Markers of Tissue Deterioration and Pain on Earth and in Space.

Purpose: Pain is an understudied physiological effect of spaceflight. Changes in inflammatory and tissue degradation markers are often associated with painful conditions. Our aim was to evaluate the changes in markers associated with tissue deterioration after a short-term spaceflight. Patients and Methods: Plasma levels of markers for systemic inflammation and tissue degeneration markers were assessed in two astronauts before and within 24 h after the 17-day Axiom Space AX-1 mission. Results: After the spaceflight, C-reactive protein (CRP) was reduced in both astronauts, while INFγ, GM-CSF, TNFα, BDNF, and all measured interleukins were consistently increased. Chemokines demonstrated variable changes, with consistent positive changes in CCL3, 4, 8, 22 and CXCL8, 9, 10, and consistent negative change in CCL8. Markers associated with tissue degradation and bone turnover demonstrated consistent increases in MMP1, MMP13, NTX and OPG, and consistent decreases in MMP3 and MMP9. Conclusion: Spaceflight induced changes in the markers of systemic inflammation, tissue deterioration, and bone resorption in two astronauts after a short, 17-day, which were often consistent with those observed in painful conditions on Earth. However, some differences, such as a consistent decrease in CRP, were noted. All records for the effect of space travel on human health are critical for improving our understanding of the effect of this unique environment on humans.

Augmentation of musculoskeletal soft tissue morphology within low back pain patients may suggest the presence of physiological stress shielding: An in vivo study.

INTRODUCTION: The pathomechanism of low back pain (LBP) remains unknown. However, changes to mechanical properties of soft tissues affected by LBP may indicate the presence of stress shielding, which may manifest via tissue remodeling. This study investigates the potential for physiological stress shielding within the lumbar spine by examining differences within lumbar soft tissue morphology between control and LBP subjects. METHODS: Through MRI, the total and functional cross-sectional area (tCSA, fCSA) and fatty infiltration (FI) of the lumbar multifidus (MF), erector spinae (ES), quadratus lumborum (QL), psoas major (PM), and thoracolumbar fascia (TLF) were measured from the L1/L2 to L5/S1 intervertebral disc levels of 69 subjects (36 LBP and 33 control subjects). Statistical analysis was conducted using Mann-Whitney U. P < 0.05 denoted significance. RESULTS: Comparison of male LBP patients and male healthy controls yielded an increase in tCSA and fCSA within the L4/L5 PM (p < 0.01), and the L4/L5 ES (p = 0.02) and PM (p < 0.01), respectively, of LBP patients. Female LBP patients' FI compared to female controls increased within the L1/L2 MF (p = 0.03), L3/L4 MF (p = 0.04) and ES (p = 0.02), and L4/L5 QL (p = 0.01). The L3/L4 TLF also demonstrated an 8% increase in LBP subjects. CONCLUSION: Male patients' results suggest elevated tissue loading during motion yielding hypertrophy in the L4/L5 ES and PM fCSA, and PM tCSA. Female LBP patients' MF, ES, and PM at L3/L4 demonstrating elevated FI coupled with TLF tCSA hypertrophy may suggest irregular stress distributions and lay the foundation for stress shielding within musculoskeletal soft tissues.

Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs.

BACKGROUND: Low back pain is a global health problem directly related to intervertebral disc (IVD) degeneration. Senolytic drugs (RG-7112 and o-Vanillin) target and remove senescent cells from IVDs in vitro, improving tissue homeostasis. One drawback of using a single senolytic agent is the failure to target multiple senescent antiapoptotic pathways. This study aimed to determine if combining the two senolytic drugs, o-Vanillin and RG-7112, could more efficiently remove senescent cells and reduce the release of inflammatory factors and pain mediators in cells from degenerating human IVDs than either drug alone. METHODS: Preliminary data evaluating multiple concentrations of o-Vanillin and RG-7112 led to the selection of four treatment groups. Monolayer and pellet cultures of cells from painful degenerate IVDs were exposed to TLR-2/6 agonist. They were then treated with the senolytics o-Vanillin and RG7112 alone or combined. p16ink4a, Ki-67, caspase-3, inflammatory mediators, and neuronal sprouting were assessed. RESULTS: Compared to the single treatments, the combination of o-Vanillin and RG-7112 significantly reduced the amount of senescent IVD cells, proinflammatory cytokines, and neurotrophic factors. Moreover, both single and combination treatments significantly reduced neuronal sprouting in rat adrenal pheochromocytoma (PC-12 cells). CONCLUSIONS: Combining o-Vanillin and RG-7112 greatly enhanced the effect of either senolytic alone. Together, these results support the potential of senolytics as a promising treatment for IVD-related low back pain.

Validation of the Critical-Care Pain Observation Tool (CPOT) in pediatric patients undergoing orthopedic surgery.

Background: Postoperative pain cannot be measured accurately among many children with intellectual and developmental disabilities, resulting in underrecognition or delay in recognition of pain. The Critical-Care Pain Observation Tool (CPOT) is a pain assessment tool that has been widely validated in critically ill and postoperative adults. Aims: The objective of this study was to validate the CPOT for use with pediatric patients able to self-report and undergoing posterior spinal fusion surgery. Methods: Twenty-four patients (10-18 years old) scheduled to undergo surgery were consented to this repeated-measure, within-subject study. To examine discriminative and criterion validation, CPOT scores and patients' self-reports of pain intensity were collected prospectively by a bedside rater before, during, and after a nonnociceptive and nociceptive procedure on the day following surgery. Patients' behavioral reactions were video recorded at the bedside and retrospectively viewed by two independent video raters to examine interrater and intrarater reliability of CPOT scores. Results: Discriminative validation was supported with higher CPOT scores during the nociceptive procedure than during the nonnociceptive procedure. Criterion validation was supported with a moderate positive correlation between the CPOT scores and the patients' self-reported pain intensity during the nociceptive procedure. A CPOT cutoff score of ≥2 was associated with the maximum sensitivity (61.3%) and specificity (94.1%). Reliability analyses revealed poor to moderate agreement between bedside and video raters and moderate to excellent consistency within video raters. Conclusions: These findings suggest that the CPOT may be a valid tool to detect pain in pediatric patients in the acute postoperative inpatient care unit after posterior spinal fusion.

Contexte: La douleur postopératoire ne peut pas être mesurée avec précision chez de nombreux enfants atteints de déficience intellectuelle et développementale, entraînant ainsi une méconnaissance ou un retard dans la reconnaissance de la douleur. Le Critical-Care Pain Observation Tool (CPOT) est un outil d'évaluation de la douleur qui a été largement validé chez les adultes gravement malades et postopératoires.Objectifs: L'objectif de cette étude était de valider le CPOT pour une utilisation auprès de patients pédiatriques capables d'autoévaluation et subissant une chirurgie de fusion vertébrale postérieure.Méthodes: Dans le cadre d'une étude intra-sujet, un consentement à cette mesure répétée a été obtenu pour vingt-quatre patients (10­18 ans) devant subir une intervention chirurgicale. Pour examiner la validation discriminante et de critère, les scores CPOT et les autoévaluations des patients concernant l'intensité de la douleur ont été collectés de manière prospective par un évaluateur au chevet du patient avant, pendant et après une procédure non nociceptive et nociceptive le lendemain de la chirurgie. Les réactions comportementales des patients ont été enregistrées sur vidéo au chevet du patient et visionnées rétrospectivement par deux des évaluateurs vidéo indépendants pour examiner la fiabilité des scores CPOT inter-évaluateurs et intra-évaluateurs.Résultats: La validation discriminante a été confirmée par l'obtention de scores plus élevés à l'échelle CPOT pendant la procédure nociceptive que pendant la procédure non nociceptive. La validation de critère a été confirmée par une corrélation positive modérée entre les scores sur l'échelle CPOT et l'intensité de la douleur autoévaluée par les patients pendant la procédure nociceptive. Un score-seuil ≥ 2 sur l'échelle CPOT a été associé à la sensibilité et la spécificité maximales (61,3 % et 94,1 %, respectivement). Les analyses de fiabilité ont révélé une concordance faible à modérée entre les évaluateurs de chevet et les évaluateurs vidéo, et une cocordance modérée à excellente parmi les évaluateurs vidéo.Conclusions: Ces résultats indiquent que le CPOT peut être un outil valide pour détecter la douleur chez les enfants patients de l'unité de soins hospitaliers postopératoires aigus après une fusion rachidienne postérieure.

Examining impact forces during posterior spinal fusion to implement in a novel physics-driven virtual reality surgical simulator.

This study aims to understand the impact forces that surgeons apply to the human spine during a posterior spinal fusion procedure towards the development of a novel spine surgical simulator for training medical residents. The foci of this study are impact forces during graft placement and spinal interbody cage insertion. This study examined the lumbar intervertebral discs of two male cadaveric specimens. Impact forces were collected during graft and spinal cage insertion over multiple levels. An impulse hammer and a camera were used to collect impact forces and displacements, respectively. The results demonstrated a logarithmic relationship between impact forces and cumulative displacement during graft placement. This was also observed between cumulative displacement and number of impacts during spinal cage insertion. A linear relationship was observed for the impact forces and number of impacts during graft placement. Results suggest that surgeons rely on the feedback experienced from impact forces during graft insertion to gauge the amount of graft that was placed in a specific area of the disc. Impact forces during cage insertion provide information about any encountered obstacles. When developing surgical simulators, designing the force feedback system should require modelling these behaviors to effectively impart corresponding skills on a trainee.

Modulating the activity of human nociceptors with a SCN10A promoter-specific viral vector tool.

Despite the high prevalence of chronic pain as a disease in our society, there is a lack of effective treatment options for patients living with this condition. Gene therapies using recombinant AAVs are a direct method to selectively express genes of interest in target cells with the potential of, in the case of nociceptors, reducing neuronal firing in pain conditions. We designed a recombinant AAV vector expressing cargos whose expression was driven by a portion of the SCN10A (NaV1.8) promoter, which is predominantly active in nociceptors. We validated its specificity for nociceptors in mouse and human dorsal root ganglia and showed that it can drive the expression of functional proteins. Our viral vector and promoter package drove the expression of both excitatory or inhibitory DREADDs in primary human DRG cultures and in whole cell electrophysiology experiments, increased or decreased neuronal firing, respectively. Taken together, we present a novel viral tool that drives expression of cargo specifically in human nociceptors. This will allow for future specific studies of human nociceptor properties as well as pave the way for potential future gene therapies for chronic pain.

Breast Hypertrophy: A Real Pain in the Back.

BACKGROUND: Bilateral breast hypertrophy comes with signs and symptoms ranging from mild to debilitating. Bilateral breast reduction (BBR) is one of the most frequently performed plastic surgery procedures, and its effects on parameters such as spinal balance, paraspinal muscle function, and physical performance have not been thoroughly evaluated. The objective of this study was to evaluate the effects of BBR using advanced spine imaging modalities, and pain resolution. METHODS: A prospective, observational, cohort study was carried out at the McGill University Health Centre. The following measures were recorded preoperatively and postoperatively for each patient: patient questionnaires (BREAST-Q and Pain), magnetic resonance imaging, and EOS low-radiation spinal scan. RESULTS: Significant postoperative pain reduction was recorded, and there was up to 148% improvement in physical tests. Improvement in all questionnaire and BREAST-Q categories was documented. Preoperative and postoperative magnetic resonance imaging did demonstrate a statistically significant absence of permanent anatomical skeletal sequelae. Postoperative improvement in thoracic kyphosis was documented. CONCLUSIONS: Quality-of-life scores are uniformly improved following BBR. Key findings following BBR include significant pain reduction and no evidence of spinal skeletal change. This is a finding of major importance in view of the practice of many insurance companies/third-party payer and health care systems that use the Schnur scale. The Schnur scale associates a weight for resection with body size that is not directly predictive of pain relief. This may indicate the need for more precise or different guidelines based on these quantitative findings. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Scoliosis in osteogenesis imperfecta: results of posterior spinal fusion in 39 patients.

PURPOSE: To evaluate the outcomes of scoliosis corrective surgery in Osteogenesis Imperfecta (OI) patients with primarily pedicles screw fixation in terms of correcting and maintaining the correction of the spinal deformity, and to assess for several peri-operative parameters and complications associated with this surgical treatment. METHODS: Retrospective case series of 39 consecutive patients with OI treated surgically for scoliosis. The surgeries were performed between 2002 and 2020 by three different surgeons. All patients' medical peri-operative and post-operative charts were evaluated. Radiological assessment was performed by evaluation of the pre-operative, immediate post-operative and last follow-up plain radiographs. RESULTS: There were 20 females and 19 males included in this review with a mean age of 14 years (range, 6-20 years) at the time of surgery. The median follow-up time was 7.9 years. The mean pre-operative cobb angle (CA) of the major curve was 76.5 degrees (SD ± 18.9), decreasing to 42.6 (SD ± 17.4) in the long-term post-operative follow-up (P < 0.001). A total of 21 adverse events in 16 patients were noted. Only 4 patients required subsequent invasive surgical treatment or prolonged hospital stay. All other patients were treated conservatively with no lasting complication. CONCLUSION: Scoliosis surgical correction in OI patients seems to yield acceptable results, with maintained coronal plane surgical correction in the long-term follow-up. Even though a high peri-operative complications rate is observed in this series, there were no long-term sequelae or lasting complications. LEVEL OF EVIDENCE: Level IV, Case series.

The Psychosocial Characteristics and Somatosensory Function of Children and Adolescents Who Meet the Criteria for Chronic Nociplastic Pain.

Purpose: Nociplastic pain distinguishes individuals with pain and hypersensitivity in body regions with apparently normal tissues, without any signs of neuropathy, but with contribution of central and/or peripheral sensitization. There is a lack of literature describing nociplastic pain in the pediatric population. The objective of this study was to investigate the differences between pediatric patients with nociplastic pain compared with patients with non-nociplastic pain. Patients and Methods: This study included 414 pediatric patients followed at an interdisciplinary centre for complex pain. All patients underwent an exhaustive pain assessment consisting of face-to-face interviews, validated self-report questionnaires and quantitative sensory testing. Recently established criteria for chronic nociplastic pain, and quantitative sensory testing was used to describe and stratify our cohort. Results: One hundred and sixty-five patients (40%) were stratified as having possible nociplastic pain and two hundred and forty-nine (60%) patients, as non-nociplastic pain. Patients with nociplastic pain displayed pain hypersensitivity in the region of pain, more symptoms of panic and social phobia, and worse sleep quality than patients with non-nociplastic pain. The proportion of patients achieving a meaningful clinical outcome after completion of their treatment (medications, physiotherapy, psychology, nursing, social worker, and/or interventional procedures) was lower in patients with nociplastic pain (62%) than those without nociplastic pain (86%). Conclusion: Our results suggest that patients who meet the criteria for nociplastic pain can be identified in a population of children and adolescents being treated in a center for complex pain. Combining screening with validated questionnaires and quantitative sensory testing facilitates the phenotyping and graded severity of patients with nociplastic pain in daily clinical practice.

Association between the Use of Quantitative Sensory Testing and Conditioned Pain Modulation and the Prescription of Medication and Interventional Procedures in Children with Chronic Pain Conditions.

The evidence supporting the use of pharmacological treatments in pediatric chronic pain is limited. Quantitative sensory testing (QST) and conditioned pain modulation evaluation (CPM) provide information on pain phenotype, which may help clinicians to tailor the treatment. This retrospective study aimed to evaluate the association between the use of QST/CPM phenotyping on the selection of the treatment for children with chronic pain conditions. We retrospectively analyzed the medical records of 208 female patients (mean age 15 ± 2 years) enrolled in an outpatient interdisciplinary pediatric complex pain center. Pain phenotype information (QST/CPM) of 106 patients was available to the prescribing physician. The records of 102 age- and sex-matched patients without QST/CPM were used as controls. The primary endpoint was the proportion of medications and interventions prescribed. The secondary endpoint was the duration of treatment. The QST/CPM group received less opioids (7% vs. 28%, respectively, p < 0.001), less anticonvulsants (6% vs. 25%, p < 0.001), and less interventional treatments (29% vs. 44%, p = 0.03) than controls. Patients with an optimal CPM result tended to be prescribed fewer antidepressants (2% vs. 18%, p = 0.01), and patients with signs of allodynia and/or temporal summation tended to be prescribed fewer NSAIDs (57% vs. 78%, p = 0.04). There was no difference in the duration of the treatments between the groups. QST/CPM testing appears to provide more targeted therapeutic options resulting in the overall drop in polypharmacy and reduced use of interventional treatments while remaining at least as effective as the standard of care.

Regional and age-related diversity of human mature oligodendrocytes.

Morphological and emerging molecular studies have provided evidence for heterogeneity within the oligodendrocyte population. To address the regional and age-related heterogeneity of human mature oligodendrocytes (MOLs) we applied single-cell RNA sequencing to cells isolated from cortical/subcortical, subventricular zone brain tissue samples, and thoracolumbar spinal cord samples. Unsupervised clustering of cells identified transcriptionally distinct MOL subpopulations across regions. Spinal cord MOLs, but not microglia, exhibited cell-type-specific upregulation of immune-related markers compared to the other adult regions. SVZ MOLs showed an upregulation of select number of development-linked transcription factors compared to other regions; however, pseudotime trajectory analyses did not identify a global developmental difference. Age-related analysis of cortical/subcortical samples indicated that pediatric MOLs, especially from under age 5, retain higher expression of genes linked to development and to immune activity with pseudotime analysis favoring a distinct developmental stage. Our regional and age-related studies indicate heterogeneity of MOL populations in the human CNS that may reflect developmental and environmental influences.

Single-Cell RNA-Seq Analysis of Cells from Degenerating and Non-Degenerating Intervertebral Discs from the Same Individual Reveals New Biomarkers for Intervertebral Disc Degeneration.

In this study, we used single-cell transcriptomic analysis to identify new specific biomarkers for nucleus pulposus (NP) and inner annulus fibrosis (iAF) cells, and to define cell populations within non-degenerating (nD) and degenerating (D) human intervertebral discs (IVD) of the same individual. Cluster analysis based on differential gene expression delineated 14 cell clusters. Gene expression profiles at single-cell resolution revealed the potential functional differences linked to degeneration, and among NP and iAF subpopulations. GO and KEGG analyses discovered molecular functions, biological processes, and transcription factors linked to cell type and degeneration state. We propose two lists of biomarkers, one as specific cell type, including C2orf40, MGP, MSMP, CD44, EIF1, LGALS1, RGCC, EPYC, HILPDA, ACAN, MT1F, CHI3L1, ID1, ID3 and TMED2. The second list proposes predictive IVD degeneration genes, including MT1G, SPP1, HMGA1, FN1, FBXO2, SPARC, VIM, CTGF, MGST1, TAF1D, CAPS, SPTSSB, S100A1, CHI3L2, PLA2G2A, TNRSF11B, FGFBP2, MGP, SLPI, DCN, MT-ND2, MTCYB, ADIRF, FRZB, CLEC3A, UPP1, S100A2, PRG4, COL2A1, SOD2 and MT2A. Protein and mRNA expression of MGST1, vimentin, SOD2 and SYF2 (p29) genes validated our scRNA-seq findings. Our data provide new insights into disc cells phenotypes and biomarkers of IVD degeneration that could improve diagnostic and therapeutic options.

Phenotyping Chronic Musculoskeletal Pain in Male and Female Adolescents: Psychosocial Profiles, Somatosensory Profiles and Pain Modulatory Profiles.

PURPOSE: A major limitation in treatment outcomes for chronic pain is the heterogeneity of the population. Therefore, a personalized approach to the assessment and treatment of children and adolescents with chronic pain conditions is needed. The objective of the study was to subgroup pediatric patients with chronic MSK pain that will be phenotypically different from each other based on their psychosocial profile, somatosensory function, and pain modulation. PATIENTS AND METHODS: This observational cohort study recruited 302 adolescents (10-18 years) with chronic musculoskeletal pain and 80 age-matched controls. After validated self-report questionnaires on psychosocial factors were completed, quantitative sensory tests (QST) and conditioned pain modulation (CPM) were performed. RESULTS: Three psychosocial subgroups were identified: adaptive pain (n=125), high pain dysfunctional (n=115), high somatic symptoms (n=62). Based on QST, four somatosensory profiles were observed: normal QST (n=155), thermal hyperalgesia (n=98), mechanical hyperalgesia (n=34) and sensory loss (n=15). Based on CPM and temporal summation of pain (TSP), four distinct groups were formed, dysfunctional central processing group (n=27) had suboptimal CPM and present TSP, dysfunctional inhibition group (n=136) had suboptimal CPM and absent TSP, facilitation group (n=18) had optimal CPM and present TSP, and functional central processing (n=112) had optimal CPM and absent TSP. A significant association between the psychosocial and somatosensory profiles. However, no association was observed between the psychosocial or somatosensory profiles and pain modulatory profiles. CONCLUSION: Our results provide evidence that adolescents with chronic musculoskeletal pain are a heterogenous population comprising subgroups that may reflect distinct mechanisms and may benefit from different treatment approaches. The combination of screening self-reported questionnaires, QST, and CPM facilitate subgrouping of adolescents with chronic MSK pain in the clinical context and may ultimately contribute to personalized therapy.

Prevention of postoperative pancreatic fistula after pancreatectomy: results of a Canadian RAND/UCLA appropriateness expert panel.

BACKGROUND: We aimed to define the appropriateness of interventions for the prevention of postoperative pancreatic fistulas (POPF) after pancreatectomy, given the lack of consistent data on this topic. METHODS: Using the RAND/UCLA appropriateness method, we assembled an expert panel to rate clinical scenarios for interventions to prevent POPF after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). RESULTS: The following interventions were rated appropriate: individualized risk prediction for all patients; perioperative pasireotide administration for patients undergoing PD who have a soft pancreatic gland and a pancreatic duct size of less 3 mm and for patients undergoing DP; pancreaticogastrostomy for patients undergoing PD who have a soft pancreatic gland and pancreaticojejunostomy for PD for patients with a pancreatic duct size of 6 mm or greater regardless of pancreatic gland texture; duct-to-mucosa anastomosis for all patients undergoing PD and dunking anastomosis for patients undergoing PD who have a pancreatic duct size of less than 3 mm with a firm pancreatic gland; simple stapled and reinforced stapled transection for all DP; surgical drains for PD and DP in patients with a soft pancreatic gland; and open and minimally invasive surgery for DP and open surgery for PD. The following were rated inappropriate: gastrointestinal anastomosis for stump closure in all DP and omission of surgical drain in PD for patients with a pancreatic duct diameter less than 3 mm and a soft pancreatic gland. CONCLUSION: The expert panel identified appropriate and inappropriate scenarios for POPF prevention following pancreatectomy, to provide guidance to clinicians. However, the appropriateness of the interventions in the majority of the clinical scenarios was rated as uncertain, demonstrating equipoise.

Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain.

Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E (Apoe) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans.

Spine Surgeons Burnout and Quality of Life: Results of a Worldwide Survey.

STUDY DESIGN: Cross-sectional survey study. OBJECTIVE: To evaluate the prevalence of burnout, assess the personal and professional characteristics associated with burnout in spine surgeons and determine their quality of life. SUMMARY OF BACKGROUND DATA: Burnout is a syndrome characterized by emotional exhaustion, depersonalization, and decreased sense of accomplishment that leads to decreased effectiveness at work. To date, there has been a lack of information on the prevalence of burnout among spine surgeons worldwide and the risk factors associated with this condition. METHODS: An electronic survey with members of AO Spine was performed in May 2018. The survey evaluated demographic variables, practice characteristics, burnout, and quality of life. Maslach Burnout Inventory (MBI) and EuroQol 5-dimensions (EQ5D) were used to evaluate burnout and quality of life, respectively. RESULTS: A total of 818 surgeons from 86 countries completed the survey. The prevalence of burnout was 30.6%. In the multiple linear model, emotional fatigue was independently associated with younger age (B = -0.17, CI95% = -0.26 to -0.07, P < 0.0001), and longer working hours per week (B = -2.71, CI95% = -4.34 to -1.07, P = 0.001); depersonalization was independently associated with younger age (B = -0.13, CI95% = -0.19 to -0.07, P < 0.0001), practicing outside Latin America (LA) (B = 0.71, CI95% = 0.41-1.01, P < 0.0001) and currently being a fellow (B = 0.54, CI95% = 0.06-1.02, P = 0.02); and higher scores of personal fulfilment was associated with practicing in LA (B = -1.27, CI95% = -1.69 to -0.85, P < 0.0001). CONCLUSION: Burnout is a common condition among spine surgeons worldwide. There is a significant association between burnout scores and decreased general quality of life. These results highlight the need to develop interventional programs to better identify, prevent, and manage this condition among practicing spine surgeons.Level of Evidence: 4.

Liver-First Approach for Synchronous Colorectal Metastases: Analysis of 7360 Patients from the LiverMetSurvey Registry.

BACKGROUND: The liver-first approach in patients with synchronous colorectal liver metastases (CRLM) has gained wide consensus but its role is still to be clarified. We aimed to elucidate the outcome of the liver-first approach and to identify patients who benefit at most from this approach. METHODS: Patients with synchronous CRLM included in the LiverMetSurvey registry between 2000 and 2017 were considered. Three strategies were analyzed, i.e. liver-first approach, colorectal resection followed by liver resection (primary-first), and simultaneous resection, and three groups of patients were analyzed, i.e. solitary metastasis, multiple unilobar CRLM, and multiple bilobar CRLM. In each group, patients from the three strategy groups were matched by propensity score analysis. RESULTS: Overall, 7360 patients were analyzed: 4415 primary-first, 552 liver-first, and 2393 simultaneous resections. Compared with the other groups, the liver-first group had more rectal tumors (58.0% vs. 31.2%) and higher hepatic tumor burden (more than three CRLMs: 34.8% vs. 24.0%; size > 50 mm: 35.6% vs. 22.8%; p < 0.001). In patients with solitary and multiple unilobar CRLM, survival was similar regardless of treatment strategy, whereas in patients with multiple bilobar metastases, the liver-first approach was an independent positive prognostic factor, both in unmatched patients (3-year survival 65.9% vs. primary-first 60.4%: hazard ratio [HR] 1.321, p = 0.031; vs. simultaneous resections 54.4%: HR 1.624, p < 0.001) and after propensity score matching (vs. primary-first: HR 1.667, p = 0.017; vs. simultaneous resections: HR 2.278, p = 0.003). CONCLUSION: In patients with synchronous CRLM, the surgical strategy should be decided according to the hepatic tumor burden. In the presence of multiple bilobar CRLM, the liver-first approach is associated with longer survival than the alternative approaches and should be evaluated as standard.

A roadmap to surgery in osteogenesis imperfecta: results of an international collaboration of patient organizations and interdisciplinary care teams.

Background and purpose - Involvement of patient organizations is steadily increasing in guidelines for treatment of various diseases and conditions for better care from the patient's viewpoint and better comparability of outcomes. For this reason, the Osteogenesis Imperfecta Federation Europe and the Care4BrittleBones Foundation convened an interdisciplinary task force of 3 members from patient organizations and 12 healthcare professionals from recognized centers for interdisciplinary care for children and adults with osteogenesis imperfecta (OI) to develop guidelines for a basic roadmap to surgery in OI.Methods - All information from 9 telephone conferences, expert consultations, and face-to-face meetings during the International Conference for Quality of Life for Osteogenesis Imperfecta 2019 was used by the task force to define themes and associated recommendations.Results - Consensus on recommendations was reached within 4 themes: the interdisciplinary approach, the surgical decision-making conversation, surgical technique guidelines for OI, and the feedback loop after surgery.Interpretation - The basic guidelines of this roadmap for the interdisciplinary approach to surgical care in children and adults with OI is expected to improve standardization of clinical practice and comparability of outcomes across treatment centers.

Toll-like receptor 2 induced senescence in intervertebral disc cells of patients with back pain can be attenuated by o-vanillin.

BACKGROUND: There is an increased level of senescent cells and toll-like teceptor-1, -2, -4, and -6 (TLR) expression in degenerating intervertebral discs (IVDs) from back pain patients. However, it is currently not known if the increase in expression of TLRs is related to the senescent cells or if it is a more general increase on all cells. It is also not known if TLR activation in IVD cells will induce cell senescence. METHODS: Cells from non-degenerate human IVD were obtained from spine donors and cells from degenerate IVDs came from patients undergoing surgery for low back pain. Gene expression of TLR-1,2,4,6, senescence and senescence-associated secretory phenotype (SASP) markers was evaluated by RT-qPCR in isolated cells. Matrix synthesis was verified with safranin-O staining and Dimethyl-Methylene Blue Assay (DMMB) confirmed proteoglycan content. Protein expression of p16INK4a, SASP factors, and TLR-2 was evaluated by immunocytochemistry (ICC) and/or by enzyme-linked immunosorbent assay (ELISA). RESULTS: An increase in senescent cells was found following 48-h induction with a TLR-2/6 agonist in cells from both non-degenerate and degenerating human IVDs. Higher levels of SASP factors, TLR-2 gene expression, and protein expression were found following 48-h induction with TLR-2/6 agonist. Treatment with o-vanillin reduced the number of senescent cells, and increased matrix synthesis in IVD cells from back pain patients. Treatment with o-vanillin after induction with TLR-2/6 agonist reduced gene and protein expression of SASP factors and TLR-2. Co-localized staining of p16INK4a and TLR-2 demonstrated that senescent cells have a high TLR-2 expression. CONCLUSIONS: Taken together our data demonstrate that activation of TLR-2/6 induce senescence and increase TLR-2 and SASP expression in cells from non-degenerate IVDs of organ donors without degeneration and back pain and in cells from degenerating human IVD of patients with disc degeneration and back pain. The senescent cells showed high TLR-2 expression suggesting a link between TLR activation and cell senescence in human IVD cells. The reduction in senescence, SASP, and TLR-2 expression suggest o-vanillin as a potential disease-modifying drug for patients with disc degeneration and back pain.

Risk of early complication following anterior vertebral body tethering for idiopathic scoliosis.

PURPOSE: The purpose of this study was to determine peri-operative morbidity associated with anterior vertebral body tethering (aVBT) for idiopathic scoliosis. METHOD: Of 175 patients treated with aVBT, 120 patients had 2 year follow up and were included in this study. Prospectively collected clinical and radiographic data was analyzed retrospectively. RESULTS: Pre-operatively, the mean patient age was 12.6 year (8.2-15.7 year), Risser 0-3, with main thoracic scoliosis 51.2° (40-70°). Immediately post-operative, scoliosis improved to 26.9° (6-53°; p < 0.05), at 1-year post-operative was 23.0° (- 11 to 50°; p < 0.01 vs immediate post-op) and at 2-year post-operative was 27.5° (- 5 to 52; p = 0.64 vs immediate post-op). Pre-operative T5-T12 kyphosis was 16.0° (- 23 to 52°), post-operative was 16.9° (- 7 to 44°), at 1-year was 17.5° (- 14 to 61°) and at 2-year was 17.0° (- 10 to 50°; p = 0.72 vs pre-op). All patients underwent thoracoscopic approach, EBL 200 ml (20-900 ml), surgical time 215.3 min (111-472 min), anesthesia time 303.5 min (207-480 min), ICU stay of 0.2 day (0-2 days), and post-operative hospital stay 4.5 days (2-9 days). During the in-hospital peri-operative period, there were no unplanned return to the operating room (UPROR) and there was a 0.8% rate of complication: one pneumothorax requiring reinsertion of chest tube. By 90 days post-operative, there was no UPROR and a 5% rate of complication. Five additional patients developed complications after discharge: one CSF leak treated with blood patch injection in the clinic and resolved, two pleural effusions requiring chest tubes, one superficial wound infection and one pneumonia treated with outpatient antibiotics. By 1-year post-op, there was a 1.7% rate of UPROR and 8.3% rate of complication. Four additional patients developed complications beyond 90 days: two upper limb paresthesia required outpatient medical management, one CSF leak which initially treated blood patch injection in the clinic initially which then required UPROR, and one compensatory lumbar curve add on that was treated with extension of the tether. By 2-years post-op, there was a 6.7% rate of UPROR and 15.8% rate of complication. 9 additional complications developed after 1 year. One curve progression, one keloid scar, one right leg weakness, 4 cable failures and 2 curve overcorrections. CONCLUSION: This large, multicenter series of aVBT demonstrated a 15.8% complication rate and a 6.7% UPROR rate at 2 year post-operatively. This early study during the learning curve of aVBT found higher rates of CSF leaks and overall complications than would be expected for PSFI at 1 year post-operatively and a higher rate of overall complications and of UPROR than would be expected for PSFI at 2 year post-operatively. As is common with new procedures, the complication rate may fall with further experience.