Ability of NAD and Sirt1 to epigenetically suppress albuminuria.

The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.

Neck and shoulder pain in thoracic adolescent idiopathic scoliosis 10 years after posterior spinal fusion.

PURPOSE: We aimed to determine the clinical significance of neck and shoulder pain (NSP) 10 years after posterior spinal fusion (PSF) for thoracic adolescent idiopathic scoliosis (AIS) and the relationship between radiographic parameters and NSP. METHODS: Of 72 patients who underwent PSF for thoracic AIS (Lenke 1 or 2) between 2000 and 2013, we included 52 (46 females; Lenke type 1 in 34 patients and type 2 in 18; mean age, 25.6 years) who underwent NSP evaluation using visual analog scale (VAS, 10 cm) 10 years postoperatively (follow-up rate, 72.2%). Correlation analyses were performed using Spearman's rank correlation coefficient (r). RESULTS: The VAS for NSP was 2.6 cm in median and 3.4 cm in mean at 10 years. The VAS had significant negative correlations with several SRS-22 domain scores (rs = - 0.348 for pain, - 0.347 for function, - 0.308 for mental health, and - 0.372 for total) (p < 0.05). In addition, the VAS score was significantly correlated with cervical lordosis (CL) (rs = 0.296), lumbar lordosis (rs = - 0.299), and sacral slope (rs = 0.362) (p < 0.05). Furthermore, at the 10-year follow-up, CL was significantly negatively correlated with T1 slope (rs = - 0.763) and thoracic kyphosis (TK) (- 0.554 for T1-12 and - 0.344 for T5-12) (p < 0.02). CONCLUSION: NSP was associated with deterioration in SRS-22 scores, indicating that NSP is a clinically significant long-term issue in PSF for thoracic AIS. Restoring or maintaining the TK and T1 slopes, which are controllable factors during PSF, may improve cervical lordosis and alleviate NSP at 10-year follow-up.

Quantitative assessment of muscle activity of back and lower extremities, whole body sagittal alignment, body sway, and health-related quality of life in adult spinal deformity patients before and after spinopelvic correction surgery: From the standpoint of the "cone of economy".

BACKGROUND AND AIMS: Pain and muscle fatigue in the low back and lower extremity associated with adult spinal deformity (ASD) markedly limit daily activities and affect quality of life. This study aimed to clarify if spinal correction surgery decreases the muscle activity requirements in relation to alignment and balance parameters. METHODS: Integrated electromyogram (I-EMG) studies of the low back and lower extremity in addition to whole body alignment, body sway, and health-related quality of life (HRQOL) were evaluated in 16 patients with ASD before and after surgery. Sixteen healthy volunteers were included as control subjects. Muscle activities of the bilateral lumbar paravertebral, biceps femoris, rectus femoris, gastrocnemius, and tibialis anterior were measured using surface electromyogram in both resting and working standing positions. Surgical outcomes were based on improvements in muscle fatigue using the sum of the whole muscle I-EMGs and body sway. HRQOL was evaluated by SRS-22r, which measures 4 domains (function, pain, self-image, mental health) and subtotal scores. RESULTS: In controls, the sum of the 10 whole I-EMGs (mVms; mean ± SD) was 3316 ± 1247 in the resting standing position and 5625 ± 2065 in the working standing position. The I-EMG values were higher in ASD patients than in healthy subjects; in the resting standing position, the sum of the whole 10 I-EMGs significantly decreased from baseline (9125 ± 3529) to 3 (6088 ± 1793) and 6 (6381 ± 1776) months postoperatively (p < 0.01). In the working standing position, the sum in ASD patients also significantly decreased from baseline (14,160 ± 5474) to 3 (8085 ± 2540) and 6 (8557 ± 3025) months postoperatively (p < 0.01). I-EMG values did not differ significantly between the 3- and 6-month time points in either condition. Body sway was also improved postoperatively at 3 months and maintained at 6 months along with the amelioration of whole-body sagittal alignment, and 4 domains and subtotal SRS-22r scores significantly increased postoperatively. CONCLUSION: Following spinopelvic correction surgery, whole body sagittal alignment was improved, and muscle activity based on I-EMG and body sway were significantly decreased. The SRS-22r scores after surgery also indicated significant improvement, suggesting that muscle fatigue in the standing position was ameliorated, i.e., the "cone of economy" was normalized.

Characteristics of Spinal Morphology according to the Global Alignment and Proportion (GAP) Score in a Diverse, Asymptomatic Cohort: Multi-Ethnic Alignment Normative Study.

STUDY DESIGN: Multi-Ethnic Alignment Normative Study (MEANS) cohort: prospective, cross-sectional, multi-center. OBJECTIVE: To analyze the distribution of GAP scores in the MEANS cohort and compare the spinal shape via stratification by GAP alignment category, age, and country. SUMMARY OF BACKGROUND DATA: The GAP score has been used to categorize spinal morphology and prognosticate adult spinal deformity surgical outcomes and mechanical complications. We analyzed a large, multiethnic, asymptomatic cohort to assess the distribution of GAP scores. METHODS: 467 healthy volunteers without spinal disorders were recruited in 5 countries. Sagittal radiographic parameters were measured via the EOS imaging system. The GAP total and constituent factor scores were calculated for each patient. Kruskal-Wallis rank sum test was performed to compare variables across groups, followed by post hoc Games Howell test. Fisher's exact test was used to compare categorical variables. The significance level was set to P<0.05. RESULTS: In the MEANS cohort, 13.7% (64/467) of volunteers were≥60 years old, and 86.3% (403/467) were<60 years old. 76.9% (359/467) was proportioned, 19.5% (91/467) was moderately disproportioned, and 3.6% (17/467) was severely disproportioned. There was no significant difference in the frequency of proportioned, moderately, or severely disproportioned GAP between subjects from different countries (P=0.060). Those with severely disproportioned GAP alignment were on average 14.5 years older (P=0.016), had 23.1° lower magnitude lumbar lordosis (LL) (P<0.001), 14.2° higher pelvic tilt (P<0.001), 13.3° lower sacral slope (P<0.001), 24.1° higher pelvic-incidence (PI)-LL mismatch (P<0.001), 18.2° higher global tilt (P<0.001) than those with proportioned GAP; thoracic kyphosis and PI were not significantly different (P>0.05). CONCLUSION: The GAP system applies to a large, multi-ethnic, asymptomatic cohort. Spinal alignment should be considered on a spectrum, as 19.5% of the asymptomatic volunteers were classified as moderately disproportioned and 3.6% severely disproportioned. Radiographic malalignment does not always indicate symptoms or pathology. LEVEL OF EVIDENCE: 3.

Anatomical Pelvic Parameters Using the Anterior Pelvic Plane: Normative Values and Estimation of the Standing Sagittal Alignment in Healthy Volunteers.

Introduction: In this study, we aim to estimate the natural standing sagittal alignment in patients with adult spinal deformity (ASD), firstly by investigating the normative values of anatomical pelvic parameters based on the anterior pelvic plane (APP) in a healthy population, and to clarify the relationships between the anatomical and positional pelvic parameters in standing position. Methods: The images of biplanar slot-scanning full-body stereoradiography in 140 healthy Japanese volunteers (mean age, 39.5 years; 59.3% female) were examined. In addition to three-dimensional measurements including pelvic incidence (PI), sacral slope (SS), and pelvic tilt (PT), the APP angle (APPA; anterior tilting=positive) was measured as the angle between the APP and the vertical line using the two-dimensional lateral image. Anatomical SS and PT (aSS and aPT) were calculated as the angles of SS and PT in reference to APP. Results: The mean (range) values of APPA, aSS, and aPT were determined to be 0.7° (-16.8°/15.5°), 36.8° (18.3°/64.9°), and 13.2° (-0.6°/28.7°), respectively. Moreover, SS was found to be significantly correlated with PI and aSS, while PT was significantly correlated with PI, aSS, aPT, and body weight. Also, PT was significantly larger in females than in males. Multiple linear regression analysis deduced the following equations: SS=0.404×aSS+0.203×PI+12.463, PT=-0.391×aSS+0.774×PI+1.950×sex (male=0, female=1)-12.971, wherein aSS had the greatest effect for predicting SS among the included factors and PI had the greatest effect for predicting PT. In addition, no significant differences were noted between PT/PI and aPT/PI. Conclusions: As per the results of this study, significant correlations were noted among parameters and predicting models for positional parameters (SS and PT) using anatomical parameters (aSS and aPT) in a healthy population. This novel measurement concept based on the APP has been considered to be useful in estimating natural SS and PT in standing position using the anatomical pelvic parameters in patients with ASD.

Characteristics of Spinal Morphology According to the "Current" and "Theoretical" Roussouly Classification Systems in a Diverse, Asymptomatic Cohort: Multi-Ethnic Alignment Normative Study (MEANS).

STUDY DESIGN: Cross-sectional cohort study. OBJECTIVE: To classify spinal morphology using the "current" and "theoretical" Roussouly systems and assess sagittal alignment in an asymptomatic cohort. METHODS: 467 asymptomatic volunteers were recruited from 5 countries. Radiographic parameters were measured via the EOS imaging system. "Current" and "theoretical" Roussouly classification was assigned with sagittal whole spine imaging using sacral slope (SS), pelvic incidence (PI), and the lumbar apex. One-way analysis of variance (ANOVA) was performed to compare subject characteristics across Roussouly types, followed by post hoc Bonferroni correction. RESULTS: Volunteers were categorized into 4 groups (Types 1-4) and 1 subgroup (Type 3 AP) using the "current" and "theoretical" Roussouly systems. The mean PI in "current" Roussouly groups was 40.8° (Type 1), 43.6° (Type 2), 52.4° (Type 3), 62.4° (Type 4), and 43.7° (Type 3AP). The mean PI in "theoretical" Roussouly groups was 36.5° (Type 1), 39.1°(Type 2), 52.5° (Type 3), 67.3° (Type 4), and 51.0° (Type 3AP). The difference in PI between "current" and "theoretical" Roussouly types was significant for Type 1 (P = .02), Type 2 (P < .001), Type 4 (P < .001), and Type 3AP (P < .001). 34.7% of subjects had a "current" Roussouly type different from the "theoretical" type. Type 3 theoretical shape had the most frequent mismatch, constituting 61.1% of the mismatched subjects. 51.5% of mismatched Type 3 become "current" Type 4. CONCLUSION: The distribution of Roussouly types differs depending on whether the "current" or "theoretical" classification are employed. A sizeable proportion of volunteers exhibited current and theoretical type mismatch, highlighting the need to interpret sagittal alignment cautiously when utilizing the Roussouly system.

The Importance of Pelvic Obliquity in Assessing Spinal Coronal Alignment: Normative Values, Demographic, and Radiographic Correlations.

STUDY DESIGN: Prospective, cross-sectional study. OBJECTIVE: In a geographically diverse population of asymptomatic volunteers, we sought to report the incidence of pelvic obliquity (PO), establish normative values of PO across patient factors, and assess the correlation of PO with radiographic parameters. SUMMARY OF BACKGROUND DATA: PO is defined as the misalignment of the pelvis and can be assessed through several anatomic landmarks. Significant PO, whether caused by leg-length discrepancy or not, can lead to coronal malalignment which causes severe pain and disability. Significant emphasis has been placed on achieving appropriate sagittal alignment in recent decades; however, a greater understanding of coronal alignment is needed, and PO is a crucial aspect of evaluating the coronal plane in adult spinal deformity patients. METHODS: Asymptomatic adult volunteers, ages 18-80 years, enrolled patients from 5 countries (France, Japan, Singapore, Tunisia, and the United States) in the "multiethnic alignment normative study" cohort (IRB 201812144). The included volunteers had no known spinal disorder(s), no significant neck or back pain (Visual Analog Scale: ≤2; Oswestry Disability Index: ≤20), and no abnormal alignment (Cobb ≤20°). PO was measured in the frontal plane as the distance between the highest points of each acetabulum, calculated along the vertical axis in millimeters (mm). The incidence of PO was defined as PO ≥10 mm. Kruskal-Wallis, Wilcoxon rank-sum, Pearson correlation, and linear regression were used. RESULTS: A total of 467 patients were included, and PO values by age, sex, body mass index, and country were provided. The overall incidence of PO ≥10 mm was 4.3%, and a nonsignificant trend toward increased PO with age was seen ( P = 0.077). No significant differences were seen in PO between sex, ethnicity, or body mass index groups. No significant correlation existed between PO and other commonly used coronal radiographic measurements. CONCLUSION: PO ≥10 mm occurred in 4.3% of asymptomatic volunteers. Despite the importance of recognizing PO in preventing coronal malalignment, PO did not seem to be associated with other radiographic and demographic information, which underscores the importance of intentionally assessing for any PO before surgery. These results in an asymptomatic population provide a foundation for studying PO in patients with spinal pathology.

Characteristics of back pain in patients with adolescent idiopathic scoliosis: Considerations in candidates for corrective surgery.

BACKGROUND: Previous studies have demonstrated that the point prevalence of back pain ranges from 12 % to 33 % and that the lifetime prevalence of back pain ranges from 28 % to 51 % in adolescents. However, few studies on back pain in patients with Adolescent idiopathic scoliosis (AIS) have been conducted, and these studies had significant limitations, including a lack of comparative controls and detailed information about scoliotic deformity or pain location. This study aimed to determine whether adolescents with AIS experience back pain in specific regions. METHODS: This retrospective case-control study included 189 female adolescents with AIS who underwent corrective fusion from 2008 to 2020. Questionnaires on back pain and health-related quality of life (HRQOL) using the Scoliosis Research Society Outcomes Instrument-22 (SRS-22) were conducted preoperatively. The control group included 2909 general female adolescents. RESULTS: The mean Cobb angles in the main thoracic and thoracolumbar/lumbar curves were 51.4 ± 15.3° and 40.4 ± 12.9°. Back pain characteristics included higher point prevalence (25.9 %) and lifetime prevalence (64.6 %) compared to healthy controls. Adolescents with back pain showed lower scores in the pain and mental health domains of the SRS-22. Adolescents with major thoracic AIS showed more back pain in the upper and middle right back compared to adolescents with major thoracolumbar/lumbar AIS. CONCLUSION: The point and lifetime prevalence of back pain were definitely higher in patients with AIS, which affected their HRQOL. There was a relationship between pain around the right scapula and the right major thoracic curve with a rib hump deformity.

The Posterior Cranial Vertical Line: A Novel Radiographic Marker for Classifying Global Sagittal Alignment.

OBJECTIVE: To define a novel radiographic measurement, the posterior cranial vertical line (PCVL), in an asymptomatic adult population to better understand global sagittal alignment. METHODS: We performed a multicenter retrospective review of prospectively collected radiographic data on asymptomatic volunteers aged 20-79. The PCVL is a vertical plumb line drawn from the posterior-most aspect of the occiput. The horizontal distances of the PCVL to the thoracic apex (TA), posterior sagittal vertical line (PSVL, posterosuperior endplate of S1), femoral head center, and tibial plafond were measured. Classification was either grade 1 (PCVL posterior to TA and PSVL), grade 2 (PCVL anterior to TA and posterior to PSVL), or grade 3 (PCVL anterior to TA and PSVL). RESULTS: Three hundred thirty-four asymptomatic patients were evaluated with a mean age of 41 years. Eighty-three percent of subjects were PCVL grade 1, 15% were grade 2, and 3% were grade 3. Increasing PCVL grade was associated with increased age (p < 0.001), C7-S1 sagittal vertical axis (SVA) (p < 0.001), C2-7 SVA (p < 0.001). Additionally, it was associated with decreased SS (p = 0.045), increased PT (p < 0.001), and increased knee flexion (p < 0.001). CONCLUSION: The PCVL is a radiographic marker of global sagittal alignment that is simple to implement and interpret. Increasing PCVL grade was significantly associated with expected changes and compensatory mechanisms in the aging population. Most importantly, it incorporates cervical alignment parameters such as C2-7 SVA. The PCVL defines global sagittal alignment in adult volunteers and naturally distributes into 3 grades, with only 3% being grade 3 where the PCVL lies anterior to the TA and PSVL.

Usefulness and limitations of intraoperative pathological diagnosis using frozen sections for spinal cord tumors.

BACKGROUND: Intraoperative pathological diagnosis has a major influence on the intra- and postoperative management of spinal cord tumors. Thus, the aim of this study was to assess the reliability of intraoperative pathological diagnosis for spinal cord lesions by comparing it with the final pathological diagnosis and to determine its usefulness and limitations. METHOD: Three-hundred and three consecutive patients (mean age, 53.9 years) with neoplastic spinal cord lesions who underwent initial surgery between 2000 and 2021 were included. The anatomical locations of the spinal cord tumors and the implementation rate of intraoperative pathological diagnosis in each tumor type were evaluated. As the primary outcome, we determined the concordance rates between the intraoperative pathological diagnosis and the final diagnosis. When the intraoperative pathological diagnosis and final diagnosis were the same, the diagnosis was defined as a "match." Otherwise, the diagnosis was defined as a "mismatch." RESULTS: The overall implementation rate of intraoperative pathological diagnosis was 53%, with implementation rates of 71%, 45%, 47%, and 50% for intramedullary, intradural extramedullary, extradural, and dumbbell tumors, respectively. The overall concordance rate was 87.6%, with concordance rates of 80%, 95%, 75%, and 90% for intramedullary, intradural extramedullary, extradural, and dumbbell tumors, respectively (p < 0.05). The diagnoses of ependymomas, low-grade astrocytomas, and high-grade astrocytomas was occasionally difficult among intramedullary tumors. Among intradural extramedullary tumors, differentiation between grade 1 meningioma and high-grade meningioma was difficult using intraoperative pathological diagnosis. CONCLUSIONS: Surgeons must recognize the lower accuracy of intraoperative pathological diagnosis for intramedullary and extradural lesions and make a final decision by considering the intraoperative gross findings, preoperative clinical course, and imaging.

The Thoracolumbar Inflection Point in a Population of Asymptomatic Volunteers: A Multi-Ethnic Alignment Normative Study Cohort Study.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: To show population variance in the Inflection Point (IP) and its role in defining maximum Thoracic Kyphosis (TK) and Lumbar Lordosis (LL). METHODS: 468 asymptomatic adult volunteers were included in the Multi-Ethnic Normative Alignment Study (MEANS). To find parameters correlating with IP, the vertebrae and discs were numbered such that C7 was 0, T1 was 1, with T1-T2 disc being 1.5, etc. Statistical analysis was performed by a correlation matrix for IP and the 9 other selected parameters along with linear regressions. RESULTS: The overall mean IP was 12.44 approximately corresponding to T12-L1 disc with the median being 12.50, range was T8-L4. The cohort was then stratified by sex and ethnicity, but there was no significant difference in IP between groups. IP in younger subjects was 13 (L1), compared to 12.5 (T12-L1 disc) in older subjects (P < .05). IP was moderately correlated with the TK apex (r = .66). No strong correlation was found between IP and LL magnitude or apex, TK magnitude, sacral slope, or Pelvic Incidence (PI). In terms of other sagittal parameters, PI and LL demonstrated a significant positive correlation. PI and TK did not have a strong association. CONCLUSIONS: The mean IP was at the T12-L1 disc, however IP ranged from T8 to L4. Older subjects tended to have a relatively more cephalad IP. No radiographic variable was found to be a strong predictor of the IP. TK apex was found to have a moderate correlation.

Racial differences in whole-body sagittal alignment between Asians and Caucasians based on international multicenter data.

PURPOSE: To examine inherent differences adjusted for age and clinical score in whole-body sagittal (WBS) alignment involving the lower extremities between Asians and Caucasians, and to determine the relationship between age and WBS parameters by race and sex. METHODS: A total of 317 individuals consisting of 206 Asians and 111 Caucasians participated. WBS parameters including C2-7 lordotic angle, lower lumbar lordosis (lower LL, L4-S), pelvic incidence (PI), pelvic thickness, knee flexion (KF), sagittal vertical axis (SVA), and T1 pelvic angle (TPA) were evaluated radiologically. Propensity score-matching adjustments for age and the Oswestry Disability Index scores for comparative analysis between the two race cohorts and correlation analysis between age and WBS parameters for all subjects by race and sex were conducted. RESULTS: The comparative analysis included 136 subjects (age: Asians 41.1 ± 13.5, Caucasians 42.3 ± 16.2 years, p = 0.936). Racial differences in WBS parameters were observed in C2-7 lordotic angle (-1.8 ± 12.3 vs. 6.3 ± 12.2 degrees, p = 0.001), and lower LL (34.0 ± 6.6 vs. 38.0 ± 6.1 degrees, p < .001). In correlation analysis with age, moderate or more significant correlations with age were found in KF for all groups, and in SVA and TPA for females of both racial groups. Age-related changes in pelvic parameters of PI and pelvic thickness were more significant in Caucasian females. CONCLUSION: Analysis of the correlation between age and WBS parameters suggested that age-related WBS changes vary between races and should be considered during corrective spinal surgery.

Sagittal spinal alignment varies with an individual's race: results of the multi-ethnic alignment normative study (MEANS).

PURPOSE: Assess normative values of sagittal spinal and lower extremity alignment in asymptomatic volunteers of three difference races. METHODS: Asymptomatic volunteers between the ages of 18-80 years were enrolled prospectively and then analyzed retrospectively from six different centers. Volunteers included reported no significant neck or back pain, nor any known spinal disorder(s). All volunteers underwent a standing full-body or full-spine low dose stereoradiograph. Volunteers were grouped into three main races; Asian (A), Arabo-Bèrbère (B), and Caucasian (C). The Asian volunteers included in this study were from Japan and Singapore. RESULTS: There were statistical differences in the Age, ODI, and BMI of the volunteers from the three different races. Asian volunteers had the lowest age (A: 36.7, B: 45.5, C: 42.0) and BMI (A: 22.1, B: 27.1, C: 27.3). Pelvic morphology including pelvic incidence (A: 51.0, B: 52.0, C: 52.5, p = 0.37), pelvic tilt (A: 11.9, B: 12.3, C: 12.9, p = 0.44), and sacral slope (A: 39.1, B: 39.7, C: 39.6, p = 0.77) were similar amongst the 3 races. Regional spinal alignment was different between the groups. Thoracic Kyphosis (A: 32.9, B: 43.3, C: 40.0, p < 0.0001) and Lumbar lordosis (A: - 54.2, B: - 60.4, C: - 59.6, p < 0.0001) were lower in Asians compared to Caucasian and Arabo-Bèrbère volunteers despite having similar pelvic incidence. CONCLUSION: Volunteers in the Asian group had lower lumbar lordosis and thoracic kyphosis when compared to the Arabo-Bèrbère and Caucasian groups while all groups had similar pelvic morphology. Thoracic Kyphosis had no correlation with Pelvic Incidence, while Lumbar Lordosis correlated well with both Thoracic Kyphosis and Pelvic Incidence. Thoracic kyphosis may be an independent variable in establishing adequate lumbar lordosis and varies based on an individual's race.

Morphological description of sagittal lumbar spinal alignment using curve magnitude, span, and apex-the multiethnic alignment normative study (MEANS).

BACKGROUND CONTEXT: Current definition of lumbar lordosis uses the L1-S1 angle. Prevailing classification of sagittal spinal morphology, derived from a young adult population, classifies the spine into four subtypes defined by their sacral slope (SS) and curve morphology. PURPOSE: To describe physiological sagittal alignment of the lumbar spine across age groups using three main parameters that dictate the lumbar curve: angular magnitude, span, and apex. STUDY DESIGN: A large, multicenter, cross-sectional radiographic comparison study. PATIENT SAMPLE: Four hundred sixty-eight healthy, asymptomatic subjects aged 18 to 80 years from five countries (184 males, 284 females; 98 France, 119 Japan, 79 Singapore, 80 Tunisia, 92 USA, mean age 40.61±14.99 years). OUTCOME MEASURES: Sagittal lumbar profile subtypes clustered based on lumbar curve angular magnitude (ie, Cobb angle of the lumbar lordosis), span, and apex, and described by sagittal radiographic parameters. METHODS: Subjects underwent whole-body low-dose EOS stereoradiographs. Comparisons between conventional L1-S1 lumbar lordosis (cLL) and true lumbar lordosis (tLL, defined by the inflection-S1 angle) were conducted. Using the K-means clustering algorithm, lumbar curve angular magnitude, span and apex were used to classify sagittal spinal morphology into subtypes, stratified across age groups. Further univariate and multivariate analyses were conducted to compare radiographic parameters across subtypes, and identify predictors for the lumbar curve's angular magnitude, span and apex. RESULTS: Mean cLL was -57.27±11.37°, and tLL was -62.62±10.76°. Using tLL, instead of cLL, to describe sagittal spinal morphology, we found significant differences in terms of angular magnitude of the lumbar curve, the median thoracolumbar inflection vertebral level and pelvic incidence-lumbar lordosis mismatch Multivariate analysis found a larger SS, more positive T9 tilt, and more kyphotic T4-T12 predictive for a more lordotic tLL, while a larger overhang distance predicted for a less lordotic tLL (p-values<.001). In addition, a larger T9 tilt, less lordotic L1-L5 and smaller PT were predictors of a more caudal thoracolumbar inflection and lumbar apical vertebral levels (p-values<.001). Sagittal lumbar profiles of subjects age<30 years, 30≤age<60 years and age≥60 years, could be classified into 4, 6, and 3 subtypes, respectively. CONCLUSIONS: Sagittal lumbar profile subtypes vary across age groups, with more homogenous morphologies at the extremes of ages. Improved understanding of the morphological evolution of sagittal spinal profiles with age in asymptomatic individuals will help guide future individualized surgical treatment.

PCK1 Protects against Mitoribosomal Defects in Diabetic Nephropathy in Mouse Models.

SIGNIFICANCE STATEMENT: Renal gluconeogenesis plays an important role in the pathogenesis of diabetic nephropathy (DN). Proximal tubular phosphoenolpyruvate carboxykinase1 (PEPCK1) is the rate-limiting enzyme in gluconeogenesis. However, the functions of PEPCK1 have not been elucidated. We describe the novel role of PEPCK1 as a mitoribosomal protector using Pck1 transgenic (TG) mice and knockout mice. Pck1 blocks excessive glycolysis by suppressing the upregulation of excess HK2 (the rate-limiting enzyme of glycolysis). Notably, Pck1 overexpression retains mitoribosomal function and suppresses renal fibrosis. The renal and mitoribosomal protective roles of Pck1 may provide important clues for understanding DN pathogenesis and provide novel therapeutic targets. BACKGROUND: Phosphoenolpyruvate carboxykinase (PEPCK) is part of the gluconeogenesis pathway, which maintains fasting glucose levels and affects renal physiology. PEPCK consists of two isoforms-PEPCK1 and PEPCK2-that the Pck1 and Pck2 genes encode. Gluconeogenesis increases in diabetic nephropathy (DN), escalating fasting and postprandial glucose levels. Sodium-glucose cotransporter-2 inhibitors increase hepatic and renal gluconeogenesis. We used genetically modified mice to investigate whether renal gluconeogenesis and Pck1 activity are renoprotective in DN. METHODS: We investigated the expression of Pck1 in the proximal tubule (PTs) of streptozotocin (STZ)-treated diabetic mice. We studied the phenotypic changes in PT-specific transgenic (TG) mice and PT-specific Pck1 conditional knockout (CKO) mice. RESULTS: The expression of Pck1 in PTs was downregulated in STZ-treated diabetic mice when they exhibited albuminuria. TG mice overexpressing Pck1 had improved albuminuria, concomitant with the mitigation of PT cell apoptosis and deposition of peritubular type IV collagen. Moreover, CKO mice exhibited PT cell apoptosis and type IV collagen deposition, findings also observed in STZ-treated mice. Renal fibrotic changes in CKO mice were associated with increasing defects in mitochondrial ribosomes (mitoribosomes). The TG mice were protected against STZ-induced mitoribosomal defects. CONCLUSION: PCK1 preserves mitoribosomal function and may play a novel protective role in DN.

Variation in Lumbar Shape and Lordosis in a Large Asymptomatic Population: A MEANS Study.

STUDY DESIGN: Prospective, cross-sectional cohort study. OBJECTIVE: To determine the relationship between lumbar shape and sagittal parameters. SUMMARY OF BACKGROUND DATA: Understanding the lumbar shape is vital for deformity surgery. Normative sagittal parameters and spine shape remain unstudied in large, multiethnic, asymptomatic cohorts. MATERIALS AND METHODS: A prospective, cross-sectional cohort of 468 asymptomatic volunteers between 18 and 80 years was enrolled across 5 countries. Demographic data and radiographic parameters such as pelvic incidence (PI) were collected. Pearson correlation test and linear regression were used to find the relationship between lumbar lordosis (LL) and other parameters. One-way analysis of variance and Welch 2-sample t test were performed to compare lumbar shape across such categories as PI and lumbar apex followed by post hoc Bonferroni correction if needed. RESULTS: PI was moderately correlated with proximal lumbar lordosis (pLL) ( r = -0.54) and weakly correlated with distal lumbar lordosis (dLL) ( r = -0.16). Thoracic kyphosis (T1-T12) was moderately correlated with pLL ( r = -0.35) and dLL ( r = -0.29). dLL was moderately correlated with LL ( r = 0.64). 2.6% (12/468) of subjects had lumbar apex at L2, 40.2% (188/468) at L3, 56.6% at L4 (265/468), and 0.6% (3/468) at other levels. Mean PI was different between volunteers with the apex at L3 and L4. A lower mean PI was associated with the apex at L4 (49.0°), whereas a higher mean PI was associated with the apex at L3 (55.8°). The mean PI-LL mismatch for volunteers was -5.4° with a range from -35° to 39.7°. PI-LL mismatch increased from a mean of -10.1° in volunteers with low PI to a mean of 2.2° in volunteers with high PI. Age was not correlated with LL ( P = 0.84). CONCLUSIONS: In asymptomatic adult volunteers, pLL showed a moderate correlation with PI and increased with PI, whereas dLL showed a weak correlation. The lumbar apex migrated proximally with increasing PI. Segmental lordosis and apex position instead of solely global lordosis should be emphasized. LEVEL OF EVIDENCE: Level III.

Marriage and childbirth of patients who were surgically and non-surgically treated for adolescent idiopathic scoliosis: a survey at the age of 30 years or older.

PURPOSE: We aimed to investigate the marital status and childbirth in adolescent idiopathic scoliosis (AIS) patients. METHODS: This study included women who were treated surgically or non-surgically for AIS with a scoliosis magnitude ≥ 30° before surgery or at skeletal maturity and were followed up until age 30 years or older. Patients were divided into surgically treated (S-AIS, n = 55) and non-surgically treated AIS groups (N-AIS, n = 86). Data from the national fertility survey were used as control values. RESULTS: There were no significant differences in age at the final follow-up between the S- (40.7 years) and N-AIS (42.1 years) groups. The unmarried rate among all women and the nulliparous rate among married women in the S-AIS group (29.1% and 18.4%, respectively) were similar to those in the N-AIS group (26.7% and 16.1%, respectively). The mean number of children per married woman also did not differ between the S- and N-AIS groups (1.5 vs 1.4). Compared to the control group, after adjusting for age, the common odds ratio in the AIS group was 1.56 (p = 0.031) for unmarried status and 1.88 (p = 0.026) for nulliparity among married women. Moreover, the mean number of children per married woman was significantly lower in the AIS group than in the control group (1.3 vs 1.7, p < 0.001). CONCLUSION: Surgically and non-surgically treated women with AIS had a similar status with regard to marriage and childbirth, while women with AIS were more likely to be unmarried and nulliparous and to have fewer children compared to the nationwide population.

Longer Screws Can Reduce the Stress on the Upper Instrumented Vertebra With Long Spinal Fusion Surgery: A Finite Element Analysis Study.

STUDY DESIGN: A finite element analysis study. OBJECTIVE: Of proximal junctional failure, upper instrumented vertebra (UIV) fracture can causes severe spinal cord injury. Previously, we reported that higher occupancy rate of pedicle screw (ORPS) at UIV prevented UIV fracture in adult spinal deformity surgery; we had not yet tested this finding using a biomechanical study. The purpose of present study was to measure the differences in loads on the UIV according to the length of PS and ORPS. METHODS: We designed an FE model of a lumbar spine (L1-S1) using FE software. The PS was set from L2 to S1 and connected the rod. The FE model simulated flexion (8 Nm) to investigate the loads at UIV (L2) according to the length of the PS. There were 5 screw lengths examined: 40 (ORPS 36.4%), 45 (48.5%), 50 (66.7%), 55 (81.8%), and 60 mm (93.9%). RESULTS: Stress with bending motion was likely to occur at the upper front edge of the vertebral body, the pedicles, and the screw insertion point. The maximum equivalent stress according to screw lengths of 40, 45, 50, 55, and 60 mm were 45.6, 37.2, 21.6, 13.3, and 14.8 MPa, respectively. The longer screw, the less stress was applied to UIV. No remarkable change was observed between the screw lengths of 55 and 60 mm. CONCLUSIONS: Increasing ORPS to 81.8% or more reduced the load on the UIV. To prevent UIV fracture, the PS length in the UIV should be more than ORPS 81.8%.

Evaluating flexibility and predicting curve correction using fulcrum-bending radiographs in Lenke type 2 adolescent idiopathic scoliosis.

BACKGROUND: Fulcrum-bending (FB) correction is considered to provide the best estimation of main thoracic (MT) curve flexibility and postoperative correction in surgical treatment for adolescent idiopathic scoliosis (AIS). However, few studies evaluated the usefulness of FB radiographs for proximal thoracic (PT) curve. We aimed to perform flexibility assessments using both active side-bending (SB) and FB radiographs and evaluate surgical outcomes after posterior spinal fusion (PSF) for Lenke type 2 AIS. METHODS: This study included 38 consecutive patients with Lenke type 2 AIS who underwent PSF using a pedicle screw construct with a minimum 2-year follow-up. Radiographic parameters, including correction rate, SB and FB flexibility, and FB correction index (FBCI: [correction rate/FB flexibility] × 100), were evaluated preoperatively, immediately after surgery, and at the 2-year follow-up. The clinical outcomes were preoperatively evaluated using the Scoliosis Research Outcomes Instrument-22 and at the follow-up. RESULTS: All scoliosis curves significantly improved and shoulder balance shifted toward left shoulder elevation (all comparisons, p < 0.0001). There were significant differences between the SB and FB corrections in the PT and MT curves (p < 0.0001). The magnitudes of the discrepancies between the SB and FB corrections in the PT and MT curves were 11.2° ± 5.2° and 11.6° ± 7.2°, respectively. FB correction did not differ from postoperative Cobb angles correction immediately after surgery or at the 2-year follow-up; the mean FBCIs in the PT and MT curves were 98.8% and 105.5%, respectively. The self-image domain SRS-22 scores had significantly increased at the 2-year follow-up (p < 0.0001). CONCLUSIONS: There were significant differences between the SB and FB corrections, and FB correction tended to approximate the postoperative curve correction (FBCI = 100%) for PT and MT curves in patients with Lenke type 2 AIS. FB flexibility is more reliable than SB flexibility in evaluating actual curve flexibility even for the PT curve.

The age-specific normative values of standing whole-body sagittal alignment parameters in healthy adults: based on international multicenter data.

PURPOSE: To investigate the age-specific normative values of whole-body sagittal alignment (WBSA) including global balance parameters in healthy adults and to clarify the correlations among parameters based on the data from three international multicenter. METHODS: Three hundred and seventeen healthy subjects (range: 20-84 y.o., mean: 43.8 ± 14.7 y.o.) were included and underwent whole-body biplanar X-ray imaging system. Spinopelvic parameters and knee flexion (KF), the center of acoustic meatus (CAM)-hip axis (HA), and C2 dentiform apophyse (OD)-HA, the cranial center (Cr)-HA were evaluated radiologically. Sub-analysis for correlation analysis between age and parameters and among parameters was performed to investigate age-specific change and compensatory mechanisms. RESULTS: For age-related change, C2-7 angle (r = .326 for male/.355 for female), KF (r = .427/.429), and SVA (r = .234/.507) increased with age in both male and female group. For global parameters related to the center of the gravity, correlations with age were not significant (r = .120/.161 for OD-HA, r = .163/.275 for Cr-HA, r = .149/.262 for CAM-HA). Knee flexion (KF) has correlation with global parameters (i.e., SVA, OD-HA, Cr-HA, CAM-HA) and does not have correlations with local spinopelvic alignment. CONCLUSION: While several local alignment changes with age were found, changes in global parameters related to the center of gravity were kept relatively mild by the chain of compensation mechanisms including the lower limbs. We showed the normative values for a comprehensive WBSA in standing posture from large international healthy subjects' database.