Low muscle density in children with osteogenesis imperfecta using opportunistic low-dose chest CT: a case-control study.

BACKGROUND: The aim of the study was to investigate the muscle differences in children with osteogenesis imperfecta (OI) using opportunistic low-dose chest CT and to compare different methods for the segmentation of muscle in children. METHODS: This single center retrospective study enrolled children with OI and controls undergoing opportunistic low-dose chest CT obtained during the COVID pandemic. From the CT images, muscle size (cross-sectional area) and density (mean Hounsfield Units [HU]) of the trunk muscles were measured at the mid-T4 and the mid-T10 level using two methods, the fixed thresholds and the Gaussian mixture model. The Bland-Altman method was also used to compute the strength of agreement between two methods. Comparison of muscle results between OI and controls were analyzed with Student t tests. RESULTS: 20 children with OI (mean age, 9.1 ± 3.3 years, 15 males) and 40 age- and sex-matched controls were enrolled. Mean differences between two methods were good. Children with OI had lower T4 and T10 muscle density than controls measured by the fixed thresholds (41.2 HU vs. 48.0 HU, p < 0.01; 37.3 HU vs. 45.9 HU, p < 0.01). However, children with OI had lower T4 muscle size, T4 muscle density, T10 muscle size and T10 muscle density than controls measured by the Gaussian mixture model (110.9 vs. 127.2 cm2, p = 0.03; 44.6 HU vs. 51.3 HU, p < 0.01; 72.6 vs. 88.0 cm2, p = 0.01; 41.6 HU vs. 50.3 HU, p < 0.01, respectively). CONCLUSIONS: Children with OI had lower trunk muscle density indicating that OI might also impair muscle quality. Moreover, the fixed thresholds may not be suitable for segmentation of muscle in children.

Effective atomic number of paraspinal muscles is associated with acute vertebral fracture risk.

OBJECTIVES: To investigate the relations among effective atomic number (Zeff), density, and area of paraspinal muscles, volumetric BMD (vBMD), and acute vertebral fractures (VF) by using spectral base images (SBIs) and routine CT images. METHODS: A total of 223 patients (52 men and 171 women) with acute VF and seven hundred and seventy-six subjects (286 men and 390 women) without VF of at least 60 years were enrolled and underwent dual-layer detector CT scans. We quantified the cross-sectional area (paraSMA), density (paraSMD) and Zeff of paraspinal muscles by CT images and SBIs and measured vBMD of the lumbar spine by quantitative CT. RESULTS: Higher vBMD was associated with lower VF risk in both sexes (adjusted OR, 0.33 and 0.43). After adjusting for age and BMI, the associations of ParaSMD with VF were not significant in men, and in women the association was borderline significant (OR, 0.80; 95% CI, 0.64 to 1.00). However, higher Zeff of paraspinal muscles was associated with lower VF risk in men (adjusted OR, 0.59; 0.36 to 0.96) but not in women. The associations of all muscle indexes with VF were not significant after further adjusting for vBMD. CONCLUSIONS: A higher Zeff of paraspinal muscles is associated with lower VF risk in older men but not in older women. The density, area and Zeff of paraspinal muscles were not vBMD independent risk factors for acute VF. ADVANCES IN KNOWLEDGE: The effective atomic number of paraspinal muscles might be a potential marker for vertebral fracture risk prediction.

Inter-rater variability and repeatability in the assessment of the Tanner-Whitehouse classification of hand radiographs for the estimation of bone age.

OBJECTIVE: To determine which bones and which grades had the highest inter-rater variability when employing the Tanner-Whitehouse (T-W) method. MATERIALS AND METHODS: Twenty-four radiologists were recruited and trained in the T-W classification of skeletal development. The consistency and skill of the radiologists in determining bone development status were assessed using 20 pediatric hand radiographs of children aged 1 to 18 years old. Four radiologists had a poor concordance rate and were excluded. The remaining 20 radiologists undertook a repeat reading of the radiographs, and their results were analyzed by comparing them with the mean assessment of two senior experts as the reference standard. Concordance rate, scoring, and Kendall's W were calculated to evaluate accuracy and consistency. RESULTS: Both the radius, ulna, and short finger (RUS) system (Kendall's W = 0.833) and the carpal (C) system (Kendall's W = 0.944) had excellent consistency, with the RUS system outperforming the C system in terms of scores. The repeatability analysis showed that the second rating test, performed after 2 months of further bone age assessment (BAA) practice, was more consistent and accurate than the first. The capitate had the lowest average concordance rate and scoring, as well as the lowest overall concordance rate for its D classification. Moreover, the G classifications of the seven carpal bones all had a concordance rate less than 0.6. The bones with lower Kendall's W were likewise those with lower scores and concordance rates. CONCLUSION: The D grade of the capitate showed the highest variation, and the use of the Tanner-Whitehouse 3rd edition (T-W3) to determine bone age (BA) was frequently inconsistent. A more comprehensive description with a focus on inaccuracy bones or ratings and a modification to the T-W3 approach would significantly advance BAA.

Age and BMI have different effects on subcutaneous, visceral, liver, bone marrow, and muscle adiposity, as measured by CT and MRI.

OBJECTIVE: We analyzed quantitative computed tomography (CT) and chemical shift-encoded magnetic resonance imaging (MRI) data from a Chinese cohort to investigate the effects of BMI and aging on different adipose tissue (AT) depots. METHODS: In 400 healthy, community-dwelling individuals aged 22 to 83 years, we used MRI to quantify proton density fat fraction (PDFF) of the lumbar spine (L2-L4) bone marrow AT (BMAT), the psoas major and erector spinae (ES) muscles, and the liver. Abdominal total AT, visceral AT (VAT), and subcutaneous AT (SAT) areas were measured at the L2-L3 level using quantitative CT. Partial correlation analysis was used to evaluate the relationship of each AT variable with age and BMI. Multiple linear regression analysis was performed in which each AT variable was evaluated in turn as a function of age and the other five independent AT measurements. RESULTS: Of the 168 men, 29% had normal BMI (<24.0 kg/m2), 47% had overweight (24.0-27.9 kg/m2), and 24% had obesity (≥ 28.0 kg/m2). In the 232 women, the percentages were 46%, 32%, and 22%, respectively. Strong or very strong correlations with BMI were found for total AT, VAT, and SAT in both sexes. BMAT and ES PDFF was strongly correlated with age in women and moderately correlated in men. In both sexes, BMAT PDFF correlated only with age and not with any of the other AT depots. Psoas PDFF correlated only with ES PDFF and not with age or the other AT depots. Liver PDFF correlated with BMI and VAT and weakly with SAT in men. VAT and SAT correlated with age and each other in both sexes. CONCLUSIONS: Age and BMI are both associated with adiposity, but their effects differ depending on the type of AT.

Reference Values for Paravertebral Muscle Size and Myosteatosis in Chinese Adults, a Nationwide Multicenter Study.

RATIONALE AND OBJECTIVES: The paravertebral muscles, characterized by their susceptibility to severe size loss and fat infiltration in old age, lack established reference values for age-related variations in muscle parameters. This study aims to fill this gap by establishing reference values for paravertebral muscles in a Chinese adult population. MATERIALS AND METHODS: This cross-sectional study utilized the baseline data from the prospective cohort China Action on Spine and Hip (CASH). A total of 4305 community-dwelling participants aged 21-80 years in China were recruited between 2013 and 2017. Pregnant women, individuals with metal implants, limited mobility or diseases/conditions (spinal tumor, infection, etc.) affecting lumbar vertebra were excluded from the study. Psoas and paraspinal muscles were measured in quantitative computed tomography (QCT) images at the L3 and L5 levels using Osirix software. Age-related reference values for muscle area, density, and fat fraction were constructed as percentile charts using the lambda-mu-sigma (LMS) method. RESULTS: The paravertebral muscles exhibited an age-related decline in muscle area and density, coupled with an increase in muscle fat fraction. Between the ages of 25 and 75, the reductions in psoas and paraspinal muscle cross-sectional area at the L3 level were - 0.47%/yr and - 0.53%/yr in men, and - 0.19%/yr and - 0.23%/yr in women, respectively. Notably, accelerated muscle loss was observed during menopause and postmenopause in women (45-75 years) and intermittently during middle and old age in men (35-55 and 60-75 years). Besides, the age-related decreases in PSMA, PMA, and PSMD and the increases in PSMFF were more pronounced in L5 than in L3 CONCLUSION: This study shows distinct patterns of accelerated muscle loss were identified in menopausal and postmenopausal women and in middle-aged and old men. The findings contribute valuable information for future investigations on paravertebral muscle loss and myosteatosis.

Comparisons of Hounsfield units and volumetric bone density in discriminating vertebral fractures on lumbar CT scans.

OBJECTIVES: To compare the performance of areal Hounsfield units (aHUs), volumetric Hounsfield units (vHUs), and volumetric bone mineral density (vBMD) by quantitative CT (QCT) in discriminating vertebral fractures (VFs) risk. METHODS: We retrospectively included CT scans of the lumbar spine 101 VFs cases (60 women, mean age: 64 ± 4 years; 41 men, mean age: 73 ± 10 years) and sex- and age-matched 101 control subjects (60 women, mean age: 64 ± 4 years; 41 men, mean age: 72 ± 7 years). In order to assess the discriminatory capability of aHU, vHU, and vBMD measurements at the L1 and L2 levels in identifying VFs, we conducted binary logistic regression and receiver operating characteristic (ROC) curve analyses in men and women. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: In both men and women with and without VFs, aHU, vHU, and vBMD were highly correlated with each other (r2 from 0.832 to 0.957, all P < .001). There was a statistically significant difference in aHU, vHU, and vBMD between subjects with and without VFs (P < .001). When age, gender, and BMI were taken into account as covariances and adjusted simultaneously, odds ratios (ORs) for aHU, vHU, and vBMD values, which represent the risk of VFs, were significant (P < .001). Compared with aHU and vHU, vBMD was more strongly associated with VF risk (vBMD: OR, 6.29; 95% CI, 3.83-10.35 vs vHU: OR, 3.64; 95% CI, 2.43-5.46 vs aHU: OR, 2.56; 95% CI, 1.79-3.67). In both men and women, further, vBMD had higher values for AUC, sensitivity, specificity, PPV, and NPV compared to vHU, with vHU in turn surpassing aHU. The area under the receiver operating characteristic curve (AUC) for discriminating VFs using the average aHU, vHU, and vBMD of 2 vertebrae was 0.72, 0.77, and 0.87 in men and 0.76, 0.79, and 0.86 in women. In both men and women, there exist statistically significant differences in the AUC when employing the 3 measurements-namely, aHU, vHU, and vBMD-to discriminate fractures (P < .05). CONCLUSIONS: The QCT-measured vBMD is more associated with acute VFs than vHU and aHU values of the lumbar spine. Although the use of vHU and aHU values for the diagnosis of osteoporosis and discriminating fracture risk is limited to scanner- and imaging protocol-specific, they have great potential for opportunistic osteoporosis screening, particularly vHU. ADVANCES IN KNOWLEDGE: The novelty of this study presents a comparison of the VF discriminative capabilities among aHU, vHU, and vBMD. The vHU values introduced in this study demonstrate a greater capacity to discriminate fractures compared to aHU, presenting an improved clinical choice. Although its discriminatory capability is slightly lower than that of vBMD, it is more convenient to measure and does not require specialized software.

Associations of Quantitative and Qualitative Muscle Parameters With Second Hip Fracture Risk in Older Women: A Prospective Cohort Study.

Older women with a first hip fracture exhibit heightened susceptibility and incidence of second fracture and potentially severe consequences. This prospective study was to compare the predictive power of qualitative and quantitative muscle parameters for a second hip fracture in older women with a first hip fracture. A total of 206 subjects were recruited from the longitudinal Chinese Second Hip Fracture Evaluation study. Hip computed tomography (CT) scans were obtained immediately after the first fracture. Muscle fat infiltration was assessed according to the Goutallier classification qualitatively. Quantitative parameters included cross-sectional area and density of gluteus maximus (G.MaxM) and gluteus medius and minimus (G.Med/MinM) muscles. CT X-ray absorptiometry was used to measure the areal bone mineral density (aBMD) of the contralateral femur. Cox proportional hazards models were used to compute hazard ratios (HR) of second hip fracture risk. The mean age of subjects was 74.9 (±9.5) years at baseline. After 4.5 years, 35 had a second hip fracture, 153 without a second hip fracture, and 18 died. Except for the combined G.MinM Goutallier grade 3 and 4 groups before adjustment for covariates (HR = 5.83; 95% confidence interval [CI] 1.49-22.83), there were no significant HRs for qualitative classification to predict a second hip fracture. Among quantitative metrics, after adjustment for covariates, G.Med/MinM density was significant in the original (HR = 1.44; CI 1.02-2.04) and competing risk analyses (HR = 1.46; CI 1.02-2.07). After additional adjustment for femoral neck (FN) aBMD, G.Med/MinM density remained borderline significant for predicting a second hip fracture in competing risk analysis (HR = 1.43; CI 0.99-2.06; p = 0.057). Our study revealed that Goutallier classification was less effective than quantitative muscle metrics for predicting hip second fracture in this elderly female cohort. After adjustment for FN aBMD, G.Med/MinM density is a borderline independent predictor of second hip fracture risk. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Site-Specific Differences in Bone Mineral Density of Proximal Femur Correlate with the Type of Hip Fracture.

The aim of this study was to investigate whether site-specific differences in bone mineral density (BMD) of proximal femur correlate with the type of hip fracture using quantitative computed tomography. Femoral neck (FN) fractures were classified as nondisplaced or displaced subtypes. Intertrochanteric (IT) fractures were classified as A1, A2, or A3. The severe hip fractures were identified as displaced FN fractures or unstable IT fractures (A2 and A3). In total, 404 FN fractures (89 nondisplaced and 317 displaced) and 189 IT fractures (76 A1, 90 A2, and 23 A3) were enrolled. Areal BMD (aBMD) and volumetric BMD (vBMD) were measured in the regions of total hip (TH), trochanter (TR), FN, and IT of the contralateral unfractured femur. IT fractures exhibited lower BMD than FN fractures (all p ≤ 0.01). However, unstable IT fractures had higher BMD compared with stable ones (p < 0.01). After adjusting for covariates, higher BMD in TH and IT were associated with IT A2 (A1 vs. A2: odds ratios (ORs) from 1.47 to 1.69, all p < 0.01). Low bone measurements were risk factors for stable IT fractures (IT A1 vs. FN fracture subtypes: ORs from 0.40 to 0.65, all p < 0.01). There are substantial site-specific differences in BMD between IT fractures A1 and displaced FN fractures. Higher bone density was associated with unstable IT fracture when compared with stable ones. The understanding of biomechanics of various fracture types could help to improve the clinical management of these patients.

The lumbar spinal endplate lesions grades and association with lumbar disc disorders, and lumbar bone mineral density in a middle-young general Chinese population.

BACKGROUND: Lumbar vertebral endplates lesions (LEPLs), one of the etiologies of low back pain (LBP), are one of the most prevalent causes of health-care costs. Despite progressively becoming the focus in recent years, almost all studies have concentrated on symptomatic patients rather than general populations. As a result, our study was designed to determine the prevalence and distribution patterns of LEPLs in a middle-young general population, as well as their associations with lumbar disc herniation (LDH), lumbar disc degeneration (LDD), and lumbar vertebral volumetric bone mineral density (vBMD). METHODS: Seven hundred fifty-four participants aged 20-60 years were recruited from the subjects enrolled in a 10-year longitudinal study of degeneration of the spine and knee being conducted at the Beijing Jishuitan Hospital and 4 of them were excluded due to the missing of MRIs. In this observational study, a lumbar quantitative computed tomography (QCT) and MRI scan were performed among participants within 48 h. T2-weighted sagittal lumbar MRI images for all included subjects were identified for LEPLs by two independent observers based on morphological and local characteristics. Lumbar vertebral vBMD was measured with QCT. The age, BMI, waistline, hipline, lumbar vBMD, LDD, and LDH were measured to investigate their associations with LEPLs. RESULTS: The prevalence of LEPLs was higher among the male subjects. 80% of endplates were recognition as no lesions with a substantial disparity between female (75.6%) and male subjects (83.4%) (p < 0.001). The most common lesions were "wavy/irregular" and "notched", and "fracture" is most involved in L3-4 inferior endplate both in two genders. LEPLs were found to be associated with LDH (≥ 2 levels: OR = 6.859, P < 0.001; 1 level: OR = 2.328, P = 0.002 in men. OR = 5.004, P < 0.001; OR = 1.805, P = 0.014 in women) reference for non-LDH, and hipline in men (OR = 1.123, P < 0.001). CONCLUSIONS: LEPLs are the common findings on lumbar MRIs in general population, particularly in men. The presence of these lesions and advance from slightly to severely could be mainly attributed to LDH and men's higher hipline.

Association between triglyceride-glucose index and worsening renal function in the elderly.

Background: Triglyceride-glucose (TyG) index is a simple marker of insulin resistance. However, insufficient data is available on whether the TyG index is associated with worsening renal function (WRF) in the elderly. Therefore, this study was designed to explore the association between the TyG index and WRF based on a community elderly cohort. Methods: In this study, 7,822 elderly (aged ≥ 65 years) adults from southern China were enrolled and divided into four groups according to the TyG index quartiles. The primary endpoint was incident chronic kidney disease (CKD), defined as incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Additional endpoints included a decline in eGFR of 30% and 40% during the follow-up period. Results: During the median 2.04 year follow-up period, 1,541 (19.7%) participants developed CKD. After adjusting for confounding factors, multivariable Cox regression models revealed significant associations between TyG index and incident CKD (HR per SD increase, 1.21; 95% CI: 1.14-1.29), a decline in eGFR of 30% (HR per SD increase, 1.38; 95% CI: 1.26-1.50), and decline in eGFR of 40% (HR per SD increase, 1.42; 95% CI: 1.24-1.63). Furthermore, compared with those in Q1, participants in Q4 demonstrated a higher risk of developing CKD (HR, 1.59; 95% CI: 1.35-1.88). These positive associations remained consistent across different subgroup populations. Conclusion: Our study suggests a positive and independent association between the TyG index and WRF in the elderly.

Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial STAT3 to promote the development of arterial thrombosis.

BACKGROUND: Thrombotic events cannot be completely prevented by antithrombotics, implicating a therapeutic gap due to inflammation, a not yet sufficiently addressed mechanism. Neutrophil extracellular traps (NETs) are an essential interface between inflammation and thrombosis, but exactly how the NETotic process is initiated and maintained during arterial thrombosis remains incompletely understood. METHODS AND RESULTS: We found that the plasma concentrations of C5a were higher in patients with ST-elevation myocardial infarction (STEMI) than in patients with angina and higher in mice with left common carotid artery (LCCA) thrombosis induced by FeCl3 than in control mice. We observed that the thrombus area and weight were decreased and that NET formation in the thrombi was reduced in the group treated with the selective C5aR1 receptor inhibitor PMX53 compared with the NaCl group. In vitro, NETosis was observed when C5a was added to neutrophil cultures, and this effect was reversed by PMX53. In addition, our data showed that C5a increased the production of mitochondrial reactive oxygen species (ROS) and that the promotion of NET formation by C5a was mitochondrial ROS (Mito-ROS) dependent. Furthermore, we found that C5a induced the production of Mito-ROS by inhibiting mitochondrial STAT3 activity. CONCLUSIONS: By inhibiting mitochondrial STAT3 to elicit Mito-ROS generation, C5a triggers the generation of NETs to promote the development of arterial thrombosis. Hence, our study identifies complement C5a as a potential new target for the treatment and prevention of thrombosis.

Interleukin 35 protects cardiomyocytes following ischemia/reperfusion-induced apoptosis via activation of mitochondrial STAT3.

Mitochondrial reactive oxygen species (mtROS)-induced apoptosis has been suggested to contribute to myocardial ischemia/reperfusion injury. Interleukin 35 (IL-35), a novel anti-inflammatory cytokine, has been shown to protect the myocardium and inhibit mtROS production. However, its effect on cardiomyocytes upon exposure to hypoxia/reoxygenation (H/R) damage has not yet been elucidated. The present study aimed to investigate the potential protective role and underlying mechanisms of IL-35 in H/R-induced mouse neonatal cardiomyocyte injury. Mouse neonatal cardiomyocytes were challenged to H/R in the presence of IL-35, and we found that IL-35 dose dependently promotes cell viability, diminishes mtROS, maintains mitochondrial membrane potential, and decreases the number of apoptotic cardiomyocytes. Meanwhile, IL-35 remarkably activates mitochondrial STAT3 (mitoSTAT3) signaling, inhibits cytochrome c release, and reduces apoptosis signaling. Furthermore, co-treatment of the cardiomyocytes with the STAT3 inhibitor AG490 abrogates the IL-35-induced cardioprotective effects. Our study identified the protective role of IL-35 in cardiomyocytes following H/R damage and revealed that IL-35 protects cardiomyocytes against mtROS-induced apoptosis through the mitoSTAT3 signaling pathway during H/R.

Identification of Transcriptional Variation in Aortic Remodeling Using a Murine Transverse Aortic Constriction (TAC) Model.

Arterial remodeling is a major pathological consequence of hypertension, which is recognized as the most common chronic non-communicable disease. However, the detailed mechanism of how arterial remodeling is induced by hypertension has not yet been fully elucidated. Evaluating the transcriptional changes in arterial tissue in response to elevated blood pressure at an early stage may provide new insights and identify novel therapeutic candidates in preventing arterial remodeling. Here, we used the ascending aorta of the transverse aortic constriction (TAC) model to induce arterial remodeling in C57BL/6 male mice. Age-matched mice were subjected to sham surgery as controls. The TAC model was only considered successful if the mice conformed to the criteria (RC/LC blood flow velocity with 5-10-fold change) 1 week after the surgery. Two weeks after surgery, the ascending aorta developed severe remodeling in TAC mice as compared to the sham group. High throughput sequencing was then applied to identify differentially expressed (DE) transcripts. In silicon analysis were then performed to systematically network transcriptional changes. A total of 1,019 mRNAs were significantly changed between TAC and the sham group at the transcriptional level. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis revealed that stress/stimulus/immune-related biological processes played a crucial role during arterial remodeling. Our data provide a comprehensive understanding of global gene expression changes in the TAC model, which suggests that targeting inflammation and vascular smooth cell transformation are potential therapeutic strategies to interfere with the aortic remodeling at an early stage in the development of hypertension.

Selection of scFvs specific for the HepG2 cell line using ribosome display.

The aim of this study was to construct a ribosome display library of single chain variable fragments (scFvs) associated with hepatocarcinoma and screen such a library for hepatocarcinoma-binding scFvs. mRNA was isolated from the spleens of mice immunized with hepatocellular carcinoma cell line HepG2. Heavy and k chain genes (VH and k) were amplified separately by RT-PCR, and an anti-HepG2 VH/k chain ribosome display library was constructed by assembling VH and k into the VH/k chain with a specially constructed linker by SOE-PCR. The VH/k chain library was transcribed and translated in vitro using a rabbit reticulocyte lysate system. In order to isolate specific scFvs, recognizing HepG2 negative selection on a normal hepatocyte line WRL-68 was carried out before three rounds of positive selection on HepG2. After three rounds of panning, cell enzyme-linked immunosorbent assay (ELISA) showed that one of the scFvs had high affinity for the HepG2 cell and lower affinity for the WRL-68 cell. In this study, we successfully constructed a native ribosome display library. Such a library would prove useful for direct intact cell panning using ribosome display technology. The selected scFv had a potential value for hepatocarcinoma treatment.