Percutaneous endoscopic interlaminar discectomy for high-grade migrated lumbar disc herniation: clinical efficacy and safety assessment.

PURPOSE: This study aimed to assess the clinical effectiveness and safety of percutaneous endoscopic interlaminar discectomy (PEID) in the management of high-grade migrated Lumbar disc herniation (LDH). METHODS: A total of 328 patients who underwent PEID for high-grade migrated LDH between May 2020 and January 2023 in our hospital were selected. Patients were categorized into high-grade migrated group and low-grade migrated group according to preoperative MRI findings. The preoperative and postoperative evaluations of clinical outcomes, such as Visual Analogue Scale (VAS) for lower backs and legs, Oswestry Disability Index (ODI), and modified MacNab criteria for surgical success, were compared between groups. RESULTS: No statistically significant differences were found in hospitalization time, surgery time, intraoperative hemorrhage, number of intraoperative fluoroscopies, or incision length between the two groups. The lower back and leg VAS scores and ODI exhibited a statistically significant decrease in both groups across all postoperative time intervals. However, the difference between the two groups was not statistically significant. Postoperative nerve root stimulation symptoms were reported in two and three cases in the high-grade migrated group and low-grade migrated group, respectively. One patient in the high-grade migrated group underwent reoperation due to re-herniation at the same segment. There was no significant difference in the rate of excellent-good cases between the two groups, with an overall rate of 94.7%. CONCLUSION: In treating high-grade migrated disc herniation, PEID offers advantages such as reduced trauma, small incision, quicker recovery and satisfactory clinical safety and efficacy.

The efficacy and safety of mini-open (air/water medium) endoscopy-assisted anterior cervical discectomy and fusion for the treatment of cervical spondylotic myelopathy.

PURPOSE: To compare the clinical efficacy of mini-open (air/water medium) endoscopy-assisted anterior cervical discectomy and fusion (MOEA-ACDF) and anterior cervical decompression and fusion (ACDF) for cervical spondylotic myelopathy (CSM). METHODS: This study retrospectively analysed the clinical data of CSM patients who received surgical treatment from January 1, 2020, to December 31, 2022. Patients were divided into two groups according to the surgical method: the MOEA-ACDF group and the ACDF group. The preoperative and postoperative imaging results at one week and the last follow-up examination were compared between the two groups. The Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS) score and neck disability index (NDI) score were used to evaluate the clinical outcomes preoperatively, one week postoperatively and at the last follow-up examination. The minimum follow-up duration was 12 months. RESULTS: A total of 131 CSM patients who underwent surgery at our institution were included, including 61 patients in the MOEA-ACDF group and 70 patients in the ACDF group. In the MOEA-ACDF group, the postoperative C2-C7 Cobb angle and HAVB were significantly greater than the preoperative values (P < 0.05). In the ACDF group, the postoperative C2-C7 Cobb angle was also significantly greater than the preoperative value, and the C2-C7 ROM and HAVB significantly decreased (P < 0.05). The postoperative neurological function of the patients in both groups improved, and the postoperative VAS score and NDI score significantly decreased. Compared with ACDF, MOEA-ACDF is associated with a significantly larger postoperative C2-C7 Cobb angle and significantly better C2-C7 ROM and HAVB, as well as better clinical efficacy (P < 0.05). CONCLUSIONS: MOEA-ACDF combines endoscopic systems with ACDF technology to treat CSM, but its clinical efficacy is not inferior to that of ACDF in the short- to intermediate-term. It can effectively and safely restore the cervical intervertebral height, physiological curvature, and range of motion.

Combined Molybdenum Gelatine Methacrylate Injectable Nano-Hydrogel Effective Against Diabetic Bone Regeneration.

Introduction: Bone defects in diabetes mellitus (DM) remain a major challenge for clinical treatment. Fluctuating glucose levels in DM patients lead to excessive production of reactive oxygen species (ROS), which disrupt bone repair homeostasis. Bone filler materials have been widely used in the clinical treatment of DM-related bone defects, but overall they lack efficacy in improving the bone microenvironment and inducing osteogenesis. We utilized a gelatine methacrylate (GelMA) hydrogel with excellent biological properties in combination with molybdenum (Mo)-based polyoxometalate nanoclusters (POM) to scavenge ROS and promote osteoblast proliferation and osteogenic differentiation through the slow-release effect of POM, providing a feasible strategy for the application of biologically useful bone fillers in bone regeneration. Methods: We synthesized an injectable hydrogel by gelatine methacrylate (GelMA) and POM. The antioxidant capacity and biological properties of the synthesized GelMA/POM hydrogel were tested. Results: In vitro, studies showed that hydrogels can inhibit excessive reactive oxygen species (ROS) and reduce oxidative stress in cells through the beneficial effects of pH-sensitive POM. Osteogenic differentiation assays showed that GelMA/POM had good osteogenic properties with upregulated expression of osteogenic genes (BMP2, RUNX2, Osterix, ALP). Furthermore, RNA-sequencing revealed that activation of the PI3K/Akt signalling pathway in MC3T3-E1 cells with GelMA/POM may be a potential mechanism to promote osteogenesis. In an in vivo study, radiological and histological analyses showed enhanced bone regeneration in diabetic mice, after the application of GelMA/POM. Conclusion: In summary, GelMA/POM hydrogels can enhance bone regeneration by directly scavenging ROS and activating the PI3K/Akt signalling pathway.

[Targeted muscle reinnervation: a surgical technique of human-machine interface for intelligent prosthesis].

Objective: To review targeted muscle reinnervation (TMR) surgery for the construction of intelligent prosthetic human-machine interface, thus providing a new clinical intervention paradigm for the functional reconstruction of residual limbs in amputees. Methods: Extensively consulted relevant literature domestically and abroad and systematically expounded the surgical requirements of intelligent prosthetics, TMR operation plan, target population, prognosis, as well as the development and future of TMR. Results: TMR facilitates intuitive control of intelligent prostheses in amputees by reconstructing the "brain-spinal cord-peripheral nerve-skeletal muscle" neurotransmission pathway and increasing the surface electromyographic signals required for pattern recognition. TMR surgery for different purposes is suitable for different target populations. Conclusion: TMR surgery has been certified abroad as a transformative technology for improving prosthetic manipulation, and is expected to become a new clinical paradigm for 2 million amputees in China.

Cefazolin/BMP-2-Loaded Mesoporous Silica Nanoparticles for the Repair of Open Fractures with Bone Defects.

The study aimed to explore the feasibility of a nanodrug delivery system to treat open fractures with bone defects. We developed a cefazolin (Cef)/bone morphogenetic protein 2 (BMP-2)@mesoporous silica nanoparticle (MSN) delivery system; meanwhile, Cef/MBP-2@ poly(lactic-co-glycolic acid) (PLGA) was also developed as control. For the purpose of determining the osteogenic and anti-inflammatory actions of the nanodelivery system, we cultured bone marrow mesenchymal stem cells (BMSCs) and constructed a bone defect mouse model to evaluate its clinical efficacy. After physicochemical property testing, we determined that MSN had good stability and did not easily accumulate or precipitate and it could effectively prolong the Cef's half-life by nearly eight times. In BMSCs, we found that compared with the PLGA delivery system, MSNs better penetrated into the bone tissue, thus effectively increasing BMSCs' proliferation and migration ability to facilitate bone defect repair. Furthermore, the MSN delivery system could improve BMSCs' mineralization indexes (alkaline phosphatase [ALP], osteocalcin [OCN], and collagen I [Col I]) to effectively improve its osteogenic ability. Moreover, the MSN delivery system could inhibit inflammation in bone defect mice, which was mainly reflected in its ability to reduce the release of IL-1ß and IL-4 and increase IL-10 levels; it could also effectively reduce apoptosis of CD4+ and CD8+ T cells, thus improving their immune function. Furthermore, the percentage of new bones, bone mineral density, trabecular volume, and trabecular numbers in the fracture region were improved in mice treated with MSN, which allowed better repair of bone defects. Hence, Cef/BMP-2@MSN may be feasible for open fractures with bone defects.

3D printing of reduced glutathione grafted gelatine methacrylate hydrogel scaffold promotes diabetic bone regeneration by activating PI3K/Akt signaling pathway.

Diabetic individuals are frequently associated with increased fracture risk and poor bone healing capacity, and the treatment of diabetic bone defects remains a great challenge in orthopedics. In this study, an antioxidant hydrogel was developed using reduced glutathione grafted gelatine methacrylate (GelMA-g-GSH), followed by 3D printing to form a tissue engineering scaffold, which possessed appropriate mechanical property and good biocompatibility. In vitro studies displayed that benefitting from the sustained delivery of reduced glutathione, GelMA-g-GSH scaffold enabled to suppress the overproduction of reactive oxygen species (ROS) and reduce the oxidative stress of cells. Osteogenic experiments showed that GelMA-g-GSH scaffold exhibited excellent osteogenesis performance, with the elevated expression levels of osteogenesis-related genes and proteins. Further, RNA-sequencing revealed that activation of PI3K/Akt signaling pathway of MC3T3-E1 seeded on GelMA-g-GSH scaffold may be the underlying mechanism in promoting osteogenesis. In vivo, diabetic mice calvarial defects experiment demonstrated enhanced bone regeneration after the implantation of GelMA-g-GSH scaffold, as shown by micro-CT and histological analysis. In summary, 3D-printed GelMA-g-GSH scaffold can not only scavenge ROS, but also promote proliferation and differentiation of osteoblasts by activating PI3K/Akt signaling pathway, thereby accelerating bone repair under diabetes.

[Targeted one channel percutaneous transforaminal endoscopic discectomy for the treatment of adjacent segment degeneration after spinal fusion surgery in young patients].

OBJECTIVE: To compare clinical efficacy between targeted one-channel percutaneous transforaminal endoscopic discectomy (TO-PTED) and transforaminal lumbar interbody fusion (TLIF) in treatment of adjacent segment degeneration (ASD) after spinal fusion surgery in young patients. METHODS: The clinical data of 64 patients with adjacent segment degeneration after spinal fusion fusion surgery from September 2017 to February 2019 were retrospectively analyzed. Among them, 30 patients were treated with TO-PTED (TO-PTED group), there were 19 males and 11 females, aged from 23 to 34 years, with a mean of(31.20±1.67) years;the course of disease was from 10 to 39 months, with a mean of (26.30±0.41) months. And other 34 patients were treated with TILF(TILF group), there were 21 males and 13 females, aged from 22 to 34 years, with a mean of (31.10±1.74) years;the course of disease was from 11 to 40 months, with a mean of (27.10±0.32) months. The operation time, intraoperative blood loss, hospitalization time, X-ray fluoroscopy times were compared between two groups. Visual analogue scale(VAS) and Japanese Orthopaedic Association(JOA) scores were used to evaluate the clinical efficacy between two groups before operation, 1 month after operation and at the final follow-up. RESULTS: Operation time, intraoperative blood loss, hospitalization time, X-ray fluoroscopy times were (76.30±5.08) min, (38.80±4.21) ml, (3.90±1.13) d, (8.80±2.53) times in TO-PTED group, and (118.50±11.06) min, (162.71±19.31)ml, (7.30±1.42)d, (4.10±0.82) times in TLIF group, respectively, the difference between the two groups was statistically significant. All patients were followed up from 12 to 24 months, with a mean of (18.00±5.63) months. VAS and JOA scores at 1 month after surgery and at final follow-up were obviously improved, and TO-PTED group was superior than TLIF group. CONCLUSION: Both TO-PTED and TLIF can achieve good results in the treatment of adjacent segment degeneration after spinal fusion surgery in young patients. TO-PTED has advantages in reducing operation time, intraoperative blood loss and postoperative recovery time, but it will increase the number of patients receiving intraoperative radiation.

Clinical outcomes of posterior pedicle screw instrumentation without osteotomy in the management of adolescent idiopathic scoliosis.

The aim of the study was to identify the effectiveness of posterior pedicle screw instrumentation without osteotomy in the management of adolescent idiopathic scoliosis (AIS).The AIS patients underwent standing anteroposterior and lateral radiography before and after surgery. Age, sex, Lenke type, preoperative and postoperative Cobb angle, and all the related complications were recorded at final follow-up.We investigated data from 137 AIS patients who underwent posterior pedicle screw instrumentation without osteotomy from January 2012 to January 2016 with >2 years follow-up. Mean age was 14.3 ±â€Š1.5 years at operation. The preoperative and latest postoperative coronal Cobb angle was 60 ±â€Š12° and 9 ±â€Š5°, respectively. Additionally, complications were noted in 6 patients. However, the prognosis of all the AIS patients was good, and the satisfaction of the Scoliosis Research Society Outcomes Instrument (SRS-22) questionnaire was 4.4 ±â€Š0.5 at final follow-up.In the management of mild and moderate AIS, satisfactory clinical results can be obtained using posterior pedicle screw instrumentation without osteotomy.

Naringenin inhibits osteoclastogenesis through modulation of helper T cells-secreted IL-4.

Naringenin (NAR) is a natural predominant flavanone and has a wide range of pharmacological activities. The aim of this study was to investigate the protective mechanisms of NAR on RANKL-induced osteoclastogenesis and osteoclast bone resorption. T cells were divided into four groups under different concentrations of NAR (0, 25, 50, 100 µM). CD4+ T cell subsets in different groups were evaluated by flow cytometry. TRAP staining, pit formation assays and F-actin ring immunofluorescent staining were performed. In addition, gene expression of osteoclast-specific markers was analyzed by qPCR and Western blot. Our results showed that compared with the control group, there were relatively fewer Th1 and Th17 cells and more Th2 cells and Treg cells in the NAR groups. Besides, the number of TRAP-positive multinucleated osteoclasts, the areas of bone resorption pits and the size and number of F-actin rings were notably decreased in the bone marrow macrophages (BMMs) treated with T-cell supernatant containing NAR. Moreover, NAR treatment dramatically reduced the expressions of cathepsin K, c-Fos, DC-STAMP, NFATc1, TRAP, and V-ATPase d2 at mRNA and protein levels. However, these effects were abolished by adding a neutralizing antibody against IL-4. In conclusion, NAR suppressed RANKL-induced osteoclastogenesis and osteoclast bone resorption by promoting the release of IL-4 from T cells.

Comparison of low density and high density pedicle screw instrumentation in Lenke 1 adolescent idiopathic scoliosis.

BACKGROUND: The correlation between implant density and deformity correction has not yet led to a precise conclusion in adolescent idiopathic scoliosis (AIS). The aim of this study was to evaluate the effects of low density (LD) and high density (HD) pedicle screw instrumentation in terms of the clinical, radiological and Scoliosis Research Society (SRS)-22 outcomes in Lenke 1 AIS. METHODS: We retrospectively reviewed 62 consecutive Lenke 1 AIS patients who underwent posterior spinal arthrodesis using all-pedicle screw instrumentation with a minimum follow-up of 24 months. The implant density was defined as the number of screws per spinal level fused. Patients were then divided into two groups according to the average implant density for the entire study. The LD group (n = 28) had fewer than 1.61 screws per level, while the HD group (n = 34) had more than 1.61 screws per level. The radiographs were analysed preoperatively, postoperatively and at final follow-up. The perioperative and SRS-22 outcomes were also assessed. Independent sample t tests were used between the two groups. RESULTS: Comparisons between the two groups showed no significant differences in the correction of the main thoracic curve and thoracic kyphosis, blood transfusion, hospital stay, and SRS-22 scores. Compared with the HD group, there was a decreased operating time (278.4 vs. 331.0 min, p = 0.004) and decreased blood loss (823.6 vs. 1010.9 ml, p = 0.048), pedicle screws needed (15.1 vs. 19.6, p < 0.001), and implant costs ($10,191.0 vs. $13,577.3, p = 0.003) in the LD group. CONCLUSIONS: Both low density and high density pedicle screw instrumentation achieved satisfactory deformity correction in Lenke 1 AIS patients. However, the operating time and blood loss were reduced, and the implant costs were decreased with the use of low screw density constructs.

Pedicle screw versus hybrid instrumentation in adolescent idiopathic scoliosis: A systematic review and meta-analysis with emphasis on complications and reoperations.

BACKGROUND: Incidence of complications and reoperations between pedicle screw (PS) and hybrid instrumentations (HI) are still controversial in adolescent idiopathic scoliosis (AIS) patients. A systematic review and meta-analysis were performed to compare overall complications, reoperations, and radiographic outcomes between the 2 constructs. METHODS: Strictly followed the PRISMA 2009 guidelines, the MEDLINE, EMBASE, and the Cochrane Library databases were used to search for literatures up to April 2016, addressing PS versus HI in AIS patients. The Newcastle-Ottawa scale was adopted to assess the quality of the studies. Data on complications, reoperations, Cobb angle of major curve, thoracic kyphosis, and proximal junctional measurement were extracted from the included studies. RevMan 5.3 and SPSS 21.0 were used for statistical analysis. RESULTS: Twenty-four case-control studies with a total of 3042 AIS patients (1582 PS, 1460 HI) were included, consisting of 1 randomized controlled trial, 1 prospective study, and 22 retrospective studies. Decreased overall complications (95% CI 0.42-0.87, P = .007; I = 38%) and reoperations (95% CI 0.22-0.62, P = .0001; I = 0%) were found in PS group compared with HI group. As regard to reasons for reoperations, increased incidence of pseudarthrosis (P = .005), dislodged instrumentation (P = .005), and deep infection (P = .016) occurred in HI group. PS group achieved a better coronal correction (95% CI -7.06 to -4.54, P < .00001; I = 34%), but HI group was more powerful in restoring thoracic kyphosis (95% CI -7.88 to -3.70, P < .00001; I = 60%), and no significant differences were found in proximal junctional measurement (95% CI -0.88 to 1.54, P = .59; I = 0%) between the 2 constructs. CONCLUSION: Compared with hybrid instrumentation, pedicle screw construct provides better coronal correction but less thoracic kyphosis restoring, with decreased incidence of overall complications and reoperations in AIS patients. As regard to the pedicle screw construct, the most common reasons for reoperation are malposition, deep infection, pseudarthrosis, and prominent implant.

A Computed Tomography-Based Comparison of Abnormal Vertebrae Pedicles Between Dystrophic and Nondystrophic Scoliosis in Neurofibromatosis Type 1.

OBJECTIVE: To explore the prevalence and distribution of abnormal vertebral pedicles in scoliosis secondary to neurofibromatosis type 1 (NF1-S) and to compare the abnormal vertebrae pedicles between dystrophic and nondystrophic scoliosis. METHODS: Using computed tomography images, we carefully measured 2652 vertebral pedicles from 56 patients with NF1-S with dystrophic scoliosis and 22 patients with NF1-S with nondystrophic scoliosis. Pedicle morphology was classified as follows: type A, a cancellous channel of >4 mm; type B, a cancellous channel of 2 to 4 mm; type C, a cancellous channel of <2 mm with an entirely cortical channel of ≥2 mm; type D, a cortical channel of <2 mm; or type E, absent pedicle. Types B, C, D, and E were defined as abnormal. RESULTS: The total prevalence of abnormal vertebral pedicles in patients with NF1-S was as high as 67%, with type B comprising 39%, type C comprising 22%, type D comprising 4%, and type E comprising 2%. A significantly greater rate of abnormal pedicles was found in dystrophic scoliosis compared with nondystrophic scoliosis (70% vs. 59%, P < 0.0001). The upper thoracic spine (87%) is the most concentrated region of abnormal pedicles compared with the lower thoracic (73%) and lumbar spine (34%). CONCLUSIONS: There is a significantly high prevalence of abnormal pedicles in patients with NF1-S and an increased rate of abnormal pedicles in dystrophic scoliosis compared with nondystrophic ones. The described pedicle classification system could serve as an objective tool to guide preoperative assessment.

Upper Thoracic versus Lower Thoracic as Site of Upper Instrumented Vertebrae for Long Fusion Surgery in Adult Spinal Deformity: A Meta-Analysis of Proximal Junctional Kyphosis.

OBJECTIVE: A meta-analysis was performed to compare incidence rates of radiographic and surgical proximal junctional kyphosis (PJK) between upper thoracic (UT) and lower thoracic (LT) vertebrae as site of upper instrumented vertebrae (UIV) endpoints for long fusion surgery in adult spinal deformity (ASD). METHODS: MEDLINE, Embase, and Cochrane Library databases were searched for English-language articles that addressed UT versus LT fixation strategies. The division of the UT and LT groups was based on UIV. Two reviewers independently assessed the quality of the studies using the Newcastle-Ottawa Scale. Data on incidence rates of radiographic and surgical PJK were extracted from the included studies. RevMan 5.3 was used for data pooling and analysis. RESULTS: Ten retrospective studies comprising 1230 patients were included. Pooled data on radiographic PJK were available in 9 studies comprising 1032 patients, and total radiographic PJK rate was 32.2%. Pooled data on surgical PJK were available in 6 studies comprising 732 patients, and total surgical PJK rate was 6.7%. Decreased radiographic PJK (95% confidence interval, 0.49-0.85; P = 0.002; I2 = 48%) and surgical PJK (95% confidence interval, 0.18-0.76; P = 0.007; I2 = 22%) were found in the UT group. CONCLUSIONS: Radiographic PJK is a very common complication of long fusion surgery in adult spinal deformity with an incidence rate of 32.2%. Surgical PJK has an incidence rate of 6.7% and should be seriously considered. The pooled results indicate that choosing UT vertebrae as the site of UIV could decrease the incidence rates of radiographic and surgical PJK.

Comparison of Consecutive, Interval, and Skipped Pedicle Screw Techniques in Moderate Lenke Type 1 Adolescent Idiopathic Scoliosis.

OBJECTIVE: To compare perioperative, radiographic, and Scoliosis Research Society-22 (SRS-22) outcomes of consecutive, interval, and skipped pedicle screw techniques in patients with moderate Lenke type 1 adolescent idiopathic scoliosis (AIS). METHODS: We retrospectively reviewed 65 consecutive moderate Lenke type 1 AIS patients at a single institution using all-pedicle screw constructs, with a minimum of 2 years of follow-up. In the consecutive group (C group, n = 22), pedicle screws were instrumented at consecutive levels bilaterally. In the interval group (I group, n = 18), pedicle screws were placed at every level on the concave side while skipping levels on the convex side. In the skipped group (S group, n = 25), pedicle screws were instrumented by skipping levels bilaterally. Perioperative, radiographic, and SRS-22 measurements were analyzed with a 1-way analysis of variance. RESULTS: No significant differences were found in length of hospital stay, fused levels, coronal correction, and SRS-22 scores among the 3 groups. Increased surgery time was found in the C group compared with the I and S groups (P = 0.001 and P = 0.005, respectively). Decreased blood loss and blood transfusions were found in the S group compared with the C group (P = 0.04 and P = 0.047, respectively). Decreased implant costs were found in the S group compared with the C and I groups (P < 0.001 and P = 0.03, respectively). CONCLUSIONS: Consecutive, interval, and skipped pedicle screw techniques all provide satisfactory deformity correction and SRS-22 outcomes with few complications. With better perioperative outcomes, interval and skipped pedicle screw techniques are the more cost-effective options for patients with moderate Lenke type 1 AIS.

Anterior versus posterior approach in Lenke 5C adolescent idiopathic scoliosis: a meta-analysis of fusion segments and radiological outcomes.

BACKGROUND: Radiological outcomes between anterior and posterior approach in Lenke 5C curves were still controversial. Meta-analysis on published articles to compare fusion segments and radiological outcomes between the two surgical approaches was performed. METHODS: Electronic database was conducted for searching studies concerning the anterior versus posterior approach in Lenke 5C curves. After quality assessment, data of means, standard deviations, and sample sizes were extracted. RevMan 5.3 was adopted for data analysis. RESULTS: Seven case-control studies involving 308 Lenke 5C AIS patients were identified in the meta-analysis. No significant differences were noted in correction rate of thoracolumbar/lumbar curve (95 % CI -6.02 to 4.32, P = 0.75) and incidence of proximal junctional kyphosis (95 % CI 0.12 to 7.19, P = 0.94) of final follow-up, in change values of thoracolumbar/lumbar curve (95 % CI -3.28 to 7.19, P = 0.46) and thoracic kyphosis (95 % CI -4.10 to 0.13, P = 0.07). The anterior approach represented a significant shorter fusion segments compared to posterior approach (95 % CI -1.72 to -0.71, P < 0.00001). The posterior approach obtained a larger increasing Cobb angle of lumbar lordosis than the anterior approach (95 % CI -6.06 to -0.61, P = 0.02). CONCLUSIONS: The anterior and posterior approach can obtain comparable coronal correction, change values of thoracic kyphosis, and incidence of proximal junctional kyphosis. The anterior approach saves approximate one more fusion segment, and the posterior approach can obtain a larger increasing Cobb angle of lumbar lordosis, from preoperation to final follow-up. TRIAL REGISTRATION: The article type of this study is meta-analysis and prospective registration is not required.