Comprehensive Spinal Tuberculosis Score: A Clinical Guide for the Management of Thoracolumbar Spinal Tuberculosis.

STUDY DESIGN: A newly proposed scoring tool was designed to assist in the clinical management of adult thoracolumbar spinal tuberculosis (TB). PURPOSE: To formulate a comprehensive yet simple scoring tool to guide decision-making in the management of adult thoracolumbar spinal TB. OVERVIEW OF LITERATURE: Spine surgeons have differing consensus in defining the threshold grade for clinico-radiological parameters when deciding between operative or conservative treatment for adult thoracolumbar spinal TB. Currently, the void in decision-making from the lack of well-defined guidelines is compensated by the surgeon's experience in treating these patients. To the best of our knowledge, no scoring system holistically integrates multiple facets of spinal TB to guide clinical decision-making. METHODS: The RAND/University of California, Los Angeles appropriateness method was employed among an expert panel of 10 spine surgeons from four apex tertiary care centers. Vital characteristics that independently influenced treatment decisions in spinal TB were identified, and a scoring tool was formulated. Points were assigned for each component based on their severity. The cutoff scores to guide clinical management were determined from the receiver operating characteristic curve based on the retrospective records of 151 patients treated operatively or non-operatively with improved functional outcomes at the 1-year follow-up. RESULTS: The components of the comprehensive spinal TB score (CSTS) are pain, kyphosis angle, vertebral destruction, and neurological status. A score classification of <5.5, 5.5-6.5, and >6.5 was established to guide the patient toward conservative, conservative/ operative, and operative management, respectively. CONCLUSIONS: The CSTS was designed to reflect the essential indicators of mechanical stability, neurological stability, and disease process stabilization in spinal TB. The scoring tool is devised to be practical and serve as a common language in the spine community to facilitate discussions and decision-making in thoracolumbar spinal TB. The validity, reliability, and reproducibility of this tool must be assessed through multicenter long-term studies.

Discovery and Characterization of Selective, First-in-Class Inhibitors of Citron Kinase.

Citron kinase (CITK) is an AGC-family serine/threonine kinase that regulates cytokinesis. Despite knockdown experiments implicating CITK as an anticancer target, no selective CITK inhibitors exist. We transformed a previously reported kinase inhibitor with weak off-target CITK activity into a first-in-class CITK chemical probe, C3TD879. C3TD879 is a Type I kinase inhibitor which potently inhibits CITK catalytic activity (biochemical IC50 = 12 nM), binds directly to full-length human CITK in cells (NanoBRET Kd < 10 nM), and demonstrates favorable DMPK properties for in vivo evaluation. We engineered exquisite selectivity for CITK (>17-fold versus 373 other human kinases), making C3TD879 the first chemical probe suitable for interrogating the complex biology of CITK. Our small-molecule CITK inhibitors could not phenocopy the effects of CITK knockdown in cell proliferation, cell cycle progression, or cytokinesis assays, providing preliminary evidence that the structural roles of CITK may be more important than its kinase activity.

Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro).

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

Cervical corpectomy in delayed presentation of irreducible cervical dislocation: experience with eight cases.

OBJECTIVE: To describe a single-staged procedure for the management of neglected subaxial cervical spine injuries. METHODS: Between January 2012 and December 2014, 12 patients presented to us with healed cervical sub axial dislocations. The deformities could not be reduced using skull traction. Eight were operated with anterior cervical corpectomy. American spinal injury Association (ASIA) grade, Neck Disability index (NDI), and Visual analog scale (VAS) score were recorded throughout the patient course and CT was done at 12 months for assessment of fusion. RESULTS: Four patients improved from ASIA C to ASIA D, two patients improved from ASIA B to ASIA E, one patient improved from ASIA D to ASIA E and one patient remained static at ASIA B. All patients except one showed evidence of fusion on CT scan at 12 months. NDI improved from preoperative range (18-32, mean 25) to postoperative range (8-16 mean, 11.25), VAS from preoperative range (3-6, mean 4.25) to postoperative range (1-3, mean 1.75). CONCLUSIONS: Single-stage in situ fixation does not disrupt ongoing natural healing and has good clinical and radiological outcomes.

Asymptomatic Construct Failure after Metastatic Spine Tumor Surgery: A New Entity or a Continuum with Symptomatic Failure?

STUDY DESIGN: Retrospective cohort study. PURPOSE: To study the incidence, onset, underlying mechanism, clinical course, and factors leading to asymptomatic construct failure (AsCF) after metastatic spinal tumor surgery (MSTS). OVERVIEW OF LITERATURE: The reported incidence rates for implant and/or construct failure after MSTS are low (1.9%-16%) and based on clinical presentations and revisions required for symptomatic failures (SFs). AsCF after MSTS has not been reported. METHODS: We conducted a retrospective analysis of 288 patients (246 for final analysis) who underwent MSTS between 2005-2015. Data collected were demographics and peri/postoperative clinical and radiological features. Early and late radiological AsCF were defined as presentation before and after 3 months, respectively. We analyzed patients with AsCF for risk factors and survival duration by performing competing risk regression analyses where AsCF was the event of interest, with SF and death as competing events. RESULTS: We observed AsCF in 41/246 patients (16.7%). The mean time to onset of AsCF after MSTS was 2 months (range, 1-9 months). Median survival of patients with AsCF was 20 and 41 months for early and late failures, respectively. Early AsCF accounted for 80.5% of cases, while late AsCF accounted for 19.5%. The commonest radiologically detectable AsCF mechanism was angular deformity (increase in kyphus) in 29 patients. Increasing age (p<0.02) and primary breast (13/41, 31.7%) (p<0.01) tumors were associated with higher AsCF rates. There was a non-significant trend towards AsCF in patients with a spinal instability neoplastic score ≥7, instrumentation across junctional regions, and construct lengths of 6-9 levels. None of the patients with AsCF underwent revision surgery. CONCLUSIONS: AsCF after MSTS is a distinct entity. Most patients with early AsCF did not require intervention. Patients who survived and maintained ambulation for longer periods had late failure. Increasing age and tumors with a better prognosis have a higher likelihood of developing AsCF. AsCF is not necessarily an indication for aggressive/urgent intervention.

Pathological Fracture of the Tibia in a Monostotic Anterior Cortical Fibrous Dysplasia: Hybrid Fixation with UnicorticalOsteoperiosteal Non-Vascularized Fibula Graft - A Case Report.

INTRODUCTION: Fibrous Dysplasia is a relatively rare Musculoskeletal disorders in which there is a defect in remodelling of immature bone to mature lamellar bone. Fibrous Dysplasia was first described by Von Recklinghausen in 1891, but it was Lichtenstein who labelled it polyostotic Fibrous Dysplasia in 1938. Union of Pathological Fractures in a bone affected by Fibrous Dysplasia poses a difficult set of Challenges for treating Physicians. CASE REPORT: We Report a 24 year-old female patient with a Pathological Fracture of the Tibia in a Monostotic Anterior Cortical Fibrous Dysplasia Hybrid Fixation with a UnicorticalOsteoperisoteal Non Vascularized Fibula Graft with a follow up until the union of fracture site on computed tomography scan and complete integration of unicorticalosteoperiosteal fibular graft . CONCLUSION: We provide additional and independent evidence that removal of the diseased cortex which were parts of the proximal and distal fragment and reconstruction of the defect in the cortex with a press- fitunicortical Non vascularized osteoperiosteal fibular strut graft with a hybrid fixation is a good treatment modality for monostotic fibrous dysplasia. Hybrid fixation includes retrograde intramedullary transarticular rodding extending across the subtalar and ankle joint into the tibia and augmentation of the primary fixation with a mono-planar rail Fixation in compression mode.

Extend of Skipped Multifocal Noncontiguous Spinal Tuberculosis Beyond Imagination: A Rare Case Report and Literature Review.

Skipped multifocal extensive spinal tuberculosis involving the whole spine is very rare, which presents with atypical presentations and imaging features. So far, only five cases have been reported. Most of these patients have only two noncontiguous lesions. We are reporting a case of an 18-year-old boy with noncontiguous multifocal spinal tuberculosis involving cervical, thoracic, thoracolumbar, and lumbar segments. The patient was treated with antituberculous drug therapy and was operated for thoracolumbar spinal lesion. He made an excellent recovery. The possibility of tuberculosis is considered for any skip lesions involving the spine cautiously. Careful physical examination, trials of antitubercular therapy, and using the whole spine magnetic resonance imaging routinely also play an important role in the diagnosis and treatment of this disease. In patients with noncontiguous spinal involvement, there is a high percentage of requirement of surgical treatment due to fulminant behavior of the disease in these patients.

Cervical Myelopathy and Lumbar Spondylolisthesis in Elderly Patients with Diffuse Idiopathic Skeletal Hyperostosis (DISH) - A Case Series.

INTRODUCTION: Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory disease, which causes the ossification of spinal longitudinal ligaments and enthesis leads to stiffness in the affected segment of the spine and neurological deficit due to compression of spinal cord or nerve roots by osteophytes. CASE PRESENTATION: We present three cases of DISH, presented with cervical myelopathy, lumbar spondylolisthesis, and dysphagia. All three patients had neurodeficit and radiological examination showed cord compression, canal stenosis, listhesis, and contiguous ossification in the spine with normal sacroiliac joints. The first patient had cervical myelopathy because of compression of cord by ossified posterior longitudinal ligament, which was managed with posterior laminectomy, decompression, and stabilization. The second patient had L4-L5 listhesis with canal stenosis, which was managed with decompression, instrumentation and fusion (TLIF). The third patient had cervical myelopathy due to C6-C7 listhesis and also had dysphagia because of compression of esophagus by anterior osteophytes, which was managed with removal of anterior osteophytes and anterior discectomy and fusion (ACDF). Postoperatively, all three patients recovered completely with no residual neurodeficit. CONCLUSION: DISH can present in various ways, which depends on the site of involvement in the spine. Early surgical intervention helps in getting a better outcome in patients with neurodeficit and prevents further complications.

Annulo-Nucleoplasty Using Disc-Fx in the Management of Degenerative Lumbar Disc Pathology: How Long Can the Effect Last?

STUDY DESIGN: Prospective analysis. OBJECTIVES: To evaluate 2-year clinical outcomes in patients undergoing Disc-FX for the management of low back pain (LBP) due to degenerate disc (DD) or contained lumbar disc herniation (CLDH). To study salient factors that can potentially influence the clinical outcomes. METHODS: We analyzed the prospectively collected data of 51 patients who underwent Disc-FX procedure for DD or CLDH, nonresponsive to 6 months of nonoperative treatment. Clinical outcome measures collected were visual analogue scale (VAS), Oswestry Disability Index (ODI), and MacNab scores. These preoperative values were compared with respective values at immediate, 6 months, 1 year, and 2 years postoperation. Minimum clinically important difference values for these outcomes in accordance with previously published data was used to evaluate the effectiveness of Disc-FX intervention. RESULTS: Of 51 patients, 84% had DD and 16% had CLDH. Significant improvement (P < .01) in VAS and ODI scores was observed at all assessment periods compared to the respective preoperative values. Based on the MacNab scores, there was significant increase (P < .01) in the proportion of patients with excellent/good MacNab outcomes at each time point after the procedure; 78% achieving excellent/good outcomes at 2-year follow-up. Ease of access to the disc space was significantly influencing VAS, ODI, and MacNab scores at 1-year and 2-year follow-ups. VAS and MacNab scores were negatively influenced by high body mass index and smoking status at 6 and 12 months postoperation. CONCLUSIONS: Our data suggests that Disc-FX may be helpful in selected patients with symptomatic degenerative disc disease providing favorable outcomes lasting up to 2 years or more. The results were more favorable in patients with easier access to disc space.

Basic concepts in metal work failure after metastatic spine tumour surgery.

PURPOSE: The development of spinal implants marks a watershed in the evolution of metastatic spine tumour surgery (MSTS), which has evolved from standalone decompressive laminectomy to instrumented stabilization and decompression with reconstruction when necessary. Fusion may not be feasible after MSTS due to poor quality of graft host bed along with adjunct chemotherapy and/or radiotherapy postoperatively. With an increase in the survival of patients with spinal tumours, there is a probability of an increase in the rate of implant failure. This review aims to help establish a clear understanding of implants/constructs used in MSTS and to highlight the fundamental biomechanics of implant/construct failures. METHODS: Published literature on implant failure after spine surgery and MSTS has been reviewed. The evolution of spinal implants and their role in MSTS has been briefly described. The review defines implant/construct failures using radiological parameters that are practical, feasible, and derived from historical descriptions. We have discussed common modes of implant/construct failure after MSTS to allow further understanding, interception, and prevention of catastrophic failure. RESULTS: Implant failure rates in MSTS are in the range of 2-8%. Variability in patterns of failure has been observed based on anatomical region and the type of constructs used. Patients with construct/implant failures may or may not be symptomatic and present either as early (< 3months) or late failures (> 3months). It has been noted that not all the implant failures after MSTS result in revisions. CONCLUSION: Based on the observed radiological criteria and clinical presentations, we have proposed a clinico-radiological classification for implant/construct failure after MSTS.

Comparison of two radiological methods in the determination of skeletal maturity in the Indian pediatric population.

To determine a more precise and reliable method between Greulich-Pyle (GP) and MacKay's (MK) method for the determination of skeletal age in an Indian pediatric population. We carried out a cross sectional study for the assessment of skeletal age on the basis of examination of hand and wrist radiographs of 106 patients (1-15 years of age) who presented with soft tissue injury to hand by the GP and the MK method. These radiographs were evaluated by a radiologist and an orthopedic surgeon independently. In girls, the mean age difference between chronological and skeletal age was 8 months by the GP method, whereas it was 17 months by MK method. For boys, the mean age difference was 10 months by the GP method and by MKs method, it was 20 months. By the GP method, 44% of the boys showed a more reliable estimate of age whereas it was 10% by the MK method. However, the same for girls was 25% by the GP method and 16% by the MK method. The inter-rater reliability for the raters was found to be κ=0.68 and this was statistically significant (P<0.001), 95% confidence interval (0.504-0.848). We concluded that the GP method appeared to be more reliable in the determination of skeletal age in the Indian pediatric population.

Management of fracture dorso-lumbar spine in a pregnant female by surgery in prone position.

Surgical management of thoraco-lumbar spine fracture in pregnancy has specific concerns during surgery like positioning, approach, and radiation exposure to fetus. We report a case of burst fracture of 12th thoracic vertebrae with paraplegia in a young female with 26 weeks of gestation. Surgery was performed in prone position on a Toronto frame. This report also discusses the management of thoraco-lumbar spine fracture in pregnancy with review of literature.

Do autologous blood transfusion systems reduce allogeneic blood transfusion in total knee arthroplasty?

PURPOSE: To study whether autologus blood transfusion systems reduce the requirement of allogneic blood transfusion in patients undergoing total knee arthroplasty. METHODS: A comprehensive search of the published literature with PubMed, Scopus and Science direct database was performed. The following search terms were used: (total knee replacement) OR (total knee arthroplasty) OR (TKA) AND (blood transfusion) OR (autologous transfusion) OR (autologous transfusion system). Using search syntax, a total of 748 search results were obtained (79 from PubMed, 586 from Science direct and 83 from Scopus). Twenty-one randomized control trials were included for this meta-analysis. RESULTS: The allogenic transfusion rate in autologus blood transfusion (study) group was significantly lower than the control group (28.4 and 53.5 %, respectively) (p value 0.0001, Relative risk: 0.5). The median units of allogenic blood transfused in study control group and control group were 0.1 (0.1-3.0) and 1.3 (0.3-2.6), respectively. The median hospital stay in study group was 9 (6.7-15.6) days and control group was 8.7 (6.6-16.7) days. The median cost incurred for blood transfusion per patient in study and control groups was 175 (85.7-260) and 254.7 (235-300) euros, respectively. CONCLUSION: This meta-analysis demonstrates that the use of auto-transfusion systems is a cost-effective method to reduce the need for and quantity of allogenic transfusion in elective total knee arthroplasty. LEVEL OF EVIDENCE: Level I.

Intramedullary Tuberculoma of Dorsal Spinal Cord: A Case Report with Review of Literature.

INTRODUCTION: Intramedullary tuberculoma (IMT)are extremely rare lesions should be distinguished from other space occupying lesions like neoplasms. Although it is a treatable condition delaying diagnosis leads to significant morbidity. CASE REPORT: We report a case of intramedullary thoracic tuberculoma with paraparesis showing deterioration of neurological status during medical treatment. Surgical resection had shown the excellent result. CONCLUSION: The possibility of IMT should be seriously considered when an intraspinal mass is found with evidence of tuberculosis. Anti-tuberculous therapy (ATT) is the mainstay of treatment and had shown good results. Surgical removal is to be considered in cases of worsening neurological status while the patient is on ATT.

γ-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: a study of their activity as glycosidase inhibitors and as immunosuppressive agents.

An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a-f, starting from the D-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-α-D-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the γ-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b-f. Iminosugars 8a-f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be α-galactosidase inhibitors while 8d and 8e were selective and moderate α-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a-f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.

Synthesis of 1,5-dideoxy-1,5-iminoribitol C-glycosides through a nitrone-olefin cycloaddition domino strategy: identification of pharmacological chaperones of mutant human lysosomal ß-galactosidase.

We report herein a newly developed domino reaction that facilitates the synthesis of new 1,5-dideoxy-1,5-iminoribitol iminosugar C-glycosides 7a-e and 8. The key intermediate in this approach is a six-membered cyclic sugar nitrone that is generated in situ and trapped by an alkene dipolarophile via a [2 + 3] cycloaddition reaction to give the corresponding isooxazolidines 10a-e in a "one-pot" protocol. The iminoribitol C-glycosides 7a-e and 8 were found to be modest ß-galactosidase (bGal) inhibitors. However, compounds 7c and 7e showed "pharmacological chaperone" activity for mutant lysosomal bGal activity and facilitated its recovery in GM1 gangliosidosis patient fibroblasts by 2-6-fold.