CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.

Resistance to glucocorticoids (GCs), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-of-function experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GCresistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease.

Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer's disease (AD). MT exists in equilibrium between reduced [leucomethylthioninium (LMT)] and oxidized (MT(+)) forms; as a chloride salt [methylthioninium chloride (MTC), "methylene blue"], it is stabilized in its MT(+) form. Although the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138-mg MT/day dose as the minimum effective dose on cognitive and imaging end points, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228-mg MT/day dose. We hypothesized that the failure of dose response may depend on differences known at the time in dissolution in simulated gastric and intestinal fluids of the 100-mg MTC capsules used to deliver the 228-mg dose and reflect previously unsuspected differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX (providing LMT in a stable anhydrous crystalline form), has enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered in the MT(+) form as MTC. A model is presented to account for the complexity of MT absorption, which may have relevance for other similar redox molecules.

Anti-inflammatory therapy after selective laser trabeculoplasty: a randomized, double-masked, placebo-controlled clinical trial.

PURPOSE: To investigate the effect of anti-inflammatory therapy on selective laser trabeculoplasty (SLT) outcomes. DESIGN: Randomized, double-masked, placebo-controlled trial. PARTICIPANTS: Patients with primary open-angle or pseudo-exfoliation glaucoma. METHODS: Patients undergoing SLT were randomized to receive placebo (artificial tears), prednisolone acetate 1%, or ketorolac tromethamine 0.5% eye drops 4 times per day for 5 days commencing immediately after SLT. MAIN OUTCOME MEASURES: Change in intraocular pressure (IOP) from baseline to the 1-month post-SLT visit. RESULTS: Mean change in IOP at the 1-month primary outcome time point, as well as all other time points, was not significantly different among groups (P = 0.99). Likewise, a repeated-measures, mixed-effects model did not find significant differences in IOP outcome at the 1-month time point (P = 0.95). The IOP was reduced in all groups at the 1-month post-SLT time point and all other time points, and no significant differences were found between groups using separate unadjusted cross-sectional analyses of variance (P > 0.15 for analyses at all time points). Treatment failure rates were not different among groups (P = 0.75), and at 1 year after SLT, the percentage of patients maintaining a 20% IOP reduction ranged from 18% to 22% in the 3 study groups. CONCLUSIONS: Anti-inflammatory therapy after SLT does not seem to substantially influence the IOP-lowering effect of SLT. In this study of patients with low baseline IOP, SLT showed limited efficacy in achieving a sustained reduction in IOP.

Pharmacogenomic Profiling of Pediatric Acute Myeloid Leukemia to Identify Therapeutic Vulnerabilities and Inform Functional Precision Medicine.

Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacologic profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene-expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug clinical data set that could be leveraged to research the unique biology of pediatric AML and sets the stage for realizing functional precision medicine for the clinical management of the disease. SIGNIFICANCE: We conducted integrated drug and genomic profiling of patient biopsies to build the functional genomic landscape of pediatric AML. Age-specific differences in drug response and new gene-drug interactions were identified. The feasibility of functional precision medicine-guided management of children with high-risk AML was successfully demonstrated in two evaluable clinical cases. This article is highlighted in the In This Issue feature, p. 476.

Carcinosarcoma ex eccrine spiradenoma of the vulva: report of the first case.

Carcinosarcoma is exceedingly rare in the vulva. We describe a case of carcinosarcoma in a 67-year-old female patient who presented with recent enlargement and pain of a vulval nodule noted for 15 years. The excised tumor showed intermixed carcinomatous (adenocarcinoma and anaplastic carcinoma) and sarcomatous elements (osteosarcoma, chondrosarcoma, and leiomyosarcoma), which focally merged with several lobules of typical eccrine spiradenoma. The inguinal lymph nodes showed metastasis of the carcinomatous component only. This case represents the first reported case of vulval carcinosarcoma of the skin adnexal origin, and has to be distinguished from sarcomatoid carcinoma of epidermal origin because of a probable more aggressive behavior.

CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity.

CD9 has been implicated in cancer progression but its prognostic relevance and therapeutic potential in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are largely unknown. In a cohort of pediatric BCP-ALL patients, we found that CD9+ cases had a significantly lower 5-year relapse-free survival rate than CD9- cases. Multivariate analysis demonstrated that CD9 positivity independently predicted inferior survival outcomes, and could be applied with established prognostic features, including prednisone response and cytogenetic status, to refine patient stratification. Administration of CD9 antibody substantially suppressed disease progression in NOD/SCID mice xenografted with CD9+ cell lines and primary leukemic blasts from patients with high-risk and refractory BCP-ALL, without compromising hematopoietic stem cell engraftment. Combination of anti-CD9 with conventional chemotherapy further reduced leukemic burden and prolonged animal survival. Mechanistically, CD9 blockade inhibited leukemic cell proliferation, induced G0/G1 cell cycle arrest, activated p38, and enhanced chemotherapeutic agent-induced apoptosis. Further, CD9 physically interacted with integrin very late antigen-4, regulated affinity to vascular cell adhesion molecule-1, and was involved in leukemia-stroma interaction. Collectively, our study established CD9 as a new prognostic marker, validated the preclinical efficacy of CD9 antibody, and laid the foundation for clinical development of CD9-targeted therapy for high-risk and refractory pediatric BCP-ALL.

Serum Profiling of Rat Dermal Exposure to JP-8 Fuel Reveals an Acute-Phase Response.

ABSTRACT Dermal exposure to JP-8 petroleum jet fuel leads to toxicological responses in humans and rodents. Serum profiling is a molecular analysis of changes in the levels of serum proteins and other molecules in response to changes in physiology. This present study utilizes serum profiling approaches to examine biomolecular changes in the sera of rats exposed to dermal applications of JP-8 (jet propulsion fuel-8). Using gel electrophoresis and electrospray ionization (ESI) mass spectrometry (MS), levels of serum proteins as well as low-mass constituents were found to change after dermal exposures to JP-8. The serum protein levels altered included the acute-phase response proteins haptoglobin, ceruloplasmin, alpha(1)-inhibitor III, and apolipoprotein A-IV. Haptoglobin levels increased after a 1-day JP-8 dermal exposure and continued to increase through 7 days of exposure. Ceruloplasmin levels increased after 5 days of exposure. Serum alpha(1)-inhibitor III was reduced after a 1-day exposure and the depletion continued after 7 days of exposure. Apolipoprotein A-IV increased after a 1-day exposure and then returned to basal levels after 3- and 5-day exposures of JP-8. Levels of the acute-phase protein alpha(2)-macroglobulin were found to not vary over these time course studies. Using ESI-MS analysis directly on the sera from rats exposed to dermal JP-8, low-mass sera constituents were found to correlate with control (acetone) or JP-8 exposure.

Does hydroxyapatite coating enhance ingrowth and improve longevity of a Zweymuller type stem? A double-blinded randomised RSA trial.

INTRODUCTION: An ongoing discussion is whether using a hydroxyapatite coating enhances the ingrowth and longevity of a femoral stem in total hip arthroplasty. The best way to predict speed of ingrowth and long-term outcome is by evaluating micromotion by radiostereometric analysis. To study the effect of hydroxyapatite (HA) coating on the migration of the SL-PLUS hip stem, we performed a prospective double blind randomised controlled trial comparing the early migration of the hydroxyapatite (HA)-coated SL-PLUS stem compared to the Standard (non-coated) SL-PLUS stem. PATIENTS AND METHODS: 51 patients were randomly assigned to receive either an uncoated or a HA-coated femoral component during total hip replacement. RSA images were obtained direct postoperatively and at 6 weeks, 12 weeks, 6 months, 12 months and 24 months. HOOS scores were obtained preoperative and at final follow-up. RESULTS: RSA evaluation demonstrated significant migration up to 3 months postoperatively in both groups. After initial setting no significant migration was observed. There was no significant difference in migration between the HA-coated group and the uncoated group. Both Harris Hip Score (HHS) and HOOS domain scores (pain and ADL) significantly improved compared to baseline at 24 months after surgery in both treatment groups (p<0.001 for all comparisons). Improvement did not differ significantly between the 2 groups. CONCLUSIONS: At 2 years follow-up, the HA-coated and uncoated Zweymuller type, distal fitting stem do not show different migration patterns.

Efficacy of Tailored Exercise Therapy on Physical Functioning in Patients With Knee Osteoarthritis and Comorbidity: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy on physical functioning and safety of tailored exercise therapy in patients with knee osteoarthritis (OA) and comorbidities. METHODS: In a randomized controlled trial, 126 participants were included with a clinical diagnosis of knee OA and at least 1 of the following target comorbidities: coronary disease, heart failure, type 2 diabetes mellitus, chronic obstructive pulmonary disease, or obesity (body mass index ≥30 kg/m2 ), with severity score ≥2 on the Cumulative Illness Rating Scale. The intervention group received a 20-week, individualized, comorbidity-adapted exercise program consisting of aerobic and strength training and training of daily activities. The control group received their current medical care for knee OA and were placed on a waiting list for exercise therapy. Primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index, subscale physical functioning (WOMAC-pf), and the 6-minute walk test (6MWT). Measurements were performed at baseline, after 20 weeks (directly posttreatment), and at 3 months posttreatment. RESULTS: Statistically significant physical functioning differences over time were found between the intervention and control group (WOMAC: B = -7.43 [95% confidence interval (95% CI) -9.99, -4.87], P < 0.001; and 6MWT: B = 34.16 [95% CI 17.68, 50.64], P < 0.001) in favor of the intervention group. At 3 months followup, the mean improvements in the intervention group were 33% on the WOMAC scale and 15% on the 6MWT. These improvements are of clinical relevance. No serious adverse events occurred during the intervention. CONCLUSION: This is the first study showing that tailored exercise therapy is efficacious in improving physical functioning and safe in patients with knee OA and severe comorbidities.

Paraoxonase gene polymorphisms and haplotype analysis in a stroke population.

BACKGROUND: Paraoxonase (PON) has anti-atherogenic activity due to its protective function against low density lipoprotein (LDL) oxidation. Alteration of enzyme activity due to polymorphisms in the PON genes may influence the development of atheroma and thus affect stroke risk. Three PON genes (PON1, PON2 and PON3) have been identifiedand mapped to chromosome 7. METHODS: We looked at the distribution of paraoxonase polymorphisms and haplotype arrangement in 397 Caucasian ischaemic stroke patients and 405 controls. We investigated 6 different common single nucleotide polymorphisms (SNP) in PON genes; two substitutions in PON1 ["A/G": Gln (Q)/Arg (R)] at codon 192 and ["T/A": Leu (L)/Met (M)] at codon 55, two in PON2 at codon 311 ["G/A": Cys (C)/Ser (S)] and codon 148 ["C/G": Ala (A)/Gly (G)] and two SNPs, both "A" to "G" substitutions, in PON3--intronic rs2074353, which we designated PON3-1 and [Ala (A)/Ala (A)] at codon 99, designated as PON3-3. Dynamic Allele Specific Hybridisation (DASH) was used as the genotyping assay. Haplotype analysis was performed using both PHASE and EHPLUS programs. RESULTS: Genotype and allele frequencies were similar in cases and controls. Lipid profiles were not influenced by PON genotype. Haplotype frequencies for the six loci (PON2-148, PON2-311, PON3-3, PON3-1, PON1-55 and PON1-192) were estimated. Comparison of the two programs showed a significant difference in haplotype arrangements with EHPLUS (p-value = 0.005) but not with PHASE Ver.2 (p-value = 0.12). The 112211 (1 = frequent allele, 2 = rare allele) haplotype arrangement was commoner in cases than controls (p = 0.015), and the 111121 haplotype was commoner in controls (p = 0.006). CONCLUSION: Our study did not identify a role for individual paraoxonase gene polymorphisms in the pathogenesis of ischaemic stroke. Findings of haplotype differences should be confirmed in large scale studies. The importance of using a well-validated haplotype analysis program is also underlined.

Optimization of Analgesics for Greater Exercise Therapy Participation Among Patients With Knee Osteoarthritis and Severe Pain: A Feasibility Study.

OBJECTIVE: Severe pain in patients with knee osteoarthritis (OA) hampers the ability to exercise. A protocol for the standardized optimization of analgesics in combination with exercise therapy was developed. The purpose of this protocol was to reduce pain, thereby allowing the patient to participate in exercise therapy. The objective of the present study was to evaluate the feasibility and outcome of the protocol. METHODS: Forty-nine patients with knee OA and severe knee pain (numerical rating scale for pain ≥7) were included. Analgesics were prescribed following an incremental protocol. After 6 weeks, a 12-week exercise therapy program was added. Information about analgesic use and exercise therapy content was recorded. Knee pain and activity limitations were assessed at baseline, after 6 weeks, and after 18 weeks. RESULTS: Statistically significant improvements in pain and activity limitations were found in intent-to-treat analysis after 6 weeks of analgesic use and after the intervention was completed. Mean improvements from baseline were 30% (P < 0.001) for pain and 17% (P < 0.001) for activity limitations after the intervention was completed. Seventy-eight percent of the patients were able to exercise according to the protocol. In these patients, exercise therapy following 6 weeks of analgesic use resulted in a further improvement of activity limitations of 10% (P = 0.004). CONCLUSION: The combined intervention of standardized analgesic prescription and exercise therapy allows most patients with knee OA and severe pain to participate in exercise therapy, leading to reduction of pain and activity limitations. These promising results need to be confirmed in a randomized controlled trial.

Measurement of dose-area product with GafChromic XR Type R film.

Many of the newer X-ray machines are equipped with electronic means to provide dose-area product (DAP) information. For machines without that ability, an alternative method is to record radiation on a film that can handle a large amount of cumulative exposure. The use of GafChromic XR Type R film was investigated for this purpose by placing it at the X-ray tube assembly to record the radiation in interventional radiological procedures. Dose-area product was determined with a reflective densitometer and then with a flatbed scanner. Precisions were demonstrated to be 5% and 2%, respectively. In a comparison with the machine-recorded DAP, a regression analysis showed the validity of both techniques for values less than 1200 Gy-cm2.

Perception of vertical and horizontal orientation in children with scoliosis.

To determine whether the perception of body posture is altered in idiopathic scoliosis, a simple neurophysiologic experiment through laser line projection was conducted to test this hypothesis in three groups of individuals: 89 children with idiopathic scoliosis (IS), 50 children with congenital scoliosis (CS) and 45 controls without scoliosis. The subjects were instructed to adjust a laser line projection to the direction of gravity in vertical and in horizontal projections in a dark environment. The performance, expressed as the deviation from the earth vertical (measured in degrees), was calculated by a computer. The three groups fulfilled the vertical and horizontal adjustments within the same accuracy. No relation with age, sex or severity of scoliotic deformity was found. Yet, the angle between vertical and horizontal laser lines was significantly related with the severity of scoliosis, both in IS and CS. In contrast to our hypothesis, it was concluded that perception of postural control in IS is not altered. Therefore, this study indicates that IS is not likely to be caused by a dysfunction of postural control.

Mitral regurgitation: comparison between edge-to-edge repair and valve replacement.

Mitral regurgitation due to bileaflet prolapse and ischemic causes can be difficult to repair. Midterm experience of the Alfieri edge-to-edge repair as an alternative to valve replacement is reported. Twenty-six patients with severe mitral regurgitation underwent the Alfieri repair between January 1998 and December 2000 (group 1); 15 cases were due to bileaflet prolapse and 7 were of ischemic origin. During the same period, valve replacement was performed in 36 patients (group 2), 20 of whom had similar indications. Follow-up was complete to a mean of 15 months (range, 1-28 months). There was no early death in either group. During follow-up, there was no reoperation in group 1, while 2 patients in group 2 required reoperations due to prosthetic valve endocarditis. There were 4 major thromboembolic or bleeding events in group 2, and none in group 1. All patients in group 1 had trivial to mild mitral regurgitation on follow-up echocardiography. The mean mitral valve gradient was significantly higher in group 2 compared to group 1 (7.2 versus 3.2 mm Hg, p = 0.001). The edge-to-edge repair is associated with good early and midterm results. Long-term follow-up is required to evaluate the durability of this technique.

Semi-automatic landmark detection in digital X-ray images of the spine.

Quantitative diagnosis of 3D scoliotic deformities depends on a number of dedicated measurements. Existing methods rely on the manual determination of a series of anatomical landmarks in X-ray images. We have developed an automatic method to alleviate the burden of this tedious task. Our method looks for a compromise between local image information and global prior constraints and finds the most probable points using dynamic programming optimization. Remaining errors can be quickly corrected by effective user interaction. The first results are promising.

3D reconstruction and analysis of the vertebral body line.

Quantitative analysis of 3D spinal deformities includes measurements related to individual vertebrae and measurements related to the overall shape of the spine. For the latter aspect, we propose to build a 3D model of the line that connects all vertebrae centres. We present two methods that allow reconstructing this vertebral body line in a quick and easy way. Various new descriptors of the spinal shape can be automatically computed. A study is under way to assess their clinical relevance and reliability.

No superiority of cemented metal-on-metal vs metal-on-polyethylene THA at 5-year follow-up.

A randomized controlled trial was performed to compare the cemented Stanmore metal-on-metal (Biomet, Warsaw, Indiana) total hip arthroplasty (THA; 102 hips) to the cemented Stanmore metal-on-polyethylene (Biomet) THA (98 hips). The primary outcome was clinical performance. Radiological performance, serum cobalt analysis, and prosthetic survival were secondary outcome measures. At a mean follow-up of 5.6 years, 5 patients were lost to follow-up, 18 died, and 4 were revised (3 metal-on- metal, 1 metal-on-polyethylene). Harris Hip Scores improved from 48 to 90 in the metal-on-metal patients (P<.001) and from 46 to 87 in the metal-on-polyethylene patients (P<.001). Oxford Hip Scores changed from 40 to 19 in the metal-on-metal group (P<.001) and from 40 to 18 in the metal-on-polyethylene group (P<.001). For both Harris and Oxford Hip Scores, there was no significant difference between the 2 groups. Five-year survival with revision for any reason was 97% (95% CI 93%-100%) in the metal-on-metal group and 99% (95% CI 97%-100%) in the metal-on-polyethylene group. All revisions were indicated for aseptic loosening (metal-on-metal: 3 cup revisions; metal-on-polyethylene: 1 total revision). At 5-year follow-up, cemented metal-on-metal THA showed no clinical superiority over metal-on-polyethylene THA.

Biomarker identification in human pancreatic cancer sera.

OBJECTIVE: The aim of this study is to identify biomarkers in sera of pancreatic cancer patients using mass spectrometry (MS) approaches. METHODS: Sera from patients diagnosed with pancreatic adenocarcinoma and sera from normal volunteers were subjected to gel electrophoresis to resolve and quantify differences in protein levels. Protein bands that differed quantitatively were digested with trypsin, and peptides were identified by electrospray ionization (ESI) ion-trap tandem MS. Mass spectra were also collected directly from pancreatic cancer sera as well as healthy control sera using ESI-MS. RESULTS: Three large-mass proteins were found to be elevated in pancreatic cancer sera versus normal sera, alpha-2 macroglobulin, ceruloplasmin, and complement 3C. Complement 3C is a major regulator of inflammatory responses. The ESI-MS of human pancreatic cancer sera versus normal sera revealed greater heterogeneity in cancer sera than control sera, especially in the low-mass region. Bootstrapping statistical analysis identified 20 low-mass serum peaks that correlated with control sera and 20 different peaks that correlated with pancreatic cancer sera. CONCLUSIONS: The fact that inflammation-sensitive proteins were identified as increased in pancreatic cancer sera supports the hypothesis that inflammatory-driven processes are involved in pancreatic carcinogenesis. Liquid ESI-MS analyses of sera hold promise for future pancreatic cancer blood tests as well as for understanding mechanisms of pancreatic carcinogenesis. The variability observed between the low-mass regions of normal versus pancreatic cancer spectra may aid in diagnosis and therapy.

Analysis of Oxford medial unicompartmental knee replacement using the minimally invasive technique in patients aged 60 and above: an independent prospective series.

We present the outcome of an independent prospective series of phase-3 Oxford medial mobile-bearing unicompartmental knee replacement surgery. Eight surgeons performed the 154 procedures in a community-based hospital between 1998 and 2003 for patients aged 60 and above. Seventeen knees were revised; in 14 cases a total knee replacement was performed, in 3 cases a component of the unicompartmental knee prosthesis was revised, resulting in a survival rate of 89% during these 2-7 years follow-up interval. This study shows that mobile-bearing unicompartmental knee replacement using a minimally invasive technique is a demanding procedure. The study emphasises the importance of routine in surgical management and strict adherence to indications and operation technique used to reduce outcome failure.

Geometric and electromyographic assessments in the evaluation of curve progression in idiopathic scoliosis.

STUDY DESIGN: The natural history of patients with idiopathic scoliosis was analyzed radiographically and electromyographically in a prospective longitudinal study. OBJECTIVES: To identify changes in geometric variables and the sequence in which these changes occur during curve progression in the natural history of patients with idiopathic scoliosis. In addition, to study the relationship between several geometric variables and electromyographic (EMG) measurements to determine their predictive value as risk factors to curve progression of the scoliotic deformity. SUMMARY OF BACKGROUND DATA: The main area of concern in treating children with adolescent idiopathic scoliosis is the unpredictability of curve progression during the early development of the deformity. METHODS: The changes in radiographic geometric and EMG variables between the first presentation and consecutive 4-6-month follow-up periods were analyzed in 105 patients with idiopathic scoliosis. Statistical analyses were performed to elucidate in more detail how spinal geometry evolves during curve progression. RESULTS: Curve severity was associated with remaining growth potential expressed as an increasing spinal growth velocity (SGV). With increasing SGV, an enhanced EMG activity at the lower part on the convex side of the curve expressed as EMG ratio was found. High EMG ratio was associated with increased axial rotation and diminished kyphosis before the rapid increase in Cobb angle. Lateral deviation, wedge angle, and axial rotation all increased during periods of progression. Changes in tilt angle and lordosis were not associated with curve progression. CONCLUSIONS: In the natural history of idiopathic scoliosis, SGV and EMG ratio at the lower end vertebra are prominent risk factors of curve progression. The asymmetric muscle activity is associated with increased axial rotation, which in its turn is associated with increasing Cobb angle and diminishing kyphosis. The combination of these variables provides insight in the physiologic and 3-dimensional biomechanical evolution of the natural history of curve progression in idiopathic scoliosis.