Co-delivery Nano System of MS-275 and V-9302 Induces Pyroptosis and Enhances Anti-Tumor Immunity Against Uveal Melanoma.

In the treatment of uveal melanoma (UVM), histone deacetylase inhibitors (HDACi) have emerged as a promising epigenetic therapy. However, their clinical efficacy is hindered by the suboptimal pharmacokinetics and the strong self-rescue of tumor cells. To overcome these limitations, reactive oxygen species (ROS)-responsive nanoparticles (NPs) are designed that encapsulate HDACi MS-275 and the glutamine metabolism inhibitor V-9302. Upon reaching the tumor microenvironment, these NPs can disintegrate, thereby releasing MS-275 to increase the level of ROS and V-9302 to reduce the production of glutathione (GSH) related to self-rescue. These synergistic effects lead to a lethal ROS storm and induce cell pyroptosis. When combined with programmed cell death protein 1 monoclonal antibodies (α-PD-1), these NPs facilitate immune cell infiltration, improving anti-tumor immunity, converting "immune-cold" tumors into "immune-hot" tumors, and enhancing immune memory in mice. The findings present a nano-delivery strategy for the co-delivery of epigenetic therapeutics and metabolic inhibitors, which induces pyroptosis in tumors cells and improves the effectiveness of chemotherapy and immunotherapy.

Acyloxyacyl Hydrolase Protects against Kidney Injury via Inhibition of Tubular CD74-Macrophage Crosstalk.

Renal fibrosis is the common pathway in the progression of chronic kidney disease (CKD). Acyloxyacyl hydrolase (AOAH) is expressed in various phagocytes and is highly expressed in proximal tubular epithelial cells (PTECs). Research shows that AOAH plays a critical role in infections and chronic inflammatory diseases, although its role in kidney injury is unknown. Here, we found that AOAH deletion led to exacerbated kidney injury and fibrosis after folic acid (FA) administration, which was reversed by overexpression of Aoah in kidneys. ScRNA-seq revealed that Aoah-/- mice exhibited increased subpopulation of CD74+ PTECs, though the percentage of total PTECs were decreased compared to WT mice after FA treatment. Additionally, exacerbated kidney injury and fibrosis seen in Aoah-/- mice was attenuated via administration of methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), an inhibitor of macrophage inhibition factor (MIF) and CD74 binding. Finally, AOAH expression was found positively correlated with estimated glomerular filtration rate while negatively correlated with the degree of renal fibrosis in kidneys of CKD patients. Thus, our work indicates that AOAH protects against kidney injury and fibrosis by inhibiting renal tubular epithelial cells CD74 signaling pathways. Targeting kidney AOAH represents a promising strategy to prevent renal fibrosis progression.

Neuroprotective and anti-inflammatory effects of eicosane on glutamate and NMDA-induced retinal ganglion cell injury.

AIM: To investigate the protective effects, antioxidant potential, and anti-inflammatory mechanisms of eicosane on glutamate-induced cell damage and on N-methyl-D-aspartate (NMDA)-induced retinal ganglion cell (RGC) injury in a mouse model of glaucoma. METHODS: The protective effects of eicosane on the rat R28 retinal precursor cell line were assessed using cell counting kit-8 assays and Hoechst-propidium iodide staining. Intracellular reactive oxygen species (ROS) production was measured using the fluorescent probe 2'-7'-dichlorofluorescin diacetate and flow cytometry. The protective role of eicosane on NMDA-induced RGC injury in a mouse glaucoma model was determined by immunostaining of frozen sections of retina. The effects of eicosane on the metabolome of the retina in mice with NMDA-induced RGC damage were evaluated by liquid chromatography-mass spectroscopy (LC-MS) and untargeted metabolomics analyses. RESULTS: Eicosane treatment significantly attenuated glutamate-induced damage to R28 cells in vitro. Eicosane also protected RGCs against NMDA-induced injury in a mouse glaucoma model. Untargeted metabolomics analyses showed that eicosane increased multiple metabolites, including L-arginine and L-carnitine, in the retina. CONCLUSION: Eicosane has protective effects, antioxidant potential, and anti-inflammatory properties in an in vitro model of glutamate-induced cell damage and in an in vivo model of NMDA-induced RGC injury in mouse glaucoma through modulation of L-arginine and/or L-carnitine metabolism.

Interleukin-19 in Bone Marrow Contributes to Bone Loss Via Suppressing Osteogenic Differentiation Potential of BMSCs in Old Mice.

BACKGROUND: Cellular senescence is an important process related to the pathogenic mechanism of different disorders, especially bone loss. During senescence, bone marrow stromal cells (BMSCs) lose their self-renewal and functional differentiation abilities. Therefore, finding signals opposing the osteogenic differentiation of BMSCs within bone marrow microenvironment is the important for elucidating these above-mentioned mechanisms. Inflammatory cytokines affect bone physiology and remodeling. However, the function of interleukin-19 (IL-19) in skeletal system remains unclear. METHODS: The mouse model of IL-19 knockout was established through embryonic stem cell injection for analyzing how IL-19 affected bone formation. Micro-CT examinations were performed to evaluate bone microstructures. We performed a three-point bending test to measure bone stiffness and the ultimate force. Antibody arrays were performed to detect interleukin family members in bone marrow aspirates. BMSCs were cultured and induced for osteogenic differentiation. RESULTS: According to our findings, there was increased IL-19 accumulation within bone marrow in old mice relative to that in their young counterparts, resulting in bone loss via the inhibition of BMSCs osteogenic differentiation. Among Wnt/ß-catenin pathway members, IL-19 strongly upregulated sFRP1 via STAT3 phosphorylation. The inhibition of STAT3 and sFRP1 abolished IL-19's inhibition against the BMSCs osteogenic differentiation. CONCLUSION: To sum up, IL-19 inhibited BMSCs osteogenic differentiation in old mice. Our findings shed novel lights on pathogenic mechanism underlying age-related bone loss and laid a foundation for further research on identifying novel targets to treat senile osteoporosis.

Interleukin-19 promotes bone resorption by suppressing osteoprotegerin expression in BMSCs in a lipopolysaccharide-induced bone loss mouse model.

Aims: Osteoporosis is characterized by decreased trabecular bone volume, and microarchitectural deterioration in the medullary cavity. Interleukin-19 (IL-19), a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. The aim of our study was to investigate the effect of IL-19 on osteoporosis. Methods: Blood and femoral bone marrow suspension IL-19 levels were first measured in the lipopolysaccharide (LPS)-induced bone loss model. Small interfering RNA (siRNA) was applied to knock down IL-19 for further validation. Thereafter, osteoclast production was stimulated with IL-19 in combination with mouse macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). The effect of IL-19 was subsequently evaluated using tartrate-resistant acid phosphatase (TRAP) staining and quantitative real-time polymerase chain reaction (RT-qPCR). The effect of IL-19 on osteoprotegerin (OPG) was then assessed using in vitro recombinant IL-19 treatment of primary osteoblasts and MLO-Y4 osteoblast cell line. Finally, transient transfection experiments and chromatin immunoprecipitation (ChIP) experiments were used to examine the exact mechanism of action. Results: In the LPS-induced bone loss mouse model, the levels of IL-19 in peripheral blood serum and femoral bone marrow suspension were significantly increased. The in vivo results indicated that global IL-19 deletion had no significant effect on RANKL content in the serum and bone marrow, but could increase the content of OPG in serum and femoral bone marrow, suggesting that IL-19 inhibits OPG expression in bone marrow mesenchymal stem cells (BMSCs) and thus increases bone resorption. Conclusion: IL-19 promotes bone resorption by suppressing OPG expression in BMSCs in a LPS-induced bone loss mouse model, which highlights the potential benefits and side effects of IL-19 for future clinical applications.

Highly Elastic and Strain Sensing Corn Protein Electrospun Fibers for Monitoring of Wound Healing.

Due to the lack of sufficient elasticity and strain sensing capability, protein-based ultrafine fibrous tissue engineering scaffolds, though favorable for skin repair, can hardly fulfill on-spot wound monitoring during healing. Herein, we designed highly elastic corn protein ultrafine fibrous smart scaffolds with a three-layer structure for motion tracking at an unpackaged state. The densely cross-linked protein networks were efficiently established by introducing a highly reactive epoxy and provided the fiber substrates with wide-range stretchability (360% stretching range) and ultrahigh elasticity (99.91% recovery rate) at a wet state. With the assistance of the polydopamine bonding layer, a silver conductive sensing layer was built on the protein fibers and endowed the scaffolds with wide strain sensing range (264%), high sensitivity (gauge factor up to 210.55), short response time (<70 ms), reliable cycling stability, and long-lasting duration (up to 30 days). The unpackaged smart scaffolds could not only support cell growth and accelerate wound closure but also track motions on skin and in vivo and trigger alarms once excessive wound deformations occurred. These features not only confirmed the great potential of these smart scaffolds for applications in tissue reconstruction and wound monitoring but also proved the possibility of employing various plant protein ultrafine fibers as flexible bioelectronics.

Alterations in Macular Microvasculature in Pterygium Patients Measured by OCT Angiography.

Previous studies have reported an association between pterygia and maculopathy, yet the underlying mechanisms and alterations to the macular microvasculature in pterygium patients have yet to be fully elucidated. Our study conducted an analysis of macular superficial vessel length density (VLD) and vessel perfusion density (VPD) to establish associations between the conjunctival and macular microvasculature in patients with unilateral and bilateral pterygia. We revealed a loss of macular microvasculature in the outer nasal (ON) region in both unilateral and bilateral pterygium patients. VLD was significantly decreased in both pterygium groups in the ON region, and VPD was notably lower in bilateral pterygium patients in the same area. Furthermore, in unilateral pterygium patients, the vessel percent pixel coverage (PPC) of the pterygium and the area of the pterygium exhibited a negative correlation with VLD in the ON region. Multiple stepwise linear regression models indicated that the PPC could best predict VLP in the ON region. Taken together, our findings suggest that patients with pterygia may be more susceptible to macular diseases, and this may be due to a compensatory increase in blood perfusion via the anterior ciliary artery. These results underscore the importance of managing maculopathy in patients with pterygia.

Anti-SOX1 antibodies-positive paraneoplastic neurological syndromes caused by thyroid carcinoma: A case report.

RATIONALE: Paraneoplastic neurological syndromes (PNSs) are a group of neurological diseases caused by distant immune effects of malignant tumors, which often occur in patients with small cell lung cancer but are not prone to occur in patients with thyroid cancer. Anti-Sry-like high mobility group box (SOX)1 antibodies (abs)-associated PNSs caused by thyroid cancer are clinically rarer. PATIENT CONCERNS: A 57-year-old Chinese male patient presented with autonomic neuropathy. A thyroid biopsy revealed the diagnosis of papillary thyroid microcarcinoma. The serum anti-SOX1 abs confirmed positive. DIAGNOSES: A diagnosis of anti-SOX1 antibodies-positive PNS was made. INTERVENTIONS: The patient received total thyroidectomy. OUTCOMES: After total thyroidectomy, the patient's symptoms resolved quickly, and the serum anti-SOX1 abs test results was negative on re-examination. LESSONS: Thyroid cancer can cause anti-SOX1 abs-associated PNS with only autonomic neuropathy.

Temporary hemiepiphysiodesis using eight-plates for angular deformities of the lower extremities in children with X-linked hypophosphataemic rickets.

PURPOSES: Temporary hemiepiphysiodesis (TH) using eight-plates is one of the most frequently performed surgeries for correcting angular deformities of the lower extremities in adolescents. Rarely have studies examined children with X-linked hypophosphataemic rickets (X-LHPR) treated with TH using eight-plates. This study was conducted to investigate the efficacy, the endpoint, and the complications of TH using eight-plates to correct angular deformities of the lower extremities in skeletally immature children. METHODS: We reviewed a total of 26 children (86 physes, 52 knees) with X-LHPR (mean age of 6.2 years, range from 2 to 13 years) who underwent TH using eight-plate to correct angular deformities of the lower extremities. Radiographs and clinical records of these patients were evaluated for demographic data and related clinical factors. RESULTS: The average correction of the mechanical lateral distal femoral angle (mLDFA) was 11.7 ± 8.7° (range from 1.0 to 29.7°), and the average correction of the mechanical medial proximal tibial angle (mMPTA) was 8.4 ± 5.0° (range from 0.3 to 16.7°). The mean deformity correction time was 22.7 months (range from 7 to 60 months), and the mean follow-up after eight-plate removal was 43.9 months (range from 24 to 101 months). Overall, 76.9% (20/26 patients) of the angular deformities of the knee were completely corrected and 15.4% (4/26) of the patients received osteotomy surgery. The femoral correction velocity (0.9° per month) was significantly higher than the proximal tibial (0.6° per month) (p = 0.02). The correction velocity of the mLDFA and mMPTA with the TH procedure was faster than that in the absence of intervention (0.9° vs. 0.2°, 0.7° vs. 0.4° per month, p < 0.05). The correction velocity of the mLDFA (1.2° vs. 0.5° per month, [Formula: see text]) and mMPTA (0.7° vs. 0.5° per month, p = 0.04) of patients whose age ≤ five years old was faster than that of patients whose age > five years old. A total of 69.2% (18/26) patients experienced one TH procedure using eight-plates only. Two patients had screw loosening (2/26, 7.7%). One patient (1/26, 3.8%) had a rebound phenomenon after the removal of eight-plate and had the TH procedure again. There was no breakage, infection, physis preclosure, or limited range of movement found in the follow-up. CONCLUSION: TH using eight-plates is a safe and effective procedure with a relatively low incidence of complication and rebound, and it could be used as part of a streamlined treatment for younger X-LHPR patients with resistant or progressive lower limb deformity despite optimal medical treatment. Early intervention can achieve better results.

Echium amoenum L. Ethanol Extract Protects Retinal Ganglion Cell after Glutamate and Optic Nerve Crush Injury.

The development of low-cost and effective natural products for treating neuron degenerative diseases have proven to be safe and potentially effective. Echium amoenum L. (Boraginaceae) is an annual herb that grows wildly in Europe and western Asia. The aim of this study was to evaluate the neuroprotective properties of an ethanol extract of E. amoenum L. The effects of E. amoenum L. extract on oxidative stress were measured in the rat R28 retinal precursor cell line. Furthermore, the protective role of the extract on the glutamate-induced and optic nerve crush (ONC) injury-induced cell death were evaluated in vitro and in vivo, respectively. Our results showed that the ethanol extract of E. amoenum L. prevented the glutamate-induced decrease in cell viability and increase in cell death in R28 cells and suppressed the overproduction of ROS induced by glutamate. Moreover, the extract significantly inhibited microglial activation and optic nerve damage induced by ONC injury in mice. In addition, the mechanism was attributed to the ability of the extract to decrease NF-κB pathway activation and its downstream inflammatory cytokine production. In conclusion, E. amoenum L. ethanol extract had a potent neuroprotective effect against glutamate-induced and ONC-induced cell death. This is likely due to its antioxidant and anti-inflammatory properties.

Automated regional citrate anticoagulation based on online monitoring of ionized calcium concentration: Proof of concept.

BACKGROUND: Regional citrate anticoagulation (RCA), a complex and effective technique, is recommended as the anticoagulation of choice for continuous renal replacement therapy. One of its key objectives is to keep the ionized calcium in the targeted range. In this study, we aimed to develop an automated RCA based on online monitoring of the ionized calcium concentration and closed-loop feedback. METHODS: We constructed calcium-selective electrodes with liquid inner contact, which measured a potentiometric signal as the output. We tested the responses, stability, and selectivity of the electrodes in flowing fluid containing calcium chloride. We compared the measurement accuracy between the electrodes and an i-STAT system in vivo. Moreover, we established closed-loop feedback using a proportional-integral-derivative controller model. We performed simulated automated RCA both in vivo and in vitro. RESULTS: The electrode gave a Nernstian response to the variation of ionized calcium concentration. It showed high stability and a relatively short response time. Changes in the fluid flow rate, solution PH, and addition of metal ions including Mg2+ and K+ did not interfere with the measurements of ionized calcium. These measurements in whole blood by the electrode were very close to those assessed by the i-STAT system. The feedback control system responded quickly to an abnormal ionized calcium concentration and regulated the infusion rates of calcium or citrate to maintain the concentration of ionized calcium within the targeted range. CONCLUSIONS: We successfully trialed automated RCA, which may help simplify the complexities of RCA in the future.

Intravenous Transplantation of Human Hair Follicle-Derived Mesenchymal Stem Cells Ameliorates Trabecular Bone Loss in Osteoporotic Mice.

Background: Hair follicles harbor a rich autologous stem cell pool and human hair follicle-derived mesenchymal stem cells (hHF-MSCs) have multi-lineage differentiation potential. Many sources of MSCs include hHF-MSCs have been attractive candidates for cell therapy, regenerative medicine and tissue engineering. The present study is to explore the effect of intravenous transplantation of hHF-MSCs on bone mass in osteoporotic mice and its mechanism, and provides prospects for clinical applications for the treatment of osteoporosis with hHF-MSCs. Methods: Physically pull out about 20 hairs with intact hair follicles from the occipital area of the scalp of healthy volunteers, and extract hair follicle-derived fibroblast-like cells. These cells were cultured and characterized in vitro. Intravenous injection of hHF-MSCs was performed on ovariectomy-induced and age-related osteoporotic SCID mice for osteoporosis treatment. The mice were sacrificed 7 weeks after the second injection and samples were collected. The long bones and L1 vertebrae were collected for micro-CT scan, histomorphometry and immunohistochemical analysis. Peripheral serum were collected for ELISA analysis and antibody array. Results: Hair follicle-derived fibroblast-like cells were defined as hHF-MSCs. Intravenous transplantation of hHF-MSCs can better restores trabecular bone mass in osteoporotic mice. The double calcein labeling assay, trap staining of bones and ELISA analysis in peripheral serum showed enhanced bone formation and weakened bone resorption after transplantation. Antibody array and immunohistochemical analysis showed that several cytokines including OPG, Wnt2b, Noggin, VCAM-1 and RANKL might be involved in this process. Conclusion: Human HF-MSCs transplantation can combat trabecular bone loss induced by menopause and aging in mice. And the above mechanism that hHF-MSCs transplantation inhibits bone resorption and promote bone formation is related to OPG, Wnt2b, VCAM-1, Noggin and RANKL.

Diagnostic Performance of MRI Versus CT in the Evaluation of Intra-articular Osteochondral Fracture in Pediatric Patients With Acute Traumatic Lateral Patellar Dislocation.

Background: Evaluation of intra-articular osteochondral fractures in children with acute traumatic lateral patellar dislocation (LPD) is important for determining treatment options. Purpose: To (1) compare the diagnostic accuracy of computed tomography (CT) and magnetic resonance imaging (MRI) for evaluating intra-articular osteochondral fractures; (2) compare the interpretation of CT and MRI images between radiologists and pediatric orthopaedic surgeons (POS); and (3) investigate any clinical factors influencing the accuracy of CT and MRI evaluations. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: We reviewed 35 knees in 35 patients (mean age, 12.2 ± 1.2 years; 12 boys and 23 girls) who were treated arthroscopically for acute traumatic LPD; 71% of the patients had patellar fractures, 54% had femoral fractures, and 60% had free osteochondral fracture fragments. All presurgical MRI and CT images were reviewed by POS who were blinded to both the reports of the radiologists and surgical records. We compared the accuracy of CT and MRI in diagnosing intra-articular osteochondral fractures against the arthroscopic findings and compared the interpretation of the images by the POS (MRI-O, CT-O) with those of the radiologists (MRI-R, CT-R). Results: There was no significant difference in diagnostic accuracy between CT and MRI for overall intra-articular osteochondral fractures by the POS or the radiologists; however, the CT-O images had a higher diagnostic specificity (84.2% vs 69.6%; P < .001) and sensitivity (88.1% vs 70.1%; P < .001) versus the MRI-R images. Regarding free fracture fragments, the CT-R images had a higher diagnostic accuracy than the MRI-R images (73.5% vs 47.1%; P = .026). When backed by clinical data, the MRI-O images had greater diagnostic accuracy (78.7% vs 60.3%; P = .001) and sensitivity (88.1% vs 30.7%; P = .021) but lower specificity compared with the MRI-R images, and the CT-O images had similar diagnostic accuracy but greater sensitivity than the CT-R images (70.1% vs 52.2%; P < .001). The diagnostic accuracy of MRI-O images was lower for children under 12 years versus children 12 years and over (67.5% vs 83.3%; P = .040). Conclusion: Compared with MRI, CT scans had better diagnostic performance in the evaluation of intra-articular osteochondral fractures in pediatric patients with acute traumatic LPD. Clinical data enhanced the diagnostic sensitivity of MRI and CT but decreased the specificity of MRI. MRI evaluations remain challenging for both POS and radiologists.

A retrospective study of treatment of genu valgum/varum with guided growth: Risk factors for a lower rate of angular correction.

The rate of angular correction (ROAC) is very unpredictable and may be affected by various factors in the treatment of genu valgum and varum by means of guided growth. The purpose of this study was to assess the ROAC in cases from our institution and to identify risk factors associated with the occurrence of lower ROAC.We retrospectively reviewed the chart records of 68 patients undergoing guided growth with figure-eight plate for the correction of genu valgum and varum. Based on the data from these patients, the annual increment of physeal growth was calculated and compared with data from the Anderson chart. The associations between patient characteristics and ROAC were evaluated with the use of univariate logistic regression.The mean rate of femoral angular correction was 10.29 degrees/year, while the mean rate of tibial angular correction was 7.92 degrees/year. In a univariate logistic regression analysis, the variables associated with a higher risk of lower ROAC included non-idiopathic coronal deformity of the knee (odds ratio = 13.58, p < 0.001) and body weight at or above the 95th percentile for children (odds ratio = 2.69, p = 0.020).Obesity and non-idiopathic coronal deformity of the knee are risk factors for lower ROAC. It is still uncertain whether severity of deformity, race, and operative procedure have a substantial effect on the rate of correction.Level III evidence.

Iliac screw instrumentation to the pelvis in children with neuromuscular and syndromic scoliosis. No lateral connectors and respect sagittal balance.

STUDY DESIGN: One-center retrospective cohort study. BACKGROUND: Compared to the traditional iliac screw technique, the modified iliac screw technique has a lower rate of distal implant failure in the treatment of neuromuscular scoliosis patients with pelvic obliquity. However, the reasons for decreased failure with the modified iliac screw technique are controversial. QUESTIONS/PURPOSES: (1) Is distal implant failure, as evident by implant breakage or disconnection, more likely to occur in patients receiving the traditional iliac screw technique (PSIS) compared to the modified S2AI (MODS2) technique? (2) After controlling for relevant confounding variables, are there other identifiable risk factors for distal implant failure? METHODS: We identified patients who underwent pelvic screw fixation by three pediatric spine surgeons from January 2007 to July 2017. Based on the starting point of the iliac screws, patients were divided into two groups. Group 1 consisted of PSIS fixation with an offset connector. Group 2 consisted of modified S2AI fixation without an offset connector. Demographic, operative, and radiographic data were obtained. RESULTS: Cobb angle, lumbar lordosis, and pelvic obliquity were not significantly different between the two groups. Overall distal implant failure was 40/100 (40%) and significant between Group 1 PSIS 29/53 (55%) and Group 2 MODS2 11/47 (23%) (p = 0.002). No other complications were significant. Three risk factors were identified with implant failure: high pelvic incidence (17-fold increase, 95% confidence interval [CI] = 5.5 to 53.1, p < 0.001), high angle rod contour (3.8-fold increase, 95% CI = 1.2 to 11.9, p = 0.023), and use of an offset connector (3.2-fold increase, 95% CI = 1.0 to 10.3, p = 0.049). Failure did not correlate with the use of a cross-link, iliac screw diameter, or screw density. Revision surgery related to distal implant failure did not significantly differ between the two groups. CONCLUSIONS: Compared to the use of an offset connector with PSIS fixation, MODS2 fixation had a lower rate of implant failure. Sagittal balance parameters, namely pelvic incidence and angle of rod bend, were the major risk factors for implant failure. LEVEL OF EVIDENCE: III.

Temporary hemiepiphysiodesis using an eight-plate implant for coronal angular deformity around the knee in children aged less than 10 years: efficacy, complications, occurrence of rebound and risk factors.

BACKGROUND: Temporary hemiepiphysiodesis (TH) using an eight-Plate implant is one of the most common surgeries used for the correction of coronal angular deformities around the knee in adolescents. However, few studies have focused on children aged less than 10 years treated with TH using an eight-Plate implant. The purpose of this study was to investigate the efficacy, correction velocity, and complications of TH with an eight-Plate implant as well as the occurrence of rebound and risk factors in this population. METHODS: This retrospective study included a total of 135 physes (101 knees) from 66 children (mean age of 4.69 years old, range from 1 to 10 years old) who underwent TH with an eight-Plate implant to correct coronal genu angular deformities in our hospital. Related clinical factors were recorded and analysed by multivariable linear and logistic regression models. RESULTS: The mean deformity correction period was 13.26 months, and the mean follow-up after eight-Plate removal was 12.71 months. In all, 94.06% (95/101 knees) of the genu angular deformities were completely corrected. Non-idiopathic genu angular deformity was found to be an independent risk factor for deformity correction failure (odds ratio (OR) = 2.47). The femoral correction velocity was significantly higher than the tibial correction velocity (1.28° vs. 0.83° per month, p < 0.001). After adjustment for other factors, younger children had higher correction velocities in the distal femur; however, genu valgum and idiopathic deformities were associated with higher correction velocities in the proximal tibia. In addition, we found three (3/101, 2.97%) knees with genu valgum that experienced rebound after removal of the eight-Plate, while five (5/101, 4.95%) knees with non-idiopathic genu angular deformity experienced screw loosening. No other complications were found, and non-idiopathic deformity was the only risk factor for complications (OR = 3.96). No risk factor was found for rebound in our study. CONCLUSIONS: TH using an eight-Plate implant is an effective procedure for coronal genu angular deformities with a low incidence of complications and rebound in patients younger than 10 years old. For this population, TH using an eight-Plate should be considered as soon as the deformity stops responding to conservative treatments. The parents of children younger than 10 years of age with non-idiopathic deformities should be informed preoperatively that the deformity may be prone to correction failure or screw loosening after eight-Plate implantation.

Risk factors for implant-related fractures after proximal femoral osteotomy in children with developmental dysplasia of the hip: a case-control study.

Background and purpose - Proximal femoral osteotomy (PFO) is commonly performed to treat children with developmental dysplasia of the hip (DDH). Implant-related femoral fractures after osteotomy are sometimes reported, but the potential risk factors for these fractures remain unclear. We investigated the association of implant-related fractures with PFO and potential risk factors for these fractures.Patients and methods - We retrospectively reviewed 1,385 children undergoing PFO for DDH in our institution from 2009 to 2016 after obtaining institutional review board (IRB) approval and identified 27 children (28 hips, fracture group) with implant-related femoral fractures after PFO. We selected 137 children (218 hips, control group) without fractures who matched the children in the fracture group by age, weight, surgeon, and surgical period. Relevant clinical data were collected and compared between the 2 groups. Multiple analyses of risk factors for implant-related fractures were conducted by logistic regression with the stepwise regression method.Results - The occurrence rate of implant-related fractures was 1.9% (27/1,385). Compared with the control group, the fracture group more commonly exhibited bilateral involvement (74% vs. 53%, p = 0.04), used a spica orthosis for immobilization after osteotomy (43% vs 21%, p = 0.01) and exhibited mild remodeling at the osteotomy site (46% vs. 19%, p = 0.003), and less commonly required capsulotomy during osteotomy (61% vs. 79%, p = 0.03). According to the multiple regression analysis, the only factor identified as an independent risk factor for implant-related fractures was mild remodeling at the osteotomy site (OR = 3.2, 95% CI 1.4-7.5). Remodeling at the osteotomy site was significantly associated with varus osteotomy (coefficient = 1.4, CI 1.03-1.8). The fracture occurred at a mean of 12 months (2.2-25) after osteotomy or 3.3 months (0-12) after implant removal. In children undergoing implant removal, the fractures mostly occurred at the osteotomy site (n = 13/15), while in those with the implant remaining, the fractures mostly occurred in the screw hole (n = 8/13).Interpretation - The type of PFO performed is not associated with implant-related fractures in children with DDH. Children with mild remodeling at the osteotomy site should be closely followed up, regardless of whether the hardware is removed, and high-intensity activity should not be permitted until moderate or extensive remodeling is confirmed. After PFO, the implants should be removed when solid union is achieved at the osteotomy site.

Finite element and biomechanical analysis of risk factors for implant failure during tension band plating.

OBJECTIVE: Tension band plating has recently gained widespread acceptance as a method of correcting angular limb deformities in skeletally immature patients. We examined the role of biomechanics in procedural failure and devised a new method of reducing the rate of implant failure. METHODS: In the biomechanical model, afterload (static or cyclic) was applied to each specimen. The residual stress of the screw combined with different screw sizes and configurations were measured and compared by X-ray diffraction. With regard to static load and similar conditions, the stress distribution was analyzed according to a three-dimensional finite element model. RESULTS: The residual stress was close to zero in the static tension group, whereas it was very high in the cyclic load group. The residual stress of screws was significantly lower in the convergent group and parallel group than in the divergent group. The finite element model showed similar results. CONCLUSIONS: In both the finite element analysis and biomechanical tests, the maximum stress of the screw was concentrated at the position where the screws enter the cortex. Cyclic loading is the primary cause of implant failure.

Analysis of risk factors for complications after femoral neck fracture in pediatric patients.

BACKGROUND: Pediatric femoral neck fracture is a rare injury but yields frequent complications. However, there is a paucity of data regarding the risk factors for these complications. PURPOSE: The present article reports the rate of complications after femoral neck fracture in pediatric patients and investigates the possible risk factors. METHODS: We retrospectively reviewed 44 children (mean age of 9.0 years, range from 2 to 14 years) who were surgically treated for femoral neck fracture in a single trauma center with a mean follow-up of 57.75 months (range from 11 to 224 months). Related clinical factors were recorded and analyzed by multivariable logistic regression. RESULTS: Fracture displacement or Delbet-type fracture had no relation to the injury mechanism. However, younger children experienced severe trauma, combined injury, and low fracture location more than older individuals did. Children with combined injuries were more likely to have a longer waiting time for surgical reduction. Common complications included avascular necrosis (AVN) in 14 cases, nonunion of fracture in 2 cases, coxa vara in 4 cases, and premature physeal closure (PPC) in 7 cases. Only the Delbet type was an independent predictor of AVN (OR = 0.14, p = 0.030). Inadequate reduction was associated with higher rates of coxa vara (OR = 33.19, p = 0.032). Epiphysis penetration in children younger than 10 years old increased the rate of PPC (p = 0.032). No significant risk factor was found for fracture nonunion. CONCLUSION: For femoral neck fracture in pediatric patients, both the injury mechanism and fracture characteristics have age-related distributions. Early reduction should be carried out as early as possible based on the safe condition of the child, but for younger children, transepiphyseal fixation should be avoided. AVN may be intrinsic to injury characteristics rather than resulting from the choice of treatment mode.

Integrated bioinformatics analysis of potential pathway biomarkers using abnormal proteins in clubfoot.

BACKGROUND: As one of the most common major congenital distal skeletal abnormalities, congenital talipes equinovarus (clubfoot) affects approximately one in one thousandth newborns. Although several etiologies of clubfoot have been proposed and several genes have been identified as susceptible genes, previous studies did not further explore signaling pathways and potential upstream and downstream regulatory networks. Therefore, the aim of the present investigation is to explore abnormal pathways and their interactions in clubfoot using integrated bioinformatics analyses. METHODS: KEGG, gene ontology (GO), Reactome (REAC), WikiPathways (WP) or human phenotype ontology (HP) enrichment analysis were performed using WebGestalt, g:Profiler and NetworkAnalyst. RESULTS: A large number of signaling pathways were enriched e.g. signal transduction, disease, metabolism, gene expression (transcription), immune system, developmental biology, cell cycle, and ECM. Protein-protein interactions (PPIs) and gene regulatory networks (GRNs) analysis results indicated that extensive and complex interactions occur in these proteins, enrichment pathways, and TF-miRNA coregulatory networks. Transcription factors such as SOX9, CTNNB1, GLI3, FHL2, TGFBI and HOXD13, regulated these candidate proteins. CONCLUSION: The results of the present study supported previously proposed hypotheses, such as ECM, genetic, muscle, neurological, skeletal, and vascular abnormalities. More importantly, the enrichment results also indicated cellular or immune responses to external stimuli, and abnormal molecular transport or metabolism may be new potential etiological mechanisms of clubfoot.