Strong cathode electroluminescence biosensor based on CeO2 functionalized PCN-222@Ag NPs for sensitive detection of p-Tau-181 protein.

Electrochemiluminescence (ECL) biosensors provide a convenient and high sensitivity method for early disease diagnosis. However, creating luminophore arrays relying on powerful ECL signals remains a daunting task. Porphyrin-centered metal organic frameworks (MOFs) exhibit remarkable potential in ECL sensing applications. In this paper, based on a simple one-pot synthesis method, PCN-222@Ag NPs doped with CeO2 was synthesized to enhance the ECL performance. Due to the strong catalytic ability of CeO2, the ECL signal strength of the new material PCN-222@CeO2@Ag NPs is much higher than that of the PCN-222@Ag NPs and PCN-222. The luminous properties of PCN-222@CeO2@Ag NPs become more intense and stable due to the excellent electronic conductivity of Ag NPs. Based on the fact that CuS@PDA composite can quench the ECL signal of PCN-222@CeO2@Ag NPs, we constructed a novel sandwich ECL immune sensor for the detection of phosphorylated Tau 181 (p-Tau-181) protein. The ECL sensor has a great linear relationship with p-Tau-181 protein concentration, ranging from 1 pg/mL to 100 ng/mL. The detection limit is as low as 0.147 pg/mL. This work provides new ideas for developing sensitive ECL sensors for the p-Tau-181 protein, the marker of Alzheimer's disease.

Is it safe for the spinal metastasis patients with preoperative deep vein thrombosis to use low-molecular-weight heparin before surgery? A prospective study.

Spine surgeons should weigh the risks of anticoagulants against their benefits in preventing deep venous thrombosis (DVT), as they may increase the risk of bleeding. Spinal metastasis patients undergoing decompression with fixation are at a high risk for DVT, which may occur preoperatively. Therefore, anticoagulants should be administered preoperatively. This study aimed to evaluate the safety of the administration of anticoagulants in treating spinal metastasis patients with preoperative DVT. Therefore, we prospectively investigated the prevalence of DVT in these patients. Patients who were diagnosed with preoperative DVT were included in an anticoagulant group. Subcutaneous low-molecular-weight heparin (LMWH) was administered. Patients without DVT were included in a non-anticoagulant group. Data on patient information, clinical parameters, blood test results, and bleeding complications were also collected. Moreover, the safety of anticoagulants was analyzed. The prevalence of preoperative DVT was 8.0%. None of the patients developed pulmonary thromboembolism. Furthermore, no significant differences in blood loss, drainage volume, hemoglobin levels, number of transfusions, or preoperative trans-catheter arterial embolization were observed between the two groups. None of the patients developed major bleeding. However, two patients experienced wound hematoma and one experienced incisional bleeding in the non-anticoagulant group. Therefore, LMWH is safe for spinal metastasis patients. Future randomized controlled trials should be conducted to evaluate the validity of perioperative prophylactic anticoagulation therapy in these patients.

Scutellarin-mediated autophagy activates exosome release of rat nucleus pulposus cells by positively regulating Rab8a via the PI3K/PTEN/Akt pathway.

To provide a basis for promising exosome-based therapies against intervertebral disc degeneration (IDD), our present research aimed to identify a mechanism underlying the vesicle release from nucleus pulposus cells (NPCs). Scutellarin (SC) is a natural chemotherapeutic agent isolated from Erigeron breviscapus with a variety of biological activities. Here, we observed the significantly elevated autophagy levels in rat NPCs under the stimulation of SC, leading to a concomitant enhancement of intracellular vesicle release, which could be attributed to the inactivation of the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (Akt) pathway. To ensure that exosome release was driven by SC via the autophagic pathway, we implemented gain-of-function and loss-of-function studies by additionally using insulin-like growth factor-1 (IGF-1) and small-interfering RNA of autophagy-related gene 5 (ATG5), and the exosome secretion decreased in the case of attenuated autophagy. Evidently, the treatment with SC exerted the remarkable upregulation of Rab8a through the overexpression of ATG5. After the respective knockdown of ATG5 and Rab8a, the increased release of exosomes induced by SC was reversed, whereas the number of intracellular vesicles was restored. Overall, it can be concluded that SC contributes to the autophagy activation in NPCs by acting on the PI3K/PTEN/Akt pathway, which upregulates the expression of Rab8a and promotes the release of exosomes, inspiring novel therapeutic strategies in preventing IDD that might be fruitfully investigated.

Prevalence and risk factors for venous thromboembolism in spinal metastasis patients undergoing decompression with internal instruments: Prospective cohort study.

OBJECTIVE: re is paucity in the literature on the epidemiological evidence of pulmonary thromboembolism (PE) and deep venous thrombosis (DVT) in spinal metastatic tumor patients. The aim of our study was to identify the incidence and risk factors for VTE in spinal metastasis patients treated with decompression with internal instruments. METHODS: We prospectively investigated the occurrence of VTE after decompression with internal fixations in 80 spinal metastasis patients. DVT was diagnosed by using a duplex ultrasonographical. PE was diagnosed by multidetector computed tomographic (CT) pulmonary angiography. Patient information and clinical parameters were collected. Risk factors were analyzed by comparing the difference between VTE and non-VTE cases. RESULTS: The incidence of developing a DVT was 6.3% (5/80). No patient suffered PE. In univariate analysis, the mean length of hospital stay after surgery until discharge for VTE group was longer than non-VTE group, ODI scores and AIS in VTE group were significantly worse than non-VTE group, D-dimer one-day postoperatively for VTE group was significantly higher than non-VTE group. In logistic regression, D-dimer at one-day postoperatively was the only risk factor. The areas under the ROC curves for the D-dimer (post) to distinguish between non-VTE and VTE was 0.971(P value=0.000). By means of the ROC analysis, the optimum thresholds of D-dimer(post) were determined to be 9.51 mg/L. The sensitivity and specificity for the optimum threshold were 100.0% and 92.0%. CONCLUSION: The prospective study of 80 patients with spinal metastasis who underwent decompression with internal fixation revealed an incidence of DVT of 6.3%, patients with increasingly D-dimer level at one-day postoperatively had a higher risk of DVT, and the optimum thresholds of D-dimer(post) were determined to be 9.51 mg/L.

Risk Factors for Incidence and Prognosis in Chondrosarcoma Patients with Pulmonary Metastasis at Initial Diagnosis.

BACKGROUND The incidence and prognostic factors of chondrosarcoma patients have been reported in early studies. However, the association between risk factors and the incidence or prognosis of chondrosarcoma patients with pulmonary metastasis remains unclear. Therefore, we assessed these risk factors among chondrosarcoma patients with pulmonary metastasis. MATERIAL AND METHODS From 1365 chondrosarcoma patients in the Surveillance, Epidemiology, and End Results (SEER) database, we collected the information of 69 patients with pulmonary metastasis at the initial diagnosis of chondrosarcoma from 2010 to 2016. We investigated the incidence, risk factors, and prognostic factors for pulmonary metastasis patients by using multivariate logistic regression and multivariate Cox regression analyses. RESULTS Data from a total of 69 (6.8%) chondrosarcoma patients with pulmonary metastasis at initial diagnosis were extracted. Patients with the following characteristics were positively associated with higher risk of pulmonary metastasis: dedifferentiated subtype, high grade of malignancy, extracompartmental tumor (Enneking B), presence of regional lymph nodes, local recurrence, large tumor size (larger than 15 cm), and being married. Older patients (older than 67 years), and patients with clear cell chondrosarcoma or large tumor size (larger than 15 cm) exhibited the worse prognosis and survival (overall and cancer-specific). Resection of the primary tumor tended to be correlated with a better prognosis. CONCLUSIONS The incidence of pulmonary metastasis in chondrosarcoma was approximately 6.8%, with poor prognosis. Identifying risk factors and their associations with the incidence and prognosis in chondrosarcoma patients with pulmonary metastasis could provide a reference for clinical surveillance and guide the design of personalized treatment plans.

A prospective randomized trial comparing anterior cervical discectomy and fusion versus plate-only open-door laminoplasty for the treatment of spinal stenosis in degenerative diseases.

OBJECTIVE: For three or more involved cervical levels, there is a debate over which approach yields the best outcomes for the treatment of multilevel cervical degenerative disease. Our objective is to compare the radiological and clinical outcomes of two treatments for multilevel cervical degenerative disease: anterior cervical discectomy and fusion (ACDF) versus plate-only open-door laminoplasty (laminoplasty). METHODS: Patients were randomized on a 1:1 randomization schedule with 17 patients in the ACDF group and 17 patients in the laminoplasty group. Clinical outcomes were assessed by a visual analog scale (VAS), Japanese Orthopedic Association (JOA) scores, operative time, blood loss, rates of complications, drainage volume, discharge days after surgery, and complications. The cervical spine curvature index (CI) and range of motion (ROM) were assessed with radiographs. RESULTS: The mean VAS score, the mean JOA score, and the rate of complications did not differ significantly between groups. The laminoplasty group had greater blood loss, a longer operative time, more drainage volume, and a longer hospital stay than the ACDF group. There were no significant differences in the CI and ROM between the two groups at baseline and at each follow-up time point. ROM in both groups decreased significantly after surgery. CONCLUSIONS: Both ACDF and laminoplasty are effective and safe treatments for multilevel cervical degenerative disease. ACDF causes fewer traumas than laminoplasty.

Degenerative Spondylolisthesis in the Fifth Lumbar Vertebra and Radiographic Parameters: A Correlation Analysis.

STUDY DESIGN: A retrospective study. OBJECTIVE: This study aimed to analyze the relationships between degenerative spondylolisthesis in the fifth lumbar vertebra (L5-DS) and radiographic parameters and to further determine the radiographic predictors of the development of L5-DS. SUMMARY OF BACKGROUND DATA: Degenerative lumbar spondylolisthesis (DLS) is a common degenerative disease of the spine; however, the correlations between L5-DS and radiographic parameters remain controversial. PATIENTS AND METHODS: This retrospective case-control study was conducted in our hospital. Between 2011 and 2014, a total of 84 subjects with L5-DS were enrolled in the DLS group, and 56 healthy volunteers were recruited to the control group. A series of radiographic parameters, including the bone mineral density, disk degenerative index, disk height, L5 vertebral size (L5-VS), lumbar lordosis angle (LL), sacral slope angle (SS), pelvic incidence (PI), facet joint angulations (FJA) of the cephalad and caudad portions, and asymmetry of the FJA, were measured in both groups by 3 examiners. RESULTS: The bone mineral density, disk degenerative index, disk height, L5-VS, LL, SS, PI, and FJA exhibited significant differences (P=0.014-0.045) between the DLS and control groups. Significant changes in the FJA of the cephalad and caudad portions in the L4-L5 and L5-S1 segments were observed between the 2 groups (P=0.00, 0.00), whereas no significant differences in the asymmetries of FJA were observed in the L4-L5 or L5-S1 segments (P=0.605-0.972). Among all of the parameters, the L5-VS (P=0.025), SS (P=0.020), LL (P=0.031), PI (P=0.014), and FJA (P=0.022) were identified as being associated with the DLS group by multiple logistic regression analysis. CONCLUSIONS: In this study, SS, LL, PI, and a more sagittal FJA were proven to be risk factors for L5-DS, whereas L5-VS was found to be a likely protective factor against L5-DS. These parameters should be considered predictors of L5-DS.

Single-Level Rigid Fixation Combined with Coflex: A Biomechanical Study.

BACKGROUND: The purpose of this biomechanical in vitro study was to compare the kinematics and intradiscal pressure achieved with 2 methods: L4-L5 pedicle screw-rod fixation (PSRF) with an upper L3-L4 Coflex device and L4-L5 PSRF alone. The results were used to characterize the biomechanics of the topping-off operation with a Coflex device for the lumbar motion segment adjacent to single-level rigid fixation. MATERIAL/METHODS: Six human cadaveric spine specimens were biomechanically tested in vitro (6 males, 0 females). The 3-dimensional specimen motion in response to applied loads during flexibility tests was determined. Loads were applied along anatomic axes to induce flexion-extension, lateral bending, and axial rotation. All specimens were first studied with intact lumbar motion segments, then with L4-L5 PSRF alone, and finally with L4-L5 PSRF with an upper L3-L4 Coflex device. A non-paired comparison of the 3 configurations under 3 different conditions was made. RESULTS: PSRF, with or without a Coflex device, significantly increased the range of motion (ROM) in the upper adjacent motion segments in all directions of loading. The intradiscal pressure (IDP) changed slightly. A correlation analysis showed that the ROM and IDP are significantly positively correlated. The application of the upper motion segment of the Coflex device provided greater stability in all directions of motion than did PSRF alone, particularly for extension (p<0.05), while use of a Coflex device did not significantly decrease the IDP compared with PSRF alone (p>0.05). CONCLUSIONS: These results suggest that L4-L5 PSRF with an L3-L4 Coflex device is more stable than L4-L5 PSRF alone. PSRF with an upper Coflex device is a promising alternative to PSRF alone. Based on these biomechanical tests, it might be considered a protective method to prevent adjacent segment degeneration (ASD), although some limitations with this in vitro study must be addressed in the future.

Polypyrrole coating on poly-(lactide/glycolide)-ß-tricalcium phosphate screws enhances new bone formation in rabbits.

Polypyrrole (PPy) has gained interest as an implant material due to its multifunctional properties and its high compatibility with several cell and tissue types. For the first time, the biocompatibility and osteointegration of PPy coating, incorporated with chondroitin sulfate (CS), were studied in vivo by implanting PPy-coated bioabsorbable bone fixation composite screws of poly-(lactide/glycolide) copolymer (PLGA) and ß-tricalcium phosphate (TCP) into New Zealand white rabbits. Uncoated bioabsorbable polymer composite screws and commercially available stainless steel cortical screws were used as reference implants. The rabbits were euthanized 12 and 26 weeks after the implantation. The systemic effects were evaluated from food and water consumption, body weight, body temperature, clinical signs, blood samples, internal organ weights, and histological examination. Local effects were studied from bone tissue and surrounding soft tissue histology. New bone formation was evaluated by micro-computed tomography, tetracycline labeling and torsion tests. Torsion tests were performed in order to capture the peak value of the torsion force during the course of the screw's loosening. The coated screws induced significantly more bone formation than the uncoated screws. In addition, none of the implants induced any systemic or local toxicity. The results suggest that PPy is biocompatible with bone tissue and is a potential coating for enhancing osteointegration in orthopedic implants.

Minimum 5 year follow-up of multi-segmental lumbar degenerative disease treated with discectomy and the Wallis interspinous device.

We evaluate the clinical effects and radiological findings of the Wallis interspinous device (Zimmer, Warsaw, IN, USA) for the treatment of multi-segmental lumbar degenerative disease after a minimum 5 year follow-up period. A total of 26 adult patients underwent a primary discectomy followed by fixation of the segment with the Wallis interspinous device between December 2007 and August 2008. Twelve men and 14 women with an age range of 43 to 56 years (average: 47.6) were included. The visual analogue scale (VAS) for low back and leg pain, Oswestry Disability Index (ODI), foraminal height (FH), anterior disc height (aDH) and posterior disc height (pDH), range of motion (ROM) and Pfirrmann grades were obtained and compared before and after surgery. The VAS and ODI significantly decreased postoperatively (p < 0.05). The postoperative FH and pDH values increased significantly compared with the preoperative levels (p < 0.01) and the increase in the FH and pDH values remained statistically significant during the follow-up period. There were no statistically significant changes in the aDH values before and after surgery (p > 0.05). Also, there were no statistically significant changes in the ROM and Pfirrmann grade at the instrumented level and at the cephalad-adjacent segment (p>0.05). In our study, no patient underwent further surgery because of a re-prolapse or progression of index level degeneration or adjacent segment disease. The Wallis interspinous device was a useful alternative for treating multi-segmental lumbar degenerative disease and it offered a significant minimum 5 year symptom control.

Establishment of intervertebral disc degeneration model induced by ischemic sub-endplate in rat tail.

BACKGROUND CONTEXT: Microcirculatory dysfunction of the sub-endplate is considered to reduce nutrient supply to the intervertebral disc (IVD); however, direct interruption or destruction of blood vessels in the bone marrow of the vertebrae body adjacent to the endplate has not yet been described, especially with regard to the calcification and ossification of the cartilaginous endplate occurring during IVD degeneration. PURPOSE: The purpose of the study was to evaluate the causal relationship between IVD degeneration and blocking of the main blood supply gateway through the endplate. STUDY DESIGN/SETTING: The study describes a new IVD degeneration model induced by ischemic sub-endplate. PATIENT SAMPLE: A total of 40 Sprague-Dawley rats were included in the study group. OUTCOME MEASURES: To assess disc height, a radiograph was taken each month for 4 months. Changes in endplate, nucleus pulposus (NP), and annulus fibrosus (AF) were evaluated by histochemical and immunohistochemical staining to detect IVD degeneration. METHODS: Injection of 30 µL absolute ethanol into the IVD of rat tail at Co7/Co8 was used to induce injury. Controls were injected with 30 µL of phosphate-buffered saline into the IVD at Co8/Co9. RESULTS: In the ethanol-injected group, disc height gradually decreased and bone sclerosis developed in the endplate. In the NP, cell transformation occurred, changing from predominantly vacuolar cells to chondrogenic cells and eventually fibrocartilaginous cells, along with fibrosis of the NP. As degeneration progressed, the AF developed disordered morphology and rough lamellae, and eventually ruptures and fibrosis. The extent of degeneration increased gradually over time, while the wavy tidemark of the growth plate regressed, and eventually disappeared. Initially positive collagen type II staining gradually decreased on the ischemic side of the sub-endplate. Except at the 3-month time point, expression of collagen type II, aggrecan, and Sox-9 in NP decreased gradually as degeneration progressed, compared with the control group. CONCLUSIONS: This model successfully reproduced IVD degeneration, which could be used for etiological studies on IVD degeneration and investigation of nutrient supply disturbance, and may provide a theoretical foundation for clinical intervention and therapy for IVD degeneration in the future.

Recurrent adamantinoma in the thoracolumbar spine successfully treated by three-level total en bloc spondylectomy by a single posterior approach.

PURPOSE: Adamantinoma is a low-grade primary malignant bone tumour with slow growth and local recurrence. Its occurrence in the spine is extremely rare, particularly with multilevel involvement. This paper wants to present the first case involving a patient with recurrent thoracolumbar spinal adamantinoma, who underwent a successful three-level spondylectomy for en bloc resection. METHODS: A 24-year-old man with osteolytic masses of T11 and T12 vertebral bodies was performed curettage by a posterior approach in 2008. The pathology report showed the excised neoplasm was a rare adamantinoma. This patient underwent a tumorectomy again because of its local recurrence nearly 3 years later. In 2012, it was unfortunately revealed that the excised tumour had relapsed and had spread to the L1 vertebral body. Due to its repeated recurrence and aggressive lesion, total en bloc spondylectomy (TES) for this malignant tumour was thought to be the best option for preventing repeated recurrence and possible cure. TES for T11-L1 thoracolumbar spine was performed and spinal reconstruction was completed with instrumentation and a titanium mesh cage through a one-stage single posterior approach. RESULTS: After three-level TES, neurological deficits of the patient demonstrated good recovery and no evidence of adamantinoma recurrence or deformity was found at 2-year follow-up. CONCLUSIONS: This is the first case involving multilevel thoracolumbar spinal adamantinoma with repeated recurrence to be successfully treated by three-level TES by a single posterior approach.

Analysis of apparent integrated backscatter coefficient and backscattered spectral centroid shift in Calcaneus in vivo for the ultrasonic evaluation of osteoporosis.

The purposes of our study were to evaluate the correlation among apparent integrated backscatter coefficient (AIB), spectral centroid shift (SCS) of ultrasonic backscatter signals and bone mineral density (BMD) and to examine the effectiveness of ultrasound variables as predictors of osteoporosis. A total of 1011 persons aged 21-80 y old were included. All study participants underwent BMD measurements of the lumbar spine (LSBMD) and the femoral neck (FNBMD). The participants also underwent calcaneal measurements to determine AIB and SCS with central frequencies of 3.5 (one transducer) and 5.0 MHz (the other transducer). AIB decreased with age and was positively correlated with BMD, while SCS increased with age and was negatively correlated with BMD. The correlation coefficient of SCS with LSBMD and FNBMD at 3.5 MHz was -0.72 and -0.70, respectively. The correlation coefficient at 5.0 MHz was -0.75 and -0.74, respectively. The correlation coefficient of AIB with LSBMD and FNBMD at 3.5 MHz was 0.65 and 0.63. The correlation coefficient at 5.0 MHz was 0.59 and 0.55, respectively. The correlation between SCS and BMD was significantly better than the correlation between AIB and BMD. Using receiver operating characteristic analysis, a significant difference was found between the areas under the curve for SCS and AIB at 3.5 MHz (0.781 vs. 0.715, respectively, p < 0.05), as well as at 5.0 MHz (0.782 vs. 0.709, respectively, p < 0.05). The optimum T-score threshold for SCS was -1.3 for both transducers. The sensitivity and specificity of SCS at 3.5 MHz and 5.0 MHz for the optimum threshold were 64%, 85%, 63% and 86%, respectively. In conclusion, the correlations among the ultrasound parameters and BMDs are strong. SCS performs better than AIB in differentiating patients with osteoporosis. Ultrasound variables may be taken into consideration as predictors of osteoporosis in the future considering its portability.

Ovarian cancer G protein-coupled receptor 1 is involved in acid-induced apoptosis of endplate chondrocytes in intervertebral discs.

Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown to be a receptor for protons. We investigated the role of proton-sensing G protein-coupled receptors in the apoptosis of endplate chondrocytes induced by extracellular acid. The expression of proton-sensing G protein-coupled receptors was examined in rat lumbar endplate chondrocytes. Knockdown of OGR1 was achieved by transfecting chondrocytes with specific short hairpin RNA (shRNA) for OGR1. Apoptotic changes were evaluated by DNA fragmentation ELISA, electron microscopy, and flow cytometry. Intracellular calcium ([Ca(2+) ]i) was analyzed with laser scanning confocal microscopy. The mechanism of OGR1 in acid-induced apoptosis of endplate chondrocytes was also investigated. We found that OGR1 was predominantly expressed in rat endplate chondrocytes, and its expression was highly upregulated in response to acidosis. Knocking down OGR1 with shRNAs effectively attenuated acid-induced apoptosis of endplate chondrocytes and increased [Ca(2+) ]i. Blocking OGR1-mediated [Ca(2+) ]i elevation inhibited acid-induced calcium-sensitive proteases such as calpain and calcineurin, and also inhibited the activation of Bid, Bad, and Caspase 3 and cleavage of poly (ADP-ribose) polymerase (PARP). OGR1-mediated [Ca(2+) ]i elevation has a crucial role in apoptosis of endplate chondrocytes by regulating activation of calcium-sensitive proteases and their downstream signaling.

A comparison between "sandwich" and conventional methods of repairing spinal dura rupture.

OBJECTIVE: To study the therapeutic efficacy of the "sandwich" method (medical glue + gelatin sponge + medical glue) of spinal dural repair for preventing cerebrospinal fluid (CSF) leaks during treatment of subdural tumors. METHODS: Fifty-four patients with spinal subdural tumors treated between April 2007 and June 2011 were retrospectively investigated. The patients were divided into two groups: a conventional group (group A) and a "sandwich" group (group B). The group A patients included 16 males and 7 females with an average tumor course of 11 months (range, 2-34 months). Four of their 23 tumors were in the cervical spine, eight thoracic, and eleven lumbar. The group B patients included 19 males and 12 females with an average tumor course of 12 months (range, 3-36 months). Five of their 31 tumors were in the cervical spines, 10 thoracic, and 16 lumbar. In group A, the dural repairs were performed with interlocking sutures and a gelatin sponge covering the dura; whereas in group B, they were performed with interlocking sutures, painting of medical glue around the dural incision, covering this with a gelatin sponge, and finally covering of the gelatin sponge with medical glue. The total volume of drainage after operation, incidence of CSF leaks, healing of the incision, and recovery of clinical performance were recorded. RESULTS: Compared to group A patients, group B patients had a significantly smaller total volume of drainage (P < 0.05) on the day of surgery, and the first, second, and third postoperative days. The incidence of CSF leakage in group B was also significantly less than in group A (P < 0.05). Before discharge, three patients in group A developd hydrops, which was successfully treated by aspiration, continuous pressure from sandbags, and the prone position. During the first 3 months of follow-up, five patients developed deep hydrops under their incisions but required no treatment. There were no obvious abnormalities in group B. CONCLUSION: After removal of subdural spinal tumors by incising the dura mater, or in related spinal surgery, application of the "sandwich" complex to the damaged spinal dura reduces the volume of drainage postoperatively and reduces the incidence of CSF leakage.