selecting SSV-1 as LIV in corrective surgeries for STK appears to produce commendable clinical results with minimal implant-associated complications over a two-year observation period.

Prevalence and distribution of ossification of ligamentum flavum at the adjacent segment of the apex in patients with degenerative kyphosis / 中华骨科杂志

Objective:To evaluate the prevalence and distribution of ossification of ligamentum flavum (OLF) at the segments adjacent to the apex in patients with degenerative kyphosis.Methods:All of 74 patients with degenerative kyphosis from January 2018 to December 2021 were retrospective reviewed. All patients were taken anteroposterior and lateral radiographs, CT scan and magnetic resonance imaging (MRI) of the entire spine. Global kyphosis, the morphology of kyphosis and the occurrence of OLF at three segments adjacent to the kyphosis apex were recorded.Results:Of the 74 patients, 54 patients (73%) developed OLF in three segments adjacent to the kyphotic apex. The mean age of the 54 patients was 61.4±6.8 years, and the mean global kyphosis was 49.5°±21.2°. Among other 20 patients without OLF, the mean age was 56.1±7.5 years, and the mean kyphosis angle was 52.1°±19.1°. There was a statistically significant difference in ages ( t=2.92, P=0.005), but no statistically significant difference was observed regarding global kyphosis ( t=0.48, P=0.634). In these 74 patients, 9 patients had angular kyphosis, of which 8 (89%) developed OLF; of the 65 patients without angular kyphosis, 46 patients (71%) developed OLF. There was no significant difference between them (χ 2=1.32, P=0.251). Among the 54 patients diagnosed with OLF, 5 patients (9%) suffered ossification of the posterior longitudinal ligament (OPLL) and 20 patients (37%) suffered dural ossification; 43 patients (80%) developed OLF at proximal segments of apex, 6 patient (11%) developed OLF at distal segments of apex, and 5 patients (9%) developed OLF both at proximal and distal segments of apex. Thirty-two patients (59%) developed OLF at the first segment adjacent to the kyphotic apex, 27 patients (50%) developed OLF at the second segment, and 15 patients (28%) developed OLF at the third segment. Conclusion:Among patients with degenerative kyphosis, about 73% may development OLF within three segments adjacent to the kyphotic apex, and it mostly occurred within two segments adjacent to the apex proximally.

The role of paraspinal muscle degeneration in coronal imbalance in patients with degenerative scoliosis.

Background: Coronal imbalance in degenerative scoliosis is common and is highly correlated with health-related quality of life. Paraspinal muscle is critical to spine stability, but little is known about its contribution to coronal imbalance in degenerative scoliosis. This study aims to investigate the relationship between paraspinal muscle (PSM) degeneration and coronal imbalance in patients with degenerative scoliosis (DS). Methods: This is a retrospective cohort study. A total of 117 patients with DS were retrospectively reviewed. Parameters of PSM (bilateral cross-sectional area, CSA; fat infiltration rate, FI%) at the apical disc and adjacent levels were quantitatively evaluated using MRI. Standing whole-spine radiograph was used to evaluate the coronal (Cobb angle, CA; coronal balance distance, CBD) and sagittal (thoracic kyphosis, TK; lumbar lordosis, LL; sagittal vertical axis, SVA) parameters. Patients were divided into 3 groups: coronal balanced (Type A), coronal imbalanced shifting to concavity (Type B), and coronal imbalanced shifting to convexity (Type C). Results: Based on our criteria, 56 patients were assigned to Type A, 34 patients to Type B, and 27 patients to Type C. There was no significant difference on the sagittal profiles and CSA between the groups. However, Type A showed significantly lower FI% than Type B and Type C on both concavity and convexity (Concave side: Type A vs. Type B vs. Type C, 30.8±8.1 vs. 45.1±7.7 vs. 38.7±12.5, P=0.001; Convex side: Type A vs. Type B vs. Type C, 32.6±10.9 vs. 46.3±7.3 vs. 40.7±11.8, P=0.004). Specifically, Cobb angle was negatively correlated with CSA, mainly at convexity (R=-0.415, P=0.008). Similarly, the increase of CBD significantly correlated with FI% at concavity (R=0.491, P=0.001) and convexity (R=0.354, P=0.025). Conclusions: DS patients with coronal imbalance demonstrated a worse PSM degeneration when compared with those without coronal imbalance. Besides, PSM degeneration strongly correlated with coronal imbalance, which implies that PSM degeneration may contribute to the coronal imbalance in patients with DS.

The Establishment of a Mouse Model for Degenerative Kyphoscoliosis Based on Senescence-Accelerated Mouse Prone 8.

Objective: Degenerative kyphoscoliosis (DKS) is a complex spinal deformity associated with degeneration of bones, muscles, discs, and facet joints. The aim of this study was to establish an animal model of degenerative scoliosis that recapitulates key pathological features of DKS and to validate the degenerative changes in senescence-accelerated mouse prone 8 (SAMP8) mice. Methods: Thirty male mice were divided into 2 groups: 10 bipedal C57BL/6J mice were used as the control group, and 20 bipedal SAMP8 mice were used as the experimental group. Mice were bipedalized under general anesthesia. The incidence of scoliosis and bone quality was determined using radiographs and in vivo micro-CT images 4, 8, and 12 weeks after surgery, respectively. Histomorphological studies of muscle samples were performed after sacrifice at 12 weeks after surgery. Results: On the 12th week, the incidence rates of kyphosis in C57BL/6J and SAMP8 groups were 50% and 100%, respectively. Overall, the incidence and angle of kyphosis were significantly higher in the bipedal SAMP8 group compared to the C57BL/6J group (44.7°± 6.2° vs. 84.3°± 10.3°, P<0.001). Based on 3D reconstruction of the entire spine, degeneration of the intervertebral disc was observed in bipedal SAMP8 mice, including the reduction of disc height and the formation of vertebral osteophytes. The bone volume ratio (BV/TV) was significantly suppressed in the bipedal SAMP8 group compared with the bipedal C57BL/6J group. In addition, HE staining and Mason staining of the paraspinal muscle tissue showed chronic inflammation and fibrosis in the muscles of the bipedal SAMP8 group. Conclusions: The SAMP8 mouse model can be taken as a clinically relevant model of DKS, and accelerated aging of the musculoskeletal system promotes the development of kyphosis.

Selection of the optimal distal fusion level for Scheuermann kyphosis with different curve patterns: when can we stop above the sagittal stable vertebra?

PURPOSE: To investigate the optimal lowest instrumented vertebra (LIV) in the treatment of Scheuermann kyphosis (SK) with different curve patterns. METHODS: Fifty-two SK patients who underwent posterior surgery between January 2010 and December 2017 with a minimum follow-up of 2 years were retrospectively reviewed. Patients were divided into two groups based on the curve pattern: the Scheuermann thoracic kyphosis (STK group) or Scheuermann thoracolumbar kyphosis (STLK group). Based on the relationship between the sagittal stable vertebra (SSV) and LIV, both groups were further divided into the SSV group and SSV-1 group. Radiographic parameters, distal junctional kyphosis (DJK) incidence and SRS-22 questionnaire scores were evaluated. RESULTS: In STK and STLK groups, there were no significant differences in most pre- and postoperative radiographic assessments between SSV and SSV-1 subgroups. DJK incidence showed no significant differences between groups during follow-up (P > 0.05). LIV-PSVL was significantly more negative in the SSV-1 group than that in the SSV group (P < 0.001). Within the SSV-1 group, patients with DJK showed a more negative LIV-PSVL (P = 0.039). Moderate correlation was observed between preoperative LIV-PSVL and DJK with a Spearman coefficient of - 0.474 (P = 0.035). Receiver operative characteristic curve analysis showed that the threshold value of preoperative LIV-PSVL to predict DJK was - 37.35 mm (area under the curve 0.882). CONCLUSION: Shorter fusion stopping at SSV-1 achieved comparable clinical outcomes and did not increase the risk of DJK for both STK and STLK patients. For patients whose preoperative LIV-PSVL < - 37.35 mm, extending fusion to SSV is an acceptable solution to prevent DJK.

Modified sequential correction technique combined 3-columns osteotomy: a safe and efficient surgical strategy for severe kyphoscoliosis / 中华骨科杂志

Objective:To investigate the feasibility and effects of modified sequential correction technique combined 3-columns osteotomy for severe kyphoscoliosis.Methods:A retrospective analysis was performed on 18 patients (7 males and 11 females) with severe kyphosis who received modified sequential correction technique combined 3-columns osteotomy in our hospital from June 2019 to April 2020. Preoperative, postoperative and final follow-up clinical and imaging outcomes were evaluated.Results:In this cohort, the average fixed segment was 11.2±3.8. The average operative duration was 401.9±68.9 min and the average intraoperative blood loss was 2 418.8±736.9 ml. The Cobb angle was improved significantly from 65.0°±16.4° pre-operatively to 41.6°±14.1° post-operatively. At final follow-up, it was 41.4°±14.3°, which was not significantly different from that after operation. Global kyphosis (GK) was 65.5°±20.8° pre-operatively and 28.1°±13.8° post-operatively with correction rate of 57.8%±17.8%. However, GK was 29.3°±14 .2° at postoperative 1 year , which was not significantly different from that after operation. There was no significant difference in C 7PL-CSVL ( F=0.449 , P=0.642) or SVA ( F=3.519, P=0.058) among the three time points. There was no alter of SEP and MEP observed during operation. Four patients had temporary lower limb numbness after operation, while the symptoms disappeared at 6 months after operation. There was no instrumental failure during the follow-up. Conclusion:Patients with severe kyphoscoliosis can obtain satisfied local correction by undergoing modified sequential correction technique combined 3-columns osteotomy without significant loss of correction at 1 year after operation. It can effectively avoid instability and dislocation of the osteotomy site and massive bleeding during the operation. As a simplified surgical procedure, it can reduce the difficulty of rod loading without prolonged operation duration. Further, this technique can ensure lower incidence of neurological complications and rod failure.

A Novel FLCN Intragenic Deletion Identified by NGS in a BHDS Family and Literature Review.

Birt-Hogg-Dubé syndrome (BHDS, MIM #135150), caused by germline mutations of FLCN gene, is a rare autosomal dominant inherited disorder characterized by skin fibrofolliculomas, renal cancer, pulmonary cysts and spontaneous pneumothorax. The syndrome is considered to be under-diagnosed due to variable and atypical manifestations. Herein we present a BHDS family. Targeted next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) revealed a novel FLCN intragenic deletion spanning exons 10-14 in four members including the proband with pulmonary cysts and spontaneous pneumothorax, one member with suspicious skin lesions and a few pulmonary cysts, as well as two asymptomatic family members. In addition, a linkage analysis further demonstrated one member with pulmonary bullae to be a BHDS-ruled-out case, whose bullae presented more likely as an aspect of paraseptal emphysema. Furthermore, the targeted NGS and MLPA data including our previous and present findings were reviewed and analyzed to compare the advantages and disadvantages of the two methods, and a brief review of the relevant literature is included. Considering the capability of the targeted NGS method to detect large intragenic deletions as well as determining deletion junctions, and the occasional false positives of MLPA, we highly recommend targeted NGS to be used for clinical molecular diagnosis in suspected BHDS patients.

Age- and gender-related sagittal spinal-pelvic alignment in Chinese adult population: a multicenter study with 786 asymptomatic subjects / 中华骨科杂志

Objective:To establish age- and gender-based normative values of sagittal spinal-pelvic alignment in Chinese adult population, and to investigate influence of age, gender and ethnicity on sagittal spinal-pelvic alignment in Chinese normal adults.Methods:A total of 786 asymptomatic Chinese adult volunteers aged between 20 and 89 years were prospectively recruited from different spine centers. The inclusion criteria were: 1) age between 20 to 89 years old; and 2) Oswestry disability index (ODI) scored lower than 20. The exclusion criteria were: 1) previous history of spinal, pelvic or lower limb pathologies that could affect the spine; 2) presence of recent and/or regular back pain; 3) previous surgeries on spine, pelvic and/or lower limb; and 4) pregnancy. Demographic characteristics of these subjects including age, gender, body weight and height were recorded. During the enrollment of volunteers, 16 groups were defined based on the age (20 s, 30 s, 40 s, 50 s, 60 s, 70 s and 80 s) and gender. Whole body biplanar standing EOS X-ray radiographs were acquired to evaluate the sagittal alignment. Spinal-pelvic parameters including pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), thoracic kyphosis (T 5-T 12, TK), lumbar lordosis (L 1-S 1, LL), lower lumbar lordosis (L 4-S 1, LLL), global tilt (GT), T1 pelvic angle (TPA) and sagittal vertical axis (SVA) were measured. Values of PI-LL and lordosis distribution index (LLL/LL, LDI) were calculated. Radiographic measurements of 100 subjects were randomly selected to determine the intra- and inter-observer reliabilities using inter- and intra-class correlation coefficients (ICC). The spinal-pelvic parameters were compared among volunteers between different age and gender groups. The comparison was also made among various ethnic population. Results:The mean value was 23.7±7.1 kg/m 2 for BMI and 6.9%±2.5% (range, 0-18%) for ODI score. Each sagittal spinal-pelvic parameter was presented with mean value and standard deviationbased on age and gender. The ICCs of radiographic measurements ranged from 0.89 to 0.95, suggesting good to excellent intra- and inter-observer reliabilities. Significant differences were observed between males and females in multiple sagittal parameters (all P values <0.05). Compared to the male subjects, significantly higher values of PI (41.4° for male vs. 45.0° for female, P<0.001), PT (10.7° for male vs. 13.9° for female, P<0.001), PI-LL (-0.5° for male vs. 1.8° for female, P<0.001), and GT (10.9° for male vs. 13.5° for female, P<0.001) were documented in female subjects. Males had significantly higher values of LLL (28.6° for male vs. 26.6° for female, P<0.001) and LDI (0.68 for male vs. 0.63 for female, P<0.001). PI-LL, SVA, GT and TPA increased with aging from Group 40 s to Group 80 s, while LL, LLL and LDI decreased gradually, and TK decreased slowly with aging. Comparison of sagittal spinal-pelvic parameters between different ethnic subjects showed that Chinese adult population presented lower PI, SS, TK and LL as compared with American population; lower PI, SS and LL as compared with Japanese population. But the variation trend with aging tended to be consistent among different ethnic populations. Conclusion:Age- and gender-based normative values of sagittal spinal-pelvic alignment were established in asymptomatic Chinese adult population. Sagittal spinal-pelvic alignment varies with age and gender, and presented different compensation mechanism among different ethnic populations. Therefore, to achieve balanced sagittal alignment, age, gender and ethnicity should be take intoconsideration when planning spine correction surgery.

Selection of the distal fusion level in posterior spinal fusion for Scheuermann kyphosis / 中华骨科杂志

Objective:To investigate the clinical outcomes and complication of posterior surgery for Scheuermann kyphosis fusing to different distal fusion levels.Methods:From January 2012 to December 2017, a consecutive cohort of 34 patients who were treated with posterior spinal instrumented correction and satisfied the inclusion criteria were retrospectively reviewed, including 29 males and 5 females, aged 17.1±4.3 years (range, 12-30 years). All of the patients had a minimum follow-up of 2 years. According to the distal fusion level, patients were divided into 2 groups. Group sagittal stable vertebra (SSV) (22 cases) included patients whose lowest instrumented vertebra (LIV) was SSV; Group SSV-1 (12 cases) included patients who had a LIV one level above the SSV. Radiographic parameters including global kyphosis (GK), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) were measured in the standing radiographs before and after operation and at the latest follow up. Intraoperative and postoperative complications were recorded. The Scoliosis Research Society-22 questionnaire (SRS-22) were conducted at pre-operation and the final follow up to evaluate the clinical outcomes. The sagittal radiographic parameters and the incidence of distal junctional kyphosis (DJK) were compared between the two groups.Results:There were no significant differences in terms of age, sex, radiographic measurements and scores of SRS-22 between two groups preoperatively ( P>0.05). The correction rates of GK in the SSV group and the SSV-1 group were 42.8%±7.6% and 43.2%±8.4% ( t=0.151, P=0.881) respectively. While the correction rates loss were 1.2%±5.2% and 3.9%±7.2% ( t=0.767, P=0.449) at the latest follow up. No significant difference was observed in terms of other radiographic parameters ( P>0.05). During the postoperative follow up period, 3 patients (16.7%) in SSV group and 2 patients (13.6%) in SSV-1 group developed DJK. The incidence of DJK did not show any significant difference between two groups ( χ2=0.057, P=0.812). At the final follow-up, the function scores of SRS-22 in SSV-1 group (4.1±0.6) was significantly higher than SSV group (3.7±0.5) ( t=2.300, P=0.028) and there was no significant difference in the rest of the domain ( P>0.05). Conclusion:Compared with stopping at SSV, fusion to SSV-1 could achieve comparable curve correction with the preservation of more lumbar motility. Moreover, it would not increase the risk of DJK. As a result, we recommend selecting SSV-1 as the ideal LIV for SK patients.