Practice Variation between Salaried and Fee-for-Service Surgeons for Lumbar Surgery.

OBJECTIVE: To examine differences in surgical practices between salaried and fee-for-service (FFS) surgeons for two common degenerative spine conditions. Surgeons may offer different treatments for similar conditions on the basis of their compensation mechanism. METHODS: The study assessed the practices of 63 spine surgeons across eight Canadian provinces (39 FFS surgeons and 24 salaried) who performed surgery for two lumbar conditions: stable spinal stenosis and degenerative spondylolisthesis. The study included a multicenter, ambispective review of consecutive spine surgery patients enrolled in the Canadian Spine Outcomes and Research Network registry between October 2012 and July 2018. The primary outcome was the difference in type of procedures performed between the two groups. Secondary study variables included surgical characteristics, baseline patient factors, and patient-reported outcome. RESULTS: For stable spinal stenosis (n = 2234), salaried surgeons performed statistically fewer uninstrumented fusion (p < 0.05) than FFS surgeons. For degenerative spondylolisthesis (n = 1292), salaried surgeons performed significantly more instrumentation plus interbody fusions (p < 0.05). There were no statistical differences in patient-reported outcomes between the two groups. CONCLUSIONS: Surgeon compensation was associated with different approaches to stable lumbar spinal stenosis and degenerative lumbar spondylolisthesis. Salaried surgeons chose a more conservative approach to spinal stenosis and a more aggressive approach to degenerative spondylolisthesis, which highlights that remuneration is likely a minor determinant in the differences in practice of spinal surgery in Canada. Further research is needed to further elucidate which variables, other than patient demographics and financial incentives, influence surgical decision-making.

A twitter analysis of patient and family experience in pediatric spine surgery.

BACKGROUND: There is little data on patient and caregiver perceptions of spine surgery in children and youth. This study aims to characterize the personal experiences of patients, caregivers, and family members surrounding pediatric spine surgery through a qualitative and quantitative social media analysis. METHODS: The Twitter application programming interface was searched for keywords related to pediatric spine surgery from inception to March 2022. Relevant tweets and accounts were extracted and subsequently classified using thematic labels. Tweet metadata was collected to measure user engagement via multivariable regression. Sentiment analysis using Natural Language Processing was performed on all tweets with a focus on tweets discussing the personal experiences of patients and caregivers. RESULTS: 2424 tweets from 1847 individual accounts were retrieved for analysis. Patients and caregivers represented 1459 (79.0%) of all accounts. Posts discussed the personal experiences of patients and caregivers in 83.5% of tweets. Pediatric spine surgery research was discussed in few posts (n=90, 3.7%). Within the personal experience category, 975 (48.17%) tweets were positive, 516 (25.49%) were negative, and 533 (26.34%) were neutral. Presence of a tag (beta: -6.1, 95% CI -9.7 to -2.5) and baseline follower count (beta<0.001, 95% CI <0.001 to <0.001) significantly affected tweet engagement negatively and positively, respectively. CONCLUSIONS: Patients and caregivers actively discuss topics related to pediatric spine surgery on Twitter. Posts discussing personal experience are most prevalent, while posts on research are scarce, unlike previous social media studies. Pediatric spine surgeons can leverage this dialogue to better understand the worries and needs of patients and their families.

Publication retraction in spine surgery: a systematic review.

PURPOSE: The number of articles retracted by peer-reviewed journals has increased in recent years. This study systematically reviews retracted publications in the spine surgery literature. METHODS: A search of PubMed MEDLINE, Ovid EMBASE, Retraction Watch, and the independent websites of 15 spine surgery-related journals from inception to September of 2022 was performed without language restrictions. PRISMA guidelines were followed with title/abstract screening, and full-text screening was conducted independently and in duplicate by two reviewers. Study characteristics and bibliometric information for each publication was extracted. RESULTS: Of 250 studies collected from the search, 65 met the inclusion criteria. The most common reason for retraction was data error (n = 15, 21.13%), followed by plagiarism (n = 14, 19.72%) and submission to another journal (n = 14, 19.72%). Most studies pertained to degenerative pathologies of the spine (n = 32, 80.00%). Most articles had no indication of retraction in their manuscript (n = 24, 36.92%), while others had a watermark or notice at the beginning of the article. The median number of citations per retracted publication was 10.0 (IQR 3-29), and the median 4-year impact factor of the journals was 5.05 (IQR 3.20-6.50). On multivariable linear regression, the difference in years from publication to retraction (p = 0.0343, ß = 6.56, 95% CI 0.50-12.62) and the journal 4-year impact factor (p = 0.0029, ß = 7.47, 95% CI 2.66-12.28) were positively associated with the total number of citations per retracted publication. Most articles originated from China (n = 30, 46.15%) followed by the United States (n = 12, 18.46%) and Germany (n = 3, 4.62%). The most common study design was retrospective cohort studies (n = 14, 21.54%). CONCLUSIONS: The retraction of publications has increased in recent years in spine surgery. Researchers consulting this body of literature should remain vigilant. Institutions and journals should collaborate to increase publication transparency and scientific integrity.

Temporal analysis of complication rates of cervical spine surgery for degenerative spine disease between younger and older cohorts using the CSORN registry: Is age just a number?

STUDY DESIGN: An ambispective review of consecutive cervical spine surgery patients enrolled in the Canadian Spine Outcomes and Research Network (CSORN) between January 2015 and September 2019. PURPOSE: To compare complication rates of degenerative cervical spine surgery over time between older (> 65) and younger age groups (< 65). More elderly people are having spinal surgery. Few studies have examined the temporal nature of complications of cervical spine surgery by patient age groups. METHODS: Adverse events were collected prospectively using adverse event forms. Binary logistic regression analysis was utilized to assess associations between risk modifiers and adverse events at the intra-, peri-operative and 3 months post-surgery. RESULTS: Of the 761 patients studied (age < 65, n = 581 (76.3%) and 65 + n = 180 (23.7%), the intra-op adverse events were not significantly different; < 65 = 19 (3.3%) vs 65 + = 11 (6.1%), p < 0.087. Peri-operatively, the < 65 group had significantly lower percentage of adverse events (65yrs (11.2%) vs. 65 + = (26.1%), p < 0.001). There were no differences in rates of adverse events at 3 months post-surgery (< 65 = 39 (6.7%) vs. 65 + = 12 (6.7%), p < 0.983). Less blood loss (OR = 0.99, p < 0.010) and shorter length of hospital stay (OR = 0.97, p < 0.025) were associated with not having intra-op adverse events. Peri-operatively, > 1 operated level (OR = 1.77, p < 0.041), shorter length of hospital stay (OR = 0.86, p < 0.001) and being younger than 65 years (OR = 2.11, p < 0.006) were associated with not having adverse events. CONCLUSION: Following degenerative cervical spine surgery, the older and younger age groups had significantly different complication rates at peri-operative time points, and the intra-operative and 3-month post-operative complication rates were similar in the groups.

Invasive Brain Computer Interface for Motor Restoration in Spinal Cord Injury: A Systematic Review.

STUDY DESIGN: Systematic review of the literature. OBJECTIVES: In recent years, brain-computer interface (BCI) has emerged as a potential treatment for patients with spinal cord injury (SCI). This is the first systematic review of the literature on invasive closed-loop BCI technologies for the treatment of SCI in humans. MATERIALS AND METHODS: A comprehensive search of PubMed MEDLINE, Web of Science, and Ovid EMBASE was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 8316 articles collected, 19 studies met all the inclusion criteria. Data from 21 patients were extracted from these studies. All patients sustained a cervical SCI and were treated using either a BCI with intracortical microelectrode arrays (n = 18, 85.7%) or electrocorticography (n = 3, 14.3%). To decode these neural signals, machine learning and statistical models were used: support vector machine in eight patients (38.1%), linear estimator in seven patients (33.3%), Hidden Markov Model in three patients (14.3%), and other in three patients (14.3%). As the outputs, ten patients (47.6%) underwent noninvasive functional electrical stimulation (FES) with a cuff; one (4.8%) had an invasive FES with percutaneous stimulation, and ten (47.6%) used an external device (neuroprosthesis or virtual avatar). Motor function was restored in all patients for each assigned task. Clinical outcome measures were heterogeneous across all studies. CONCLUSIONS: Invasive techniques of BCI show promise for the treatment of SCI, but there is currently no technology that can restore complete functional autonomy in patients with SCI. The current techniques and outcomes of BCI vary greatly. Because invasive BCIs are still in the early stages of development, further clinical studies should be conducted to optimize the prognosis for patients with SCI.

Systemic considerations for the surgical treatment of spinal metastatic disease: a scoping literature review.

Systemic assessment is a pillar in the neurological, oncological, mechanical, and systemic (NOMS) decision-making framework for the treatment of patients with spinal metastatic disease. Despite this importance, emerging evidence relating systemic considerations to clinical outcomes following surgery for spinal metastatic disease has not been comprehensively summarised. We aimed to conduct a scoping literature review of this broad topic. We searched MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL databases from Jan 1, 2000, to July 31, 2021. 61 articles were included, accounting for a total of 22 335 patients. Preoperative systemic variables negatively associated with postoperative clinical outcomes included demographics (eg, older age [>60 years], Black race, male sex, low or elevated body-mass index, and smoking status), medical comorbidities (eg, cardiac, pulmonary, hepatic, renal, endocrine, vascular, and rheumatological), biochemical abnormalities (eg, hypoalbuminaemia, atypical blood cell counts, and elevated C-reactive protein concentration), low muscle mass, generalised motor weakness (American Spinal Cord Injury Association Impairment Scale grade and Frankel grade) and poor ambulation, reduced performance status, and systemic disease burden. This is the first comprehensive scoping review to broadly summarise emerging evidence relevant to the systemic assessment component of the widely used NOMS framework for spinal metastatic disease decision making. Medical, surgical, and radiation oncologists can consider these findings when prognosticating spinal metastatic disease-related surgical outcomes on the basis of patients' systemic condition. These factors might inform a shared decision-making approach with patients and their families.

Are humanized IgE reporter systems potential game changers in serological diagnosis of human parasitic infection?

Immunoglobulin E (IgE) is thought to have evolved to protect mammalian hosts against parasitic infections or toxins and plays a central role in the pathogenesis, diagnosis, and therapy of IgE-mediated allergy. Despite the prominence of IgE responses in most parasitic infections, and in stark contrast to its use in the diagnosis of allergy, this isotype is almost completely unexploited for parasite diagnosis. Here, we discuss the perceived or real limitations of IgE-based diagnosis in parasitology and suggest that the recent creation of a new generation of very sensitive cellular IgE-based reporters may represent a powerful new diagnostic platform, but needs to be based on a very careful choice of diagnostic allergens.

A 3D, Compartmental Tumor-Stromal Microenvironment Model of Patient-Derived Bone Metastasis.

Bone is a frequent site of tumor metastasis. The bone-tumor microenvironment is heterogeneous and complex in nature. Such complexity is compounded by relations between metastatic and bone cells influencing their sensitivity/resistance to chemotherapeutics. Standard chemotherapeutics may not show efficacy for every patient, and new therapeutics are slow to emerge, owing to the limitations of existing 2D/3D models. We previously developed a 3D interface model for personalized therapeutic screening, consisting of an electrospun poly lactic acid mesh activated with plasma species and seeded with stromal cells. Tumor cells embedded in an alginate-gelatin hydrogel are overlaid to create a physiologic 3D interface. Here, we applied our 3D model as a migration assay tool to verify the migratory behavior of different patient-derived bone metastasized cells. We assessed the impact of two different chemotherapeutics, Doxorubicin and Cisplatin, on migration of patient cells and their immortalized cell line counterparts. We observed different migratory behaviors and cellular metabolic activities blocked with both Doxorubicin and Cisplatin treatment; however, higher efficiency or lower IC50 was observed with Doxorubicin. Gene expression analysis of MDA-MB231 that migrated through our 3D hybrid model verified epithelial-mesenchymal transition through increased expression of mesenchymal markers involved in the metastasis process. Our findings indicate that we can model tumor migration in vivo, in line with different cell characteristics and it may be a suitable drug screening tool for personalized medicine approaches in metastatic cancer treatment.

Drug Repurposing and De Novo Drug Discovery of Protein Kinase Inhibitors as New Drugs against Schistosomiasis.

Schistosomiasis is a neglected tropical disease affecting more than 200 million people worldwide. Chemotherapy relies on one single drug, praziquantel, which is safe but ineffective at killing larval stages of this parasite. Furthermore, concerns have been expressed about the rise in resistance against this drug. In the absence of an antischistosomal vaccine, it is, therefore, necessary to develop new drugs against the different species of schistosomes. Protein kinases are important molecules involved in key cellular processes such as signaling, growth, and differentiation. The kinome of schistosomes has been studied and the suitability of schistosomal protein kinases as targets demonstrated by RNA interference studies. Although protein kinase inhibitors are mostly used in cancer therapy, e.g., for the treatment of chronic myeloid leukemia or melanoma, they are now being increasingly explored for the treatment of non-oncological conditions, including schistosomiasis. Here, we discuss the various approaches including screening of natural and synthetic compounds, de novo drug development, and drug repurposing in the context of the search for protein kinase inhibitors against schistosomiasis. We discuss the status quo of the development of kinase inhibitors against schistosomal serine/threonine kinases such as polo-like kinases (PLKs) and mitogen-activated protein kinases (MAP kinases), as well as protein tyrosine kinases (PTKs).

The effects of combined motor control and isolated extensor strengthening versus general exercise on paraspinal muscle morphology and function in patients with chronic low back pain: a randomised controlled trial protocol.

BACKGROUND: Exercise is a common approach for the management of patients with chronic non-specific low back pain (LBP). However, there is no clear mechanistic evidence or consensus on what type of exercise is more effective than others. While considerable evidence suggests a link between lumbar muscle health (e.g., atrophy and fatty infiltration) with functional deficits, it is unknown whether exercises targeting the lumbar spine can lead to noticeable improvements in muscle health and functional outcomes. The primary aim of this study is to compare the effect of combined motor control and isolated strengthening lumbar exercises (MC + ILEX) versus a general exercise group (GE) on multifidus muscle morphology (size and composition). Secondary aims include assessing the effect of the interventions on overall paraspinal muscle health, pain and disability, as well as psychological factors as possible effect modifiers. METHODS: A total of 50 participants with chronic non-specific LBP and moderate to severe disability, aged between 18 and 60, will be recruited from the local orthopaedic clinics and university community. Participants will be randomised (1:1) to either the MC + ILEX or GE group. Participants will undergo 24 individually supervised exercise sessions over a 12-week period. The primary outcome will be multifidus morphology (atrophy) and composition (fatty infiltration). Secondary outcomes will be muscle function (e.g., % thickness change during contraction), morphology, lumbar extension strength, pain intensity and disability. Potential treatment effect modifiers including maladaptive cognitions (fear of movement, catastrophizing), anxiety, depression, physical activity, and sleep quality will also be assessed. All measurements will be obtained at baseline, 6-week and 12-week; self-reported outcomes will also be collected at 24-week. Between-subjects repeated measure analysis of variance will be used to examine the changes in paraspinal muscle morphology over the different time points. Linear mixed models will be used to assess whether baseline scores can modify the response to the exercise therapy treatment. DISCUSSION: The results of this study will help clarify which of these two common interventions promote better results in terms of overall paraspinal muscle heath, back pain, disability and psychological factors in adults with chronic LBP. TRIAL REGISTRATION: NTCT04257253 , registered prospectively on February 5, 2020.

Patient satisfaction with treatment outcomes after surgery and/or radiotherapy for spinal metastases.

BACKGROUND: Patient satisfaction is infrequently investigated despite its importance in assessing efficacy and patient comprehension. The purpose of this study was to investigate patient satisfaction with treatment outcomes after surgery and/or radiotherapy for spinal metastases and to evaluate how health-related quality of life (HRQOL) is related to patient satisfaction. METHODS: Patients with spinal metastases treated with surgery and/or radiotherapy were enrolled in a prospective, international, observational study. Demographic, histologic, treatment, and HRQOL data were collected. HRQOL was evaluated with the Numeric Rating Scale pain score, the 3-level version of the EuroQol 5-Dimension (EQ-5D-3L) instrument, and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ2.0). Patient satisfaction was derived from the SOSGOQ2.0 at 6, 12, and 26 weeks after treatment. Patients were classified as satisfied, neutral, or dissatisfied. RESULTS: Twelve weeks after treatment, 183 of the surgically treated patients (84%) were satisfied, and only 11 (5%) were dissatisfied; in contrast, 101 of the patients treated with radiotherapy alone (77%) were satisfied, and only 7 (5%) were dissatisfied. Significant improvements in pain, physical function, mental health, social function, leg function, and EQ-5D were associated with satisfaction after surgery. Satisfaction after radiotherapy was associated with significant improvements in pain, mental health, and overall SOSGOQ2.0 scores. Dissatisfaction after treatment was associated with lower baseline values for leg strength and lower social functioning scores for surgically treated patients and with lower social functioning scores and being single for patients treated with radiotherapy. CONCLUSIONS: High levels of satisfaction with treatment outcomes are observed after surgery and/or radiotherapy for spinal metastases. Posttreatment satisfaction is associated with significant improvements in pain and different dimensions of HRQOL.

Association of neurologic deficits with surgical outcomes and health-related quality of life after treatment for metastatic epidural spinal cord compression.

BACKGROUND: A critical knowledge gap exists regarding the impact of neurologic deficits on surgical outcomes and health-related quality of life (HRQOL) for patients surgically treated for metastatic epidural spinal cord compression (MESCC). METHODS: This prospective, multicenter and international study analyzed the impact of the neurologic status on functional status, HRQOL, and postoperative survival. The collected data included the patient demographics, overall survival, American Spinal Injury Association (ASIA) impairment scale, Spinal Instability Neoplastic Score, treatment details and complications and HRQOL measures, including version 2 of the 36-Item Short Form Health Survey (SF-36v2) and version 2.0 of the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ2.0). RESULTS: A total of 239 patients surgically treated for spinal metastases were included. Six weeks after treatment, 99 of the 108 patients with a preoperative ASIA grade of E remained stable, 8 deteriorated to ASIA D, and 1 deteriorated to ASIA A. Of 55 patients with ASIA D, 27 improved to ASIA E, 27 remained stable and 1 deteriorated to ASIA C. Of 11 patients with ASIA A to C, 2 improved to ASIA E, 4 improved to ASIA D, and 5 remained stable. At the 6- and 12-week follow-up, better ASIA scores were associated with better scores on multiple SF-36v2 and SOSGOQ items. Postoperatively, patients with ASIA grades of A to D were more likely to have urinary tract infections and wound complications. Patients with a baseline ASIA grade of E or D survived significantly longer. CONCLUSIONS: Patients with neurologic deficits due to MESCC have worse HRQOL and decreased overall survival. Nevertheless, surgery can result in stabilization or improvement of neurologic function which may translate into better HRQOL. Postoperative care and follow-up are challenging for patients with neurologic deficits because they experience more complications.

Survival, local control, and health-related quality of life in patients with oligometastatic and polymetastatic spinal tumors: A multicenter, international study.

BACKGROUND: The treatment of oligometastatic (≤5 metastases) spinal disease has trended toward ablative therapies, yet to the authors' knowledge little is known regarding the prognosis of patients presenting with oligometastatic spinal disease and the value of this approach. The objective of the current study was to compare the survival and clinical outcomes of patients with cancer with oligometastatic spinal disease with those of patients with polymetastatic (>5 metastases) disease. METHODS: The current study was an international, multicenter, prospective study. Patients who were admitted to a participating spine center with a diagnosis of spinal metastases and who underwent surgical intervention and/or radiotherapy between August 2013 and May 2017 were included. Data collected included demographics, overall survival, local control, and treatment information including surgical, radiotherapy, and systemic therapy details. Health-related quality of life (HRQOL) measures included the EuroQOL 5 dimensions 3-level questionnaire (EQ-5D-3L), the 36-Item Short Form Health Survey (SF-36v2), and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ). RESULTS: Of the 393 patients included in the current study, 215 presented with oligometastatic disease and 178 presented with polymetastatic disease. A significant survival advantage of 90.1% versus 77.3% at 3 months and 77.0% versus 65.1% at 6 months from the time of treatment was found for patients presenting with oligometastatic disease compared with those with polymetastatic disease. It is important to note that both groups experienced significant improvements in multiple HRQOL measures at 6 months after treatment, with no differences in these outcome measures noted between the 2 groups. CONCLUSIONS: The treatment of oligometastatic disease appears to offer a significant survival advantage compared with polymetastatic disease, regardless of treatment choice. HRQOL measures were found to improve in both groups, demonstrating a palliative benefit for all treated patients.

Low-dose zoledronate for the treatment of bone metastasis secondary to prostate cancer.

BACKGROUND: Bisphosphonates (BPs) including zoledronate (zol) have become standard care for bone metastases as they effectively inhibit tumor-induced osteolysis and associated pain. Several studies have also suggested that zol has direct anti-tumor activity. Systemic administration at high doses is the current approach to deliver zol, yet it has been associated with debilitating side effects. Local therapeutic delivery offers the ability to administer much lower total dosage, while at the same time maintaining sustained high-local drug concentration directly at the target treatment site. Here, we aimed to assess effects of lower doses of zol on bone metastases over a longer time. METHODS: Prostate cancer cell line LAPC4 and prostate-induced bone metastasis cells were treated with zol at 1, 3 and 10 µM for 7 days. Following treatment, cell proliferation was assessed using Almarblue®, Vybrant MTT®, and Live/Dead® viability/cytotoxicity assays. Additionally, cell migration and invasion were carried out using Falcon™ cell culture inserts and Cultrex® 3D spheroid cell invasion assays respectively. RESULTS: We show that treatment with 3-10 µM zol over 7-days significantly decreased cell proliferation in both the prostate cancer cell line LAPC4 and cells from spine metastases secondary to prostate cancer. Using the same low-dose and longer time course for treatment, we demonstrate that 10 µM zol also significantly inhibits tumor cell migration and 3D-cell growth/invasion. CONCLUSIONS: This project harnesses the potential of using zol at low doses for longer treatment periods, which may be a viable treatment modality when coupled with biomaterials or biodevices for local delivery.

Psychometric evaluation and adaptation of the Spine Oncology Study Group Outcomes Questionnaire to evaluate health-related quality of life in patients with spinal metastases.

BACKGROUND: The Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ) was developed as the first spine oncology-specific health-related quality of life (HRQOL) measure. This study evaluated the psychometric properties and clinical validity of the SOSGOQ in a diverse cohort of patients with spinal metastases. METHODS: An international, multicenter, prospective observational cohort study including patients with spinal metastases who underwent surgery and/or radiotherapy was conducted by the AOSpine Knowledge Forum Tumor. Demographic, tumor, and treatment data were collected. HRQOL was evaluated using the SOSGOQ and Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) at baseline and fixed follow-up times. Construct validity was assessed using multitrait scaling analyses, confirmatory factor analyses, and correlation with the SF-36 and NRS pain score. Test-retest reliability was assessed in a subgroup of patients between 12 weeks after treatment and the retest 4 to 9 days later. RESULTS: A total of 238 patients were enrolled at 9 centers across North America; 153 of these patients had HRQOL data available at 12 weeks after treatment. Multitrait scaling analyses and confirmatory factor analyses resulted in a refined version of the SOSGOQ with 4 domains and 4 single items. The revised SOSGOQ (SOSGOQ2.0) demonstrated strong correlations with SF-36 and the ability to discriminate between clinically distinct patient groups. Reliability of the SOSGOQ2.0 was demonstrated to be good, with an intraclass correlation coefficient ranging from 0.58 to 0.92 for the different domains. CONCLUSIONS: The SOSGOQ2.0 is a reliable and valid measure with which to evaluate HRQOL in patients with spinal metastases. It is recommended to use the SOSGOQ2.0 together with a generic HRQOL outcome measure to comprehensively assess HRQOL and increase sensitivity and specificity. Cancer 2018;124:1828-38. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs.

Nerve growth factor (NGF) contributes to the development of chronic pain associated with degenerative connective tissue pathologies, such as intervertebral disc degeneration and osteoarthritis. However, surprisingly little is known about the regulation of NGF in these conditions. Toll-like receptors (TLR) are pattern recognition receptors classically associated with innate immunity but more recently were found to be activated by endogenous alarmins such as fragmented extracellular matrix proteins found in degenerating discs or cartilage. In this study we investigated if TLR activation regulates NGF and which signaling mechanisms control this response in intervertebral discs. TLR2 agonists, TLR4 agonists, or IL-1ß (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1ß gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1ß treatment increased NGF protein secretion. TLR2 activation increased p38, ERK1/2, and p65 activity and increased p65 translocation to the cell nucleus. JNK activity was not affected by TLR2 activation. Inhibition of NF-κB, and to a lesser extent p38, but not ERK1/2 activity, blocked TLR2-driven NGF up-regulation at both the transcript and protein levels. These results provide a novel mechanism of NGF regulation in the intervertebral disc and potentially other pathogenic connective tissues. TLR2 and NF-κB signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-κB inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.

Thirty-Day Complications of Conventional and Computer-Assisted Total Knee and Total Hip Arthroplasty: Analysis of 103,855 Patients in the American College of Surgeons National Surgical Quality Improvement Program Database.

BACKGROUND: Computer-assisted surgery (CAS) has gained popularity in orthopedics for both total knee arthroplasty (TKA) and total hip arthroplasty (THA) in the past decades. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify patients who underwent a primary, unilateral THA and TKA from 2011 to 2013. Multivariate analysis was conducted to compare the postoperative complications in patients whose surgery involved the use of CAS with those by conventional techniques. RESULTS: We identified 103,855 patients who had THA and TKA in the database between 2011 and 2013. There were higher overall adverse events (odds ratio [OR], 1.40; CI, 1.22-1.59), minor events (OR, 1.38; CI, 1.21-1.58), and requirements for blood transfusion (OR, 1.44; CI, 1.25-1.67) in the conventional group when compared with CAS for TKA. However, rate of reoperation was higher in the CAS group for TKA (OR, 1.60; CI, 1.15-2.25). The results also showed higher overall adverse events (OR, 2.61; CI, 2.09-3.26), minor events (OR, 2.82; CI, 2.24-3.42), and requirements for blood transfusion (OR, 3.41; CI, 2.62-4.44) in the conventional group when compared to CAS for THA. Nevertheless, superficial wound infections (OR, 0.46; CI, 0.26-0.81) were shown to be higher in the CAS group undergoing THA. CONCLUSION: The use of CAS in THA and TKA reduced the number of minor adverse events in the first 30 days postoperatively. However, CAS was associated with an increased number of reoperations and superficial infections. The clinical benefits and disadvantages of CAS should be considered when determining the potential benefit-cost ratio of this technology.

The use of computer-assisted surgery as an educational tool for the training of orthopedic surgery residents in pedicle screw placement: a pilot study and survey among orthopedic residents.

BACKGROUND: The training of orthopedic residents in adequate pedicle screw placement is very important. We sought to investigate orthopedic residents' perspectives on the use of computer-assisted surgery (CAS) in a training trial. METHODS: Orthopedic residents were randomly assigned to independently place a screw using the free-hand technique and the CAS technique on 1 of 3 cadavers (Cobb angles 5º, 15º and 67º) at randomly selected thoracolumbar vertebral levels. All residents were blinded to their colleagues' pedicle screw placements and were asked to complete a short questionnaire at the end of the session to evaluate their experience with CAS. We obtained CT images for each cadaver to assess pedicle screw placement accuracy and classified placement as A) screw completely in pedicle, B) screw < 2 mm outside pedicle, C) screw 2-4 mm outside pedicle, or D) screw > 4 mm outside pedicle. RESULTS: Twenty-four orthopedic residents participated in this trial study. In total, 65% preferred using the free-hand technique in an educational setting even though most (60%) said that CAS is safer. The main reason for free-hand technique preference was the difficult technical aspects encountered with CAS. In addition, accuracy of pedicle screw placement in this trial showed that 5 screws were classified as A or B (safe zone) and 19 as grade C or D (unsafe zone) using the free-hand technique compared with 15 and 9, respectively, using CAS (p = 0.008). CONCLUSION: Orthopedic residents perceived CAS as safe and demonstrated improved accuracy in pedicle screw placement in a single setting. However, the residents preferred the free-hand technique in an educational stetting owing to the difficult technical aspects of CAS.

CONTEXTE: Il est très important d'apprendre aux médecins résidents en chirurgie orthopédique comment positionner adéquatement une vis pédiculaire. Notre objectif était d'obtenir l'opinion des médecins résidents sur le recours à la chirurgie assistée par ordinateur (CAO) dans un essai sur la formation. MÉTHODES: Des médecins résidents en chirurgie orthopédique répartis aléatoirement ont placé indépendamment une vis à l'aide d'une technique à main libre basée sur les repères topographiques et la palpation, et de la CAO dans 1 de 3 cadavres (angles de Cobb de 5°, 15° et 67°) dans une vertèbre dorsolombaire sélectionnée aléatoirement. Aucun des médecins résidents n'a pu observer le positionnement de la vis de ses collègues, et les participants ont rempli un court questionnaire à la fin de la séance pour évaluer leur expérience de la CAO. Nous avons obtenu un tomodensitogramme pour chaque cadavre afin d'évaluer la précision du positionnement de la vis pédiculaire, classée selon 4 catégories : A) vis entièrement dans le pédicule, B) vis < 2 mm hors du pédicule, C) vis de 2­4 mm hors du pédicule, ou D) vis > 4 mm hors du pédicule. RÉSULTATS: Vingt-quatre médecins résidents en chirurgie orthopédique ont participé à l'étude clinique. Au total, 65 % d'entre eux ont préféré utiliser la technique à main libre dans un contexte de formation, même si la plupart (60 %) considéraient que la CAO était plus sécuritaire. La principale raison justifiant cette préférence était le degré de difficulté technique associé à la CAO. De plus, une évaluation de la précision du positionnement a montré qu'avec la technique à main libre, 5 des vis posées se classaient dans les catégories A ou B (sécuritaire) et 19 dans les catégories C ou D (non sécuritaire), alors que la CAO a permis de positionner 15 vis dans les catégories A ou B et 9 dans les catégories C ou D (p = 0,008). CONCLUSION: Chez un sous-groupe de patients souffrant de traumatismes abdominaux pénétrants, le traitement conservateur est sécuritaire et se traduit par une durée de séjour inférieure de 1,9 jour. La présence de fluide détectée par tomodensitographie est un indicateur de l'échec du traitement.

Biochemical characterization of pathogenic mutations in human mitochondrial methionyl-tRNA formyltransferase.

N-Formylation of initiator methionyl-tRNA (Met-tRNA(Met)) by methionyl-tRNA formyltransferase (MTF) is important for translation initiation in bacteria, mitochondria, and chloroplasts. Unlike all other translation systems, the metazoan mitochondrial system is unique in using a single methionine tRNA (tRNA(Met)) for both initiation and elongation. A portion of Met-tRNA(Met) is formylated for initiation, whereas the remainder is used for elongation. Recently, we showed that compound heterozygous mutations within the nuclear gene encoding human mitochondrial MTF (mt-MTF) significantly reduced mitochondrial translation efficiency, leading to combined oxidative phosphorylation deficiency and Leigh syndrome in two unrelated patients. Patient P1 has a stop codon mutation in one of the MTF genes and an S209L mutation in the other MTF gene. P2 has a S125L mutation in one of the MTF genes and the same S209L mutation as P1 in the other MTF gene. Here, we have investigated the effect of mutations at Ser-125 and Ser-209 on activities of human mt-MTF and of the corresponding mutations, Ala-89 or Ala-172, respectively, on activities of Escherichia coli MTF. The S125L mutant has 653-fold lower activity, whereas the S209L mutant has 36-fold lower activity. Thus, both patients depend upon residual activity of the S209L mutant to support low levels of mitochondrial protein synthesis. We discuss the implications of these and other results for whether the effect of the S209L mutation on mitochondrial translational efficiency is due to reduced activity of the mutant mt-MTF and/or reduced levels of the mutant mt-MTF.

Distinctive contributions of the ribosomal P-site elements m2G966, m5C967 and the C-terminal tail of the S9 protein in the fidelity of initiation of translation in Escherichia coli.

The accuracy of pairing of the anticodon of the initiator tRNA (tRNA(fMet)) and the initiation codon of an mRNA, in the ribosomal P-site, is crucial for determining the translational reading frame. However, a direct role of any ribosomal element(s) in scrutinizing this pairing is unknown. The P-site elements, m(2)G966 (methylated by RsmD), m(5)C967 (methylated by RsmB) and the C-terminal tail of the protein S9 lie in the vicinity of tRNA(fMet). We investigated the role of these elements in initiation from various codons, namely, AUG, GUG, UUG, CUG, AUA, AUU, AUC and ACG with tRNA(fMet(CAU) (tRNA(fMet) with CAU anticodon); CAC and CAU with tRNA(fMet(GUG); UAG with tRNA(fMet(CAU) ; UAC with tRNA(fMet(GUG) ; and AUC with tRNA(fMet(GUG) using in vivo and computational methods. Although RsmB deficiency did not impact initiation from most codons, RsmD deficiency increased initiation from AUA, CAC and CAU (2- to 3.6-fold). Deletion of the S9 C-terminal tail resulted in poorer initiation from UUG, GUG and CUG, but in increased initiation from CAC, CAU and UAC codons (up to 4-fold). Also, the S9 tail suppressed initiation with tRNA(fMet(CAU) lacking the 3GC base pairs in the anticodon stem. These observations suggest distinctive roles of 966/967 methylations and the S9 tail in initiation.