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Selective fusion of thoracic and thoracolumbar/lumbar curves in adolescent idiopathic scoliosis is a concept critically debated in the literature. While some surgeons strongly believe that a more rigid and straighter spine provides predictably excellent outcomes, some surgeons recommend a mobile and less straight spine. This topic is a crucial part of surgical treatment of idiopathic scoliosis, particularly in young patients who will deal with the stress of the fusion mass at the proximal and distal junctions over many years. This study will review the literature on various aspects of selective fusion. [ABSTRACT FROM AUTHOR]

Background Current research is limited in exploring the impact of social determinants of health (SDOH) on the discharge location within elective spine surgery. Further understanding of the influence of SDOH on disposition is necessary to improve outcomes. This study explores how SDOH influence discharge disposition for patients undergoing one- or two-level posterior interbody fusion (TLIF/PLIF). Methods This was a retrospective propensity-matched cohort study . Patients who underwent TLIF/PLIF between 2017 and 2020 at a single academic medical center were identified. The chart review gathered demographics, perioperative characteristics, intra/post-operative complications, discharge disposition, and 90-day outcomes. Discharge dispositions included subacute nursing facility (SNF), home with self-care (HSC), home with health services (HHS), and acute rehab facility (ARF). Demographic, perioperative, and disposition outcomes were analyzed by chi-square analysis and one-way ANOVA based on gender, race, and income quartiles. Results Propensity score matching for significant demographic factors isolated 326 patients. The rate of discharge to SNF was higher in females compared to males (25.00% vs 10.56%; p=0.001). Men were discharged to home at a higher rate than women (75.4% vs 61.95%; p=0.010). LatinX patients had the highest rate of home discharge, followed by Asians, Caucasians, and African Americans (83.33% vs 70.31% vs 66.45% vs 65.90%; p<0.001). The post hoc Tukey test demonstrated statistically significant differences between Asians and all other races in the context of age and BMI. Additionally, patients discharged to SNF showed the highest Charlson comorbidity index (CCI) score, followed by those at ARF, HHS, and HSC (4.36 vs 4.05 vs 2.87 vs 2.37; p<0.001). The estimated median income for the cohort ranged from $52,000 to $250,001, with no significant differences in income seen across comparisons. Conclusion Discharge disposition following one- or two-level TLIF/PLIF shows significant association with gender and race. No association was seen when comparing discharge rates among zip code-level median income quartiles., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Zabat et al.)

Study Design: Single-center retrospective cohort study., Objectives: To evaluate inpatient MME administration associated with different lumbar spinal fusion surgeries., Methods: Patients ≥18 years of age with a diagnosis of Grade I or II spondylolisthesis, stenosis, degenerative disc disease or pars defect who underwent one-level Transforaminal Lumbar Interbody Fusion (TLIF) or one-level Anterior Lumbar Interbody Fusion (ALIF) or Lateral Lumbar Interbody Fusion (LLIF) through traditional MIS, anterior-posterior position or single position approaches between L2-S1. Outcome measures included patient demographics, surgical procedure and approach, perioperative clinical characteristics, incidence of ileus and inpatient MME. Statistical analysis included one-way ANOVA with a post-hoc Tukey Test and Kruskal-Wallis Test with post-hoc Mann-Whitney test. MME was calculated as per the Centers for Medicare and Medicaid Services and previous literature. Significance set at P < .05., Results: Mean age differed significantly between MIS TLIF (55.6 ± 12.5 years) and all other groups (Open TLIF 57.1 ± 12.5, SP ALIF/LLIF 57.9 ± 9.9, TP ALIF/LLIF 50.9 ± 12.7, Open ALIF/LLIF 58.4 ± 15.5). MIS TLIF had the shortest LOS compared to all groups except SP ALIF/LLIF. Total MME was significantly different between MIS TLIF and Open ALIF/LLIF (172.5 MME vs 261.1 MME, P = .044) as well as MIS TLIF and TP ALIF/LLIF (172.5 MME vs 245.4 MME, P = .009). There were no significant differences in MME/hour and incidence of ileus between all groups., Conclusion: Patients undergoing MIS TLIF had lower inpatient opioid intake compared to TP and SP ALIF/LLIF, as well as shorter LOS compared to all groups except SP ALIF/LLIF. Thus, it appears that the advantages of minimally invasive surgery are seen in minimally invasive TLIFs.

The human gut microbiota produces dozens of small molecules that circulate in blood, accumulate to comparable levels as pharmaceutical drugs, and influence host physiology. Despite the importance of these metabolites to human health and disease, the origin of most microbially-produced molecules and their fate in the host remains largely unknown. Here, we uncover a host-microbe co-metabolic pathway for generation of hippuric acid, one of the most abundant organic acids in mammalian urine. Combining stable isotope tracing with bacterial and host genetics, we demonstrate reduction of phenylalanine to phenylpropionic acid by gut bacteria; the host re-oxidizes phenylpropionic acid involving medium-chain acyl-CoA dehydrogenase (MCAD). Generation of germ-free male and female MCAD -/- mice enabled gnotobiotic colonization combined with untargeted metabolomics to identify additional microbial metabolites processed by MCAD in host circulation. Our findings uncover a host-microbe pathway for the abundant, non-toxic phenylalanine metabolite hippurate and identify β-oxidation via MCAD as a novel mechanism by which mammals metabolize microbiota-derived metabolites., (© 2023. The Author(s).)

Gut microorganisms modulate host phenotypes and are associated with numerous health effects in humans, ranging from host responses to cancer immunotherapy to metabolic disease and obesity. However, difficulty in accurate and high-throughput functional analysis of human gut microorganisms has hindered efforts to define mechanistic connections between individual microbial strains and host phenotypes. One key way in which the gut microbiome influences host physiology is through the production of small molecules 1-3 , yet progress in elucidating this chemical interplay has been hindered by limited tools calibrated to detect the products of anaerobic biochemistry in the gut. Here we construct a microbiome-focused, integrated mass-spectrometry pipeline to accelerate the identification of microbiota-dependent metabolites in diverse sample types. We report the metabolic profiles of 178 gut microorganism strains using our library of 833 metabolites. Using this metabolomics resource, we establish deviations in the relationships between phylogeny and metabolism, use machine learning to discover a previously undescribed type of metabolism in Bacteroides, and reveal candidate biochemical pathways using comparative genomics. Microbiota-dependent metabolites can be detected in diverse biological fluids from gnotobiotic and conventionally colonized mice and traced back to the corresponding metabolomic profiles of cultured bacteria. Collectively, our microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for characterizing microorganisms and interactions between microorganisms and their host., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of L-Glu or L-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous L-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport L-Gln.

Study Design: This was a single-center retrospective review., Objectives: To explore how age and gender affect PROMIS scores compared with traditional health-related quality of life (HRQL) in spine patients., Methods: Patients presenting with a primary complaint of back pain (BP) or neck pain (NP) were included. Legacy HRQLs were Oswestry Disability Index (ODI), Neck Disability Index (NDI), and Visual Analogue Scale (VAS). PROMIS Physical Function (PF), Pain Intensity (Int), and Pain Interference (Inf) were also administered to patients in a clinical setting. Patients were grouped by chief complaint, age (18-44, 45-64, 65+ years) and gender. Two parallel analyses were conducted to identify the effects of age and gender on patient-reported outcomes. Age groups were compared after propensity-score matching by VAS-pain and gender. Separately, genders were compared after propensity-score matching by age and VAS-pain., Results: A total of 484 BP and 128 NP patients were matched into gender cohorts (n = 201 in each BP group, 46 in each NP group). Among BP patients, female patients demonstrated worse disability by ODI (44.15 vs 38.45, P = .005); PROMIS-PF did not differ by gender. Among NP patients, neither legacy HRQLs nor PROMIS differed by gender when controlling for NP and age. BP and NP patients were matched into age cohorts (n = 135 in each BP group and n = 14 in each BP group). Among BP patients, ANOVA revealed differences between groups when controlling for BP and gender: ODI ( P < .001), PROMIS-PF ( P = .018), PROMIS-Int ( P < .001) PROMIS-Inf ( P < .001). Among NP patients, matched age groups differed significantly in terms of NDI ( P = .032) and PROMIS-PF ( P = .022) but not PROMIS-Int or PROMIS-Inf., Conclusions: Age and gender confound traditional HRQLs as well as PROMIS domains. However, PROMIS offers age and gender-specific scores, which traditional HRQLs lack.

Background: As the opioid crisis has gained national attention, there have been increasing efforts to decrease opioid usage. Simultaneously, patient satisfaction has been a crucial metric in the American health care system and has been closely linked to effective pain management in surgical patients. The purpose of this study was to examine rates of pain medication prescription and concurrent patient satisfaction in spine surgery patients., Methods: A total of 1729 patients undergoing spine surgery between June 25, 2017, and June 30, 2018, at a single institution by surgeons performing ≥20 surgeries per quarter, with medication data during hospitalization available, were assessed. Patients were evaluated for nonopioid pain medication prescription rates and morphine milligram equivalents (MME) of opioids used during hospitalization. Of the total cohort, 198 patients were evaluated for Press Ganey Satisfaction Survey responses. A χ 2 test of independence was used to compare percentages, and 1-way analysis of variance was used to compare means across quarters., Results: The mean total MME per patient hospitalization was 574.46, with no difference between quarters. However, mean MME per day decreased over time ( P = .048), with highest mean 91.84 in Quarter 2 and lowest 77.50 in Quarter 4. Among all procedures, acetaminophen, nonsteroidal anti-inflammatory drugs, and steroid prescription rates increased, whereas benzodiazepine and γ-aminobutyric acid-analog prescriptions decreased. There were no significant differences between quarters for mean hospital ratings ( P = .521) nor for responses to questions from the Press Ganey Satisfaction Survey regarding how often staff talk about pain ( P = .164), how often staff talk about pain treatment ( P = .595), or whether patients recommended the hospital ( P = .096). There were also no differences between quarters for responses in all other patient satisfaction questions ( P value range, .359-.988)., Conclusions: Over the studied time period, opioid use decreased and nonopioid prescriptions increased during hospitalization, whereas satisfaction scores remained unchanged. These findings indicate an increasing effort in reducing opioid use among providers and suggest the ability to do so without affecting overall satisfaction rates., Level of Evidence: 4., Clinical Relevance: The opioid epidemic has highlighted the need to reduce opioid usage in orthopedic spine surgery. This study reviews the trends for inpatient management of post-op pain in orthopedic spine surgery patients in relation to patient satisfaction. There was a significant increase in non-opioid analgesic pain medications, and a reduction in opioids during the study period. During this time, patient satisfaction as measured by Press-Ganey surveys did not show a decrease. This demonstrates that treatment of post-operative pain in orthopedic spine surgery patients can be managed with less opioids, more multimodal analgesia, and patient satisfaction will not be affected., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2020 ISASS.)

Background: Bone morphogenetic protein (BMP) and allograft containing mesenchymal stem cells (live cell) are popular biologic substitutes for iliac crest autograft used in transforaminal lumbar interbody fusion (TLIF). Use of these agents in the pathogenesis of postoperative radiculitis remains controversial. Recent studies have independently linked minimally invasive (MIS) TLIF with increased radiculitis risk compared to open TLIF. The purpose of this study was to assess the rate of postoperative radiculitis in open and MIS TLIF patients along with its relationship to concurrent biologic adjuvant use., Methods: Patients ≥18 years undergoing single-level TLIF from June 2012 to December 2018 with minimum 1-year follow-up were included. Outcome measures were rate of radiculitis, intra- and postoperative complications, revision surgery; length of stay (LOS), and estimated blood loss (EBL)., Results: There were 397 patients: 223 with open TLIFs, 174 with MIS TLIFs. One hundred and fifty-nine surgeries used bone morphogenetic protein (BMP), 26 live cell, 212 neither. Open TLIF: higher mean EBL, LOS, and Charlson Comorbidity Index (CCI) than MIS. Postoperative radiculitis in 37 patients (9.32% overall): 16 cases MIS BMP (15.69% of their cohort), 6 MIS without BMP (8.33%), 5 open BMP (8.77%), 10 open without BMP (6.02%). MIS TLIF versus open TLIF: no differences in 1-year reoperation rates, infection/wound complication, pseudarthrosis, or postoperative complication rate. BMP versus non-BMP: no differences in reoperation rates, infection/wound complication, pseudarthrosis, or postoperative complication rate. Multivariate logistic regression found that neither BMP ( P = .109) nor MIS ( P = .314) was an independent predictor for postoperative radiculitis when controlled for age, gender, body mass index, and CCI. Using paired open and MIS groups (N = 168 each) with propensity score matching, these variables were still not independently associated with radiculitis ( P = .174 BMP, P = .398 MIS). However, the combination of MIS with BMP was associated with increased radiculitis risk in both the entire patient cohort (odds ratio [OR]: 2.259 [1.117-4.569], P = .023, N = 397) and PSM cohorts (OR: 2.196 [1.045-4.616], P = .038, N = 336) compared to other combinations of surgical approach and biologic use., Conclusion: Neither the MIS approach nor BMP use is an independent risk factor for post-TLIF radiculitis. However, risk of radiculitis significantly increases when they are used in tandem. This should be considered when selecting biological adjuvants for MIS TLIF., Level of Evidence: 3., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2020 ISASS.)

N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains unknown. Using quantitative proteomics, here we show that PM20D1 circulates in tight association with both low- and high-density lipoproteins. Lipoprotein particles are powerful co-activators of PM20D1 activity in vitro and N-acyl amino acid biosynthesis in vivo. We also identify serum albumin as a physiologic N-acyl amino acid carrier, which spatially segregates N-acyl amino acids away from their sites of production, confers resistance to hydrolytic degradation, and establishes an equilibrium between thermogenic "free" versus inactive "bound" fractions. These data establish lipoprotein particles as principal extracellular sites of N-acyl amino acid biosynthesis and identify a lipoprotein-albumin network that regulates the activity of a circulating thermogenic lipid family., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Study Design: Retrospective cohort study of prospective patients undergoing minimally invasive lumbar fusion at a single academic institution., Objective: To assess differences in perioperative outcomes between primary and revision MIS (minimally invasive surgical) lumbar interbody fusion patients and compare with those undergoing corresponding open procedures., Methods: Patients ≥18 years old undergoing lumbar interbody fusion were grouped by surgical technique: MIS or open. Patients within each group were propensity score matched for comorbidities and levels fused. Patient demographics, surgical factors, and perioperative complication incidences were compared between primary and revision cases using means comparison tests, as appropriate., Results: Of the 214 lumbar interbody fusion patients included after propensity score matching, 44 (21%) cases were MIS, and 170 (79%) were open. For MIS patients, there were no significant differences between primary and revision cases in estimated blood loss (EBL; 344 vs 299 cm 3 , P = .682); however, primary cases had longer operative times (301 vs 246 minutes, P = .029). There were no differences in length of stay (LOS), intensive care unit LOS, readmission, and intraoperative or postoperative complications (all P > .05). For open patients, there were no differences between primary and revision cases in EBL ( P > .05), although revisions had longer operative times (331 vs 278 minutes, P = .018) and more postoperative complications (61.7% vs 23.8%, P < .001). MIS revision procedures were shorter than open revisions (182 vs 213 minutes, P = .197) with significantly less EBL (294 vs 965 cm 3 , P < .001), shorter inpatient and intensive care unit LOS, and fewer postoperative complications (all P < .05)., Conclusions: Clinical outcomes of revision MIS lumbar interbody fusion were similar to those of primary surgery. Additionally, MIS techniques were associated with less EBL, shorter LOS, and fewer perioperative complications than corresponding open revisions.

Genome-wide analysis of the mode of action of GSK983, a potent antiviral agent, led to the identification of dihydroorotate dehydrogenase as its target along with the discovery that genetic knockdown of pyrimidine salvage sensitized cells to GSK983. Because GSK983 is an ineffective antiviral in the presence of physiological uridine concentrations, we explored combining GSK983 with pyrimidine salvage inhibitors. We synthesized and evaluated analogs of cyclopentenyl uracil (CPU), an inhibitor of uridine salvage. We found that CPU was converted into its triphosphate in cells. When combined with GSK983, CPU resulted in large drops in cellular UTP and CTP pools. Consequently, CPU-GSK983 suppressed dengue virus replication in the presence of physiological concentrations of uridine. In addition, the CPU-GSK983 combination markedly enhanced the effect of RNA-dependent RNA polymerase (RdRp) inhibition on viral infection. Our findings highlight a new host-targeting strategy for potentiating the antiviral activity of RdRp inhibitors., Competing Interests: Declaration of Interests A patent has been filed on this work by the Stanford University Office of Technology Licensing on behalf of Q.L, A.G, and C.K. with reference label S19-283. M.S. is a paid consultant for Riboscience LLD and Advisory Board Member for Tranquis Therapeutics and Angarus Therapeutics. The other authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Study Design: Retrospective review of single institution., Objective: To assess the relationship between Patient-Reported Outcomes Measurement Information System (PROMIS) and Oswestry Disability Index (ODI) scores in thoracolumbar patients., Methods: Included: Patients ≥18 years with a thoracolumbar spine condition (spinal stenosis, disc herniation, low back pain, disc degeneration, spondylolysis). Bivariate correlations assessed the linear relationships between ODI and PROMIS (Physical Function, Pain Intensity, and Pain Interference). Correlation cutoffs assessed patients with high and low correlation between ODI and PROMIS. Linear regression predicted the relationship of ODI to PROMIS., Results: A total of 206 patients (age 53.7 ± 16.6 years, 49.5% female) were included. ODI correlated with PROMIS Physical Function ( r = -0.763, P < .001), Pain Interference ( r = 0.800, P < .001), and Pain Intensity ( r = 0.706, P < .001). ODI strongly predicted PROMIS for Physical Function ( R 2 = 0.58, P < .001), Pain Intensity ( R 2 = 0.50, P < .001), and Pain Interference ( R 2 = 0.64, P < .001); however, there is variability in PROMIS that ODI cannot account for. ODI questions about sitting and sleeping were weakly correlated across the 3 PROMIS domains. Linear regression showed overall ODI score as accounting for 58.3% ( R 2 = 0.583) of the variance in PROMIS Physical Function, 63.9% ( R 2 = 0.639) of the variance in Pain Interference score, and 49.9% ( R 2 = 0.499) of the variance in Pain Intensity score., Conclusions: There is a large amount of variability with PROMIS that cannot be accounted for with ODI. ODI questions regarding walking, social life, and lifting ability correlate strongly with PROMIS while sitting, standing, and sleeping do not. These results reinforce the utility of PROMIS as a valid assessment for low back disability, while indicating the need for further evaluation of the factors responsible for variation between PROMIS and ODI., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Peter G. Passias consults for Medicrea and SpineWave; is on the Scientific Advisory Board of Allosource; receives teaching/speaking from Zimmer Biomet and Globus; receives grant from CSRS; does a research study for Aesculap., (© The Author(s) 2019.)

The N-acyl amino acids are a family of bioactive lipids with pleiotropic physiologic functions, including in energy homeostasis. Their endogenous levels are regulated by an extracellular mammalian N-acyl amino acid synthase/hydrolase called PM20D1 (peptidase M20 domain containing 1). Using an activity-guided biochemical approach, we report the molecular identification of fatty acid amide hydrolase (FAAH) as a second intracellular N-acyl amino acid synthase/hydrolase. In vitro, FAAH exhibits a more restricted substrate scope compared to PM20D1. In mice, genetic ablation or selective pharmacological inhibition of FAAH bidirectionally dysregulates intracellular, but not circulating, N-acyl amino acids. Dual blockade of both PM20D1 and FAAH reveals a dramatic and non-additive biochemical engagement of these two enzymatic pathways. These data establish FAAH as a second intracellular pathway for N-acyl amino acid metabolism and underscore enzymatic division of labor as an enabling strategy for the regulation of a structurally diverse bioactive lipid family., Competing Interests: JK, ST, VL, WW, CF, JL No competing interests declared, (© 2020, Kim et al.)

Background: Hospital-acquired venous thromboembolisms (HA-VTE) are a significant source of morbidity and mortality in spine surgery patients. The purpose of this study was to review HA-VTE rates at our institution and evaluate the prevalence of known risk factors in patients who developed HA-VTE among both neurosurgical and orthopedic spine surgeries., Methods: Retrospective chart reviews were conducted of all spine surgery patients from January 1, 2013, to July 31, 2017, to evaluate rates of HA-VTE and prevalence of known HA-VTE risk factors among these patients. Univariate and multivariate logistic regression analysis for categorical variables and independent Student t test for continuous variables were utilized with significance set at P  < .05., Results: The overall HA-VTE rate was 0.94% (0.61% orthopedic, 1.87% neurosurgery). Patients with VTEs had higher rates of thoracic procedure ( P  = .002), posterior approach ( P  = .001), diagnosis of fracture ( P  = .013) or flatback syndrome ( P  = .028), neurosurgery division ( P  < .001), and diagnosis-related group (DRG) of noncervical malignancy ( P  = .001). Patients with VTEs had lower rates of cervical procedure ( P  < .001), diagnosis of herniated nucleus pulposus ( P  = .006) and degenerative disc disease ( P  = .001), and DRG of cervical spine fusion ( P  < .001). In the patients who sustained VTE, the neurosurgical patients had higher rates of active cancer (22.86% vs 0%, P  = .004) and age >60 (80% vs 50%, P  < .001), and orthopedic patients had higher estimated blood loss (EBL) (2436 ml vs 1176 mL, P  = .006) and rates of anterior-posterior surgery (22.58% vs 0%, P  = .003). Neurosurgery department, diagnosis of fracture, and DRG of noncervical malignancy were found to be significant independent risks for developing HA-VTE. Cervical procedures were independently associated with significantly lower risk. Postoperative anticoagulation initiated sooner in neurosurgery patients (postoperative day 1.26 vs 3.19, P  < .001)., Conclusions: The overall HA-VTE rate at our institution was 0.94% (0.61% orthopedic, 1.87% neurosurgery). In patients who sustained VTE, neurosurgical patients had higher rates of active cancer and age >60 years, and orthopedic patients had higher EBL and rates of anterior-posterior surgery. This highlights the different patient populations between the 2 departments and the need for individualized thromboprophylaxis regimens., Level of Evidence: 4., Competing Interests: Disclosures and COI: Each institution obtained approval from its local institutional review board to enroll patients in the prospective database, and informed consent was obtained from each patient., (©International Society for the Advancement of Spine Surgery 2020.)

Consumption of glucosinolates, pro-drug-like metabolites abundant in Brassica vegetables, has been associated with decreased risk of certain cancers. Gut microbiota have the ability to metabolize glucosinolates, generating chemopreventive isothiocyanates. Here, we identify a genetic and biochemical basis for activation of glucosinolates to isothiocyanates by Bacteroides thetaiotaomicron, a prominent gut commensal species. Using a genome-wide transposon insertion screen, we identified an operon required for glucosinolate metabolism in B. thetaiotaomicron. Expression of BT2159-BT2156 in a non-metabolizing relative, Bacteroides fragilis, resulted in gain of glucosinolate metabolism. We show that isothiocyanate formation requires the action of BT2158 and either BT2156 or BT2157 in vitro. Monocolonization of mice with mutant BtΔ2157 showed reduced isothiocyanate production in the gastrointestinal tract. These data provide insight into the mechanisms by which a common gut bacterium processes an important dietary nutrient., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Study Design: Retrospective cohort study., Objective: To investigate radiological differences in lumbar disc herniations (herniated nucleus pulposus [HNP]) between patients receiving microscopic lumbar discectomy (MLD) and nonoperative patients., Methods: Patients with primary treatment for an HNP at a single academic institution between November 2012 to March 2017 were divided into MLD and nonoperative treatment groups. Using magnetic resonance imaging (MRI), axial HNP area; axial canal area; HNP canal compromise; HNP cephalad/caudal migration and HNP MRI signal (black, gray, or mixed) were measured. T test and chi-square analyses compared differences in the groups, binary logistic regression analysis determined odds ratios (ORs), and decision tree analysis compared the cutoff values for risk factors., Results: A total of 285 patients (78 MLD, 207 nonoperative) were included. Risk factors for MLD treatment included larger axial HNP area ( P < .01, OR = 1.01), caudal migration, and migration magnitude ( P < .05, OR = 1.90; P < .01, OR = 1.14), and gray HNP MRI signal ( P < .01, OR = 5.42). Cutoff values for risks included axial HNP area (70.52 mm 2 , OR = 2.66, P < .01), HNP canal compromise (20.0%, OR = 3.29, P < .01), and cephalad/caudal migration (6.8 mm, OR = 2.43, P < .01). MLD risk for those with gray HNP MRI signal (67.6% alone) increased when combined with axial HNP area >70.52 mm 2 (75.5%, P = .01) and HNP canal compromise >20.0% (71.1%, P = .05) cutoffs. MLD risk in patients with cephalad/caudal migration >6.8 mm (40.5% alone) increased when combined with axial HNP area and HNP canal compromise (52.4%, 50%; P < .01)., Conclusion: Patients who underwent MLD treatment had significantly different axial HNP area, frequency of caudal migration, magnitude of cephalad/caudal migration, and disc herniation MRI signal compared to patients with nonoperative treatment., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

In response to biotic stress, plants produce suites of highly modified fatty acids that bear unusual chemical functionalities. Despite their chemical complexity and proposed roles in pathogen defense, little is known about the biosynthesis of decorated fatty acids in plants. Falcarindiol is a prototypical acetylenic lipid present in carrot, tomato, and celery that inhibits growth of fungi and human cancer cell lines. Using a combination of untargeted metabolomics and RNA sequencing, we discovered a biosynthetic gene cluster in tomato (Solanum lycopersicum) required for falcarindiol production. By reconstituting initial biosynthetic steps in a heterologous host and generating transgenic pathway mutants in tomato, we demonstrate a direct role of the cluster in falcarindiol biosynthesis and resistance to fungal and bacterial pathogens in tomato leaves. This work reveals a mechanism by which plants sculpt their lipid pool in response to pathogens and provides critical insight into the complex biochemistry of alkynyl lipid production., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Physiotherapeutic scoliosis-specific exercise (PSSE) has proven to be an important treatment for patients with adolescent idiopathic scoliosis. However, there is a lack of understanding of the role of PSSE in older adults with spinal deformity., Methods: An electronic, 14-question survey with questions regarding the use of physical therapy (PT) and PSSE for adult spinal deformity was administered to all Scoliosis Research Society members. Physician location, age, specialty, years in experience, and management preferences were quantified using descriptive analyses., Results: Of the 98 surgeons who participated in this study, the majority of respondents were from North America (71.1%), and the mean age was 51.87 ± 10.93 years; approximately 98% of respondents were orthopedic surgeons, and 48.0% had been in practice for more than 21 years. Sixty-four percent reported they prescribed PT in their practice, with 52% of respondents often using PT as nonoperative treatment; 21.4%, preoperative; and 40.8% postoperative. The primary reason for PT referral was persistent pain (40.3%), followed by impairments to the patient's balance or gait (34.3%) and difficulty with daily living activities (25.4%). The primary indications for not referring postoperative patients to PT were lack of perceived value from PT (50%), lack of evidence supporting the benefits from PT (31.3%), and a lack of physical therapists appropriately trained for scoliosis (18.8%). Of the respondents, 74% were familiar with PSSE and 66% were comfortable prescribing PSSE postoperatively. In addition, 28% of respondents agreed that >12 weeks postoperation was the ideal time for PSSE referral, followed by 6 to 8 weeks postoperation (26.2%) and immediately postoperation (18%)., Conclusions: The results show that the majority of respondents prescribed PSSE solely for nonoperative treatment. Respondents who did not prescribe PSSE reported skepticism due to a lack of perceived value. This suggests the need for further research into the benefits of PSSE., Level of Evidence: 5., Clinical Relevance: Physiotherapeutic Scoliosis Specific Exercises (PSSE) is an important non-operative treatment for patients with Adolescent Idiopathic Scoliosis (AIS) but is understudied in Adult Spinal Deformity (ASD) patients, suggesting further clinical research. This study demonstrates that only two-thirds of the respondents familiar with PSSE were comfortable prescribing PSSE postoperatively suggesting the need for further research into the effectiveness and benefits of PSSE in ASD patients., Competing Interests: Disclosures and COI: The authors received no financial support for the research, authorship, and/or publication of this article and report no conflicts of interest., (©International Society for the Advancement of Spine Surgery 2019.)

Enzymes catalyze fundamental biochemical reactions that control cellular and organismal homeostasis. Here we present an approach for de novo biochemical pathway discovery across entire mammalian enzyme families using parallel viral transduction in mice and untargeted liquid chromatography-mass spectrometry. Applying this method to the M20 peptidases uncovers both known pathways of amino acid metabolism as well as a previously unknown CNDP2-regulated pathway for threonyl dipeptide catabolism. Ablation of CNDP2 in mice elevates threonyl dipeptides across multiple tissues, establishing the physiologic relevance of our biochemical assignments. Taken together, these data underscore the utility of parallel in vivo metabolomics for the family-wide discovery of enzymatic pathways., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Study Design: Retrospective study of consecutive patients at a single institution.Objective: Examine the effect of minimally invasive surgery (MIS) versus open transforaminal lumbar interbody fusion (TLIF) surgery on long-term postoperative narcotic consumption., Objective: Examine the effect of minimally invasive versus open TLIF on short-term postoperative narcotic consumption., Methods: Differences between MIS and open TLIF, including inpatient opioid and nonopioid analgesic use, discharge opioid use, and postdischarge duration of narcotic usage were compared using appropriate statistical methods., Results: A total of 172 patients (109 open; 63 MIS) underwent primary TLIF. There was no difference in baseline characteristics. The MIS TLIF cohort had a significantly shorter operative time (223 vs 251 min, P = .006) and length of stay (2.7 vs 3.7 days, P < .001) as well as less estimated blood loss (184 vs 648 mL, P < .001). MIS TLIF had significantly less total inpatient opioid usage (167 vs 255 morphine milligram equivalent [MME], P = .006) and inpatient oxycodone usage (71 vs 105 mg, P = .049). Open TLIF cases required more ongoing opiate usage at 3-month follow-up (36% open vs 21% MIS, P = .041). A subanalysis found that patients who underwent an open TLIF with a history of preoperative opioid use are significantly more likely to remain on opioids at 6-week follow-up (87% vs 65%, P = .027), 3-month follow-up (63% vs 31%, P = .008), and 6-month follow-up (50% vs 21%, P = .018) compared with MIS TLIF., Conclusion: Patients undergoing MIS TLIF required less inpatient opioids and had a decreased incidence of opioid dependence at 3-month follow-up. Patients with preoperative opioid use undergoing MIS TLIF are less likely to require long-term opioids., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Protopsaltis reports grants from DePuy Synthes, during the conduct of the study; other from Medicrea, other from NuVasive, other from Globus, other from Innovasis, other from Zimmer, and other from Cervical Spine Research Society, outside the submitted work. Dr Errico reports personal fees from K2M, other from Fastenetix, grants and personal fees from Pfizer, grants from Medtronic, other from Harms Study Group, grants from OMEGA, grants from ISSGF, and grants from Paradigm Spine, outside the submitted work. Dr Passias reports personal fees from Zimmer Biomet, personal fees from Medicrea, personal fees from Spinewave, and grants from CSRS, outside the submitted work.

The Press Ganey survey is the most widely used instrument for measuring patient satisfaction. Understanding the factors that influence these surveys may permit better use of survey results and may direct interventions to increase patient satisfaction. Press Ganey Clinician and Group Consumer Assessment of Healthcare Providers and Systems surveys administered to ambulatory spine surgery clinic patients within a large tertiary care network from May 2016 to September 2017 were retrospectively reviewed. Mean comparison testing was performed to measure associations between patient demographics and responses to "overall provider rating" and "recommend this provider's office" survey questions. Mean difference to achieve significance was set at α<0.05. A multivariate analysis was performed to determine independent factors. A total of 1400 survey responses from the offices of 11 orthopedic spine surgeons were included. Patients 18 to 34 years old had significantly lower responses to the overall provider rating question than older patients (P<.001), and increasing patient age was correlated with improved ratings. Highest education level was inversely correlated with satisfaction scores, with patients who had attained graduate level education having the lowest satisfaction scores (P=.001). Those with commercial insurance had significantly lower ratings for recommend this provider's office (P=.042) and overall provider rating (P=.022) questions than those with other insurance types. Patients administered the survey on paper had significantly lower ratings than those administered the survey online (P=.006). Provider ratings were significantly higher when the sex and ethnicity of the patient were concordant with the provider (P=.021). This study showed that independent, nonmodifiable factors such as age, education level, and survey mode were significantly associated with the satisfaction of ambulatory spine surgery clinic patients. [Orthopedics. 2019; 42(3):143-148.]., (Copyright 2019, SLACK Incorporated.)

Background: Objective of this study is to evaluate demographics, risk factors, and incidence of instrumentation related complications (IRC) in spinal surgeries from 2009-2012. The Scoliosis Research Society (SRS) morbidity and mortality (M&M) database has tremendous value in orthopaedic surgery. SRS gathers surgeon-reported complications, including instrumentation failure, visual complications, neurological deficits, infections, and death. Limited literature exists on the incidence of perioperative instrumentation complications in deformity surgery. We utilized the SRS database to evaluate demographics, risk factors, and incidence of IRC in spinal surgeries from 2009-2012., Methods: The SRS M&M database was queried for IRC in patients undergoing surgery for scoliosis, spondylolisthesis, and kyphosis from 2009-2012. Demographics, comorbidities, diagnoses, curve magnitude, and intraoperative characteristics were analyzed. Intraoperative characteristics included surgical approach, performance of fusion or osteotomy, operative times, blood loss, instrumentation used, and documented instrumentation complication., Results: A total of 167,972 patients were identified, including 311 IRC. The overall IRC rate was 0.19% (18.5 per 10,000 patients), which decreased significantly from 2009-2012 (0.37% vs. 0.19%, P<0.001). The mean age of patients with IRC was 38.5±25.5 years. Most common comorbidities included hypertension (23.5%), pulmonary disease (13.5%), diabetes (10.6%), smoking (8.7%), and vascular disease (7.1%). IRC occurred in 206 (66.2%) patients with scoliosis, 58 (18.6%) with spondylolisthesis, and 45 (14.5%) with kyphosis. Compared to patients with spondylolisthesis, patients with kyphosis (0.27% vs. 0.11%, P<0.001) and scoliosis (0.21% vs. 0.11%, P<0.001), experienced significantly more IRC. IRC included implant failure (23.3%), migration (28.3%), and malpositioned implants (48.6%). New perioperative neurologic deficits were reported in 146 (46.9%) patients, and 84 (27%) of these implants were removed., Conclusions: IRC occur in approximately 18.5 per 10,000 deformity patients, with a rate significantly higher in patients with kyphosis. The potentially avoidable occurrence of implant malpositioning represents nearly 50% of these complications. Closer attention to posterior bony anatomy, improved intraoperative imaging with utilization of navigation or robotic guidance may decrease these complications., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Evaluate the current evidence in meta-analyses on posterior thoracolumbar minimally invasive surgery techniques and outcomes for degenerative conditions., Methods: A systematic review of the literature from 1950 to 2015., Results: The review of the literature yielded 34 meta-analysis studies evaluating posterior thoracolumbar minimally invasive techniques and outcomes for degenerative conditions. There were 11 studies included which investigated minimally invasive surgery (MIS) versus open posterior lumbar decompressions. There were 14 studies included which investigated MIS versus open posterior lumbar interbody fusions. Finally, there were 9 studies focused on navigation techniques and radiation safety within MIS procedures., Conclusions: There are 34 meta-analysis studies evaluating minimally invasive to open thoracolumbar surgery for degenerative disease. The studies show a trend toward decreased estimated blood loss, decreased length of stay, decreased complications, similar fusion rates, improved accuracy, and decreased radiation when minimally invasive techniques are used., Competing Interests: Disclosures and COI: The authors received no funding for this study and report no conflicts of interest.

Background: The purpose of this study is to evaluate the knowledge and attitudes on osteoporosis among first-time spine surgery patients., Methods: An electronic survey consisting of demographics, prior experience with osteoporosis, and the Facts on Osteoporosis Quiz (FOOQ) was sent via email to first-time spine surgery patients. Patients were then randomized into 2 groups: 1 received a brief osteoporosis information packet prior to beginning the FOOQ, and 1 proceeded directly to the survey., Results: A total of 63 patients who participated in this study, 29 in the information packet group and 34 in the non-information packet group, completed the survey. The mean FOOQ scores for the information packet patients was 16.37 (± 2.35) and for the non-information packet patients was 15.62 (± 2.87), with a P value of .12. There were no statistically significant differences between the 2 groups in terms of patient demographics or prior experience with osteoporosis. The information packet group trended to higher interest with a P value of .068., Conclusions: Our study demonstrates high FOOQ scores among all first-time spine patients as compared to historical scores in general at-risk populations. No statistical differences between FOOQ scores were noted between the group that received the information packet and the control group. This study demonstrates that patients new to spine care have a good understanding of osteoporosis and are thus willing to participate in osteoporosis treatment as part of their spine care., Competing Interests: Disclosures and COI: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Permission to reproduce copyrighted work: there is no copyrighted work in this manuscript. Institutional review board approval was obtained prior to starting this research. The authors received no financial support for the research, authorship, and/or publication of this article.

Study Design: Retrospective database study., Objectives: Analysis of economic and demographic data concerning interspinous device (ID) placement throughout the United States to improve value-based care and health care utilization., Methods: The National Inpatient Sample (NIS) database was queried for patients who underwent insertion of an interspinous process spinal stabilization device (ICD-9-CM 84.80) between 2008 and 2014 across 44 states. Demographic and economic data were obtained which included the annual number of surgeries, age, sex, insurance type, location, and frequency of routine discharge. The NIS database represents a 20% sample of discharges from US hospitals, which is weighted to provide national estimates., Results: There was a 73% decrease in ID implanted from 2008 to 2014. The mean cost associated with insertion of the device increased 28% from $13 653 in 2008 to $17 515 in 2014. The mean length of stay (LOS) increased from 1.8 to 2.4 days. Patients aged 45 to 64 years increased from 14.1% to 34.3% while patients aged 65 to 84 years decreased from 74.4% to 60.6%. By region, 34% of ID placement occurred in the South followed by 19.7% that occured in the Northeast. When stratifying by median income for patient zip code, the procedure was performed more in cities designated as higher rather than lower income areas (74.2% and 19.5%, respectively)., Conclusions: Throughout the United States, there was a progressive decline in the insertion of interspinous spacers by 73% over the study period. The total costs for the procedure increased by 28% while the aggregate national charges decreased by 55.6% between 2008 and 2014., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Ronald A. Lehman Jr reports grants from PRORP (Department of Defense Peer Reviewed Orthopaedic Research Program), personal fees and nonfinancial support from DePuy Synthes Spine, personal fees and nonfinancial support from Stryker, personal fees and nonfinancial support from Medtronics outside the submitted work. Dr Lawrence Lenke reports unpaid positions from Board Membership OREF and GSO, personal fees from Consultancy–DePuy Synthes Spine, K2M, Medtronic, personal fees from Expert Testimony–Fox Rothschild, LLP, grants from AO Spine; Scoliosis Research Society; DePuy Synthes Spine; Setting Scoliosis Straight Foundation; EOS, Royalties from Patents–Medtronic, personal fees from Travel accommodations/meeting expenses–AOSpine, Broadwater, Seattle Science Foundation, Scoliosis Research Society, The Spinal Research Foundation, grants from Fellowship Grant–AOSpine, North America, grants from Philanthropic research funding outside the submitted work. No other authors report potential conflicts of interest.

Systemic acquired resistance (SAR) is a global response in plants induced at the site of infection that leads to long-lasting and broad-spectrum disease resistance at distal, uninfected tissues. Despite the importance of this priming mechanism, the identity and complexity of defense signals that are required to initiate SAR signaling is not well understood. In this paper, we describe a metabolite, N -hydroxy-pipecolic acid ( N -OH-Pip) and provide evidence that this mobile molecule plays a role in initiating SAR signal transduction in Arabidopsis thaliana We demonstrate that FLAVIN-DEPENDENT MONOOXYGENASE 1 (FMO1), a key regulator of SAR-associated defense priming, can synthesize N -OH-Pip from pipecolic acid in planta , and exogenously applied N -OH-Pip moves systemically in Arabidopsis and can rescue the SAR-deficiency of fmo1 mutants. We also demonstrate that N -OH-Pip treatment causes systemic changes in the expression of pathogenesis-related genes and metabolic pathways throughout the plant and enhances resistance to a bacterial pathogen. This work provides insight into the chemical nature of a signal for SAR and also suggests that the N -OH-Pip pathway is a promising target for metabolic engineering to enhance disease resistance., Competing Interests: The authors declare no conflict of interest.

For decades, fungi have been a source of U.S. Food and Drug Administration-approved natural products such as penicillin, cyclosporine, and the statins. Recent breakthroughs in DNA sequencing suggest that millions of fungal species exist on Earth, with each genome encoding pathways capable of generating as many as dozens of natural products. However, the majority of encoded molecules are difficult or impossible to access because the organisms are uncultivable or the genes are transcriptionally silent. To overcome this bottleneck in natural product discovery, we developed the HEx (Heterologous EXpression) synthetic biology platform for rapid, scalable expression of fungal biosynthetic genes and their encoded metabolites in Saccharomyces cerevisiae . We applied this platform to 41 fungal biosynthetic gene clusters from diverse fungal species from around the world, 22 of which produced detectable compounds. These included novel compounds with unexpected biosynthetic origins, particularly from poorly studied species. This result establishes the HEx platform for rapid discovery of natural products from any fungal species, even those that are uncultivable, and opens the door to discovery of the next generation of natural products.

Background: Controversy exists over the ability of various lumbar interbody fusion techniques to realign global and regional balance and their effect on patient outcomes. This is a retrospective cohort study to compare thirty-day postoperative outcomes between anterior and posterior interbody fusion techniques within a large national database., Methods: A retrospective cohort study utilizing the National Surgical Quality Improvement Program (NSQIP) database included 2,372 (29.9%) single-level anterior/direct lateral interbody fusions (ALIF/DLIF) and 5,563 (70.1%) single-level posterior/transforaminal lateral interbody fusions (PLIF/TLIF) between 2013 and 2014. Emergent cases, fracture cases, and preoperative compromised wounds were not analyzed. Primary thirty-day outcomes included mortality, return to operating room, readmission, length of stay, and other major complications. Minor outcomes included urinary tract infection, superficial incisional site infection, and perioperative blood transfusion within 72 hours., Results: ALIF/DLIF was performed more for degenerative lumbar disc disease (31.0% vs. 13.9%, P<0.001), whereas PLIF/TLIF was utilized more for spondylolisthesis (19.1% vs. 24.4%, P<0.001). Thirty-day mortality was significantly higher with ALIF/DLIF (0.3% vs. 0.1%, P=0.021) in the univariate analysis and persisted in the multivariate analysis (OR =12.8; 95% CI, 1.37-119.6; P=0.025). Significantly more PLIF/TLIF patients required blood transfusions within 72 hours of surgery (9.6% vs. 7.6%, P=0.005). This difference did not persist in the multivariate analysis after controlling for covariates. Elevated ASA physical status classification, age >60, prior bleeding disorder, and preoperative anemia were significantly associated with blood transfusion requirement. More deep venous thrombosis occurred (DVT) with ALIF/DLIF compared to PLIF/TLIF (1.0% vs. 0.6%, P=0.025), which persisted in the multivariate analysis (OR =2.03; 95% CI, 1.13-3.65; P=0.017)., Conclusions: Although numerous techniques can be utilized in the treatment approach to various lumbar pathologies, anterior approaches have an increased risk of developing a perioperative DVT and early mortality. Transfusion risk is more strongly associated with elevated American Society of Anesthesiologists (ASA) class, increased age, preoperative anemia, and patients with bleeding disorders., Competing Interests: Conflicts of Interest: Dr. Ronald Lehman Jr reports grants from PRORP (Department of Defense Peer Reviewed Orthopaedic Research Program), personal fees and non-financial support from DePuy Synthes Spine, personal fees and non-financial support from Stryker, and personal fees and non-financial support from Medtronic outside the submitted work. The other authors have no conflicts of interest to declare.

Parrot feathers contain red, orange, and yellow polyene pigments called psittacofulvins. Budgerigars are parrots that have been extensively bred for plumage traits during the last century, but the underlying genes are unknown. Here we use genome-wide association mapping and gene-expression analysis to map the Mendelian blue locus, which abolishes yellow pigmentation in the budgerigar. We find that the blue trait maps to a single amino acid substitution (R644W) in an uncharacterized polyketide synthase (MuPKS). When we expressed MuPKS heterologously in yeast, yellow pigments accumulated. Mass spectrometry confirmed that these yellow pigments match those found in feathers. The R644W substitution abolished MuPKS activity. Furthermore, gene-expression data from feathers of different bird species suggest that parrots acquired their colors through regulatory changes that drive high expression of MuPKS in feather epithelia. Our data also help formulate biochemical models that may explain natural color variation in parrots. VIDEO ABSTRACT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Given the increasing societal focus on health care utilization and value-based care, it is essential to understand the demographic and economic data surrounding percutaneous vertebral augmentation procedures performed in the United States. Double-blinded prospective randomized controlled trials have shown no benefit to the use of vertebroplasty over a sham procedure in the treatment of vertebral fractures. Contrastingly, kyphoplasty may be beneficial when appropriately indicated., Methods: The National Inpatient Sample (NIS) database was queried for patients who underwent either kyphoplasty (ICD-9-CM 81.66) or vertebroplasty (ICD-9-CM 81.65) procedures between 2006 and 2014 across 44 states. Demographic and economic data were obtained which included the annual number of surgeries, age, sex, insurance type, location, and frequency of routine discharge. The NIS database represents a 20% sample of discharges from U.S. hospitals, which is weighted to provide national estimates., Results: In 2014, an estimated total number of 19,420 kyphoplasty and 6,130 vertebroplasty procedures were performed across the United States. The number of vertebroplasty procedures decreased 53% from 13,128 in 2008. Similarly, the number of kyphoplasty procedures decreased 17% from 23,320 in 2007. Based on payer, Medicare patients comprised 83% of those billed for kyphoplasty and vertebroplasty, and 75% of procedures were utilized in areas designated as "not low income". In 2014, patients in the South Atlantic region comprised 24% of vertebroplasty and 28% of kyphoplasty cases, far more than any other region. Additionally, kyphoplasty and vertebroplasty were more often performed in teaching facilities rather than community hospitals (60% and 67%, respectively)., Conclusions: Since the publication of two double-blind, prospective randomized controlled trials showed no benefit of vertebroplasty over a sham procedure, there has been a significant decrease in both kyphoplasty and vertebroplasty procedures., Competing Interests: Conflicts of Interest: SC Ludwig, MD reports the following disclosures—AO Spine North America Spine Fellowship Support (Research support); ASIP, ISD (Stock or stock options); Cervical Spine Research Society (Board or committee member); DePuy, A Johnson & Johnson Company (IP royalties; Paid consultant; Paid presenter or speaker); Globus Medical (Paid consultant; Research support); Journal of Spinal Disorders and Techniques, The Spine Journal, Contemporary Spine Surgery (Editorial or governing board); K2Medical (Paid consultant, Research support); Synthes (Paid consultant; Paid presenter or speaker); Thieme, QMP (Publishing royalties, financial or material support). LG Lenke, MD reports the following disclosures—Board Membership in OREF and GSO; Personal fees from Consultancy-DePuy Synthes Spine, K2M, and Medtronic; Personal fees from Expert Testimony-Fox Rothschild, LLP; Grants from AO Spine, Scoliosis Research Society, DePuy Synthes Spine, Setting Scoliosis Straight Foundation, EOS; Royalties from Patents-Medtronic; Personal fees from Travel accommodations/meeting expenses-AOSpine, Broadwater, Seattle Science Foundation, Scoliosis Research Society, The Spinl Research Foundation; Other grants from Fellowship Grant-AOSpine, North America, and grants from Philanthropic research funding outside the submitted work. RA Lehman, MD reports the following disclosures—Grants from PRORP (Department of Defense Peer Reviewed Orthopaedic Research Program); Personal fees and non-financial support from DePuy Synthes Spine; Personal fees and non-financial support from Stryker; Personal fees and non-financial support from Medtronic. The other authors have no conflicts of interest to declare.

Purpose: To evaluate the current evidence in the literature on treatment strategies for degenerative lumbar spine fusion in patients with osteoporosis., Methods: A systematic review of the literature from 1950 to 2015., Results: The review of the literature yielded 15 studies on the effect of treatment options for osteoporosis on lumbar fusion rates. This study evaluated only degenerative lumbar spine conditions and excluded deformity patients. One study demonstrated an association between low bone mass as measured by Hounsfield units and lower fusion rates. Six studies evaluated perioperative medical treatment of osteoporosis and showed higher fusion rates in patients treated with alendronate and teriparatide. The strongest evidence was for perioperative teriparatide. Eight studies evaluated surgical treatment strategies in patients with osteoporosis and showed that cement augmentation of pedicle screws and expandable pedicle screws demonstrated improved fusion rates than traditional pedicle screws. The strongest evidence was for expandable pedicle screws., Conclusion: There are 15 articles evaluating osteoporosis in patients undergoing lumbar fusion and the highest level of evidence is for perioperative use of teriparatide., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Autograft, while currently the gold standard for bone grafting, has several significant disadvantages including limited supply, donor site pain, hematoma formation, nerve and vascular injury, and fracture. Bone allografts have their own disadvantages including reduced osteoinductive capability, lack of osteoprogenitor cells, immunogenicity and risk of disease transmission. Thus demand exists for tissue-engineered constructs that can produce viable bone while avoiding the complications associated with human tissue grafts. This review will focus on recent advancements in tissue-engineered bone graft substitutes utilizing nanoscale technology in spine surgery applications. An evaluation will be performed of bone graft substitutes, biomimetic 3D scaffolds, bone morphogenetic protein, mesenchymal stem cells and intervertebral disc regeneration strategies.

Background: In the United States, expenditures related to spine care are estimated to account for $86 billion annually. Policy makers have set a cost-effectiveness benchmark of less than $100,000/quality adjusted life year (QALY), forcing surgeons to defend their choices economically. This study projects the cost/QALY for surgical treatment of adult spinal deformity at 5-year follow-up based on 2-year cost- and health-related quality-of-life (HRQOL) data., Methods: In a review of 541 patients with adult spinal deformity, the patients who underwent revision or were likely to undergo revision were identified and cost of surgery was doubled to account for the second procedure; all other patients maintained the cost of the initial surgery. Oswestry Disability Index (ODI) was modeled by revision status based on literature findings. Total surgical cost was based on Medicare reimbursement. Chi square and student t tests were utilized to compare cost-effective and non-cost-effective patients., Results: The average cost/QALY at 5-year follow-up was $120,311.73. A total of 40.7% of patients fell under the threshold of a cost/QALY <$100,000. Cost-effective patients had higher baseline ODI scores (45% vs 34% [P=0.001]), lower baseline total Scoliosis Research Society scores (2.89 vs 3.00 [P=0.04]), and shorter fusions (8.23 vs 9.87 [P=0.0001])., Conclusion: We found 40.7% of patients to be below the threshold of cost effectiveness. Factors associated with reaching the threshold <$100,000/QALY were greater preoperative disability, diagnosis of idiopathic scoliosis, poor preoperative HRQOL scores, and fewer fusion levels.

Folate receptor β (FR-β) is overexpressed on activated, but not resting, macrophages involved in a variety of inflammatory and autoimmune diseases. A pivotal step in atherogenesis is the subendothelial accumulation of macrophages. In nascent lesions, they coordinate the scavenging of lipids and cellular debris to define the likelihood of plaque inflammation and eventually rupture. In this study, we determined the presence of FR-β-expressing macrophages in atherosclerotic lesions by the use of a fluorine-18-labeled folate-based radiotracer. Human endarterectomized specimens were used to measure gene expression levels of FR-β and CD68. Increased FR-β and CD68 levels were found in atherosclerotic plaques compared to normal artery walls by quantitative real-time polymerase chain reaction. Western blotting and immunohistochemistry demonstrated prominent FR-β protein levels in plaques. FR-β-positive cells colocalized with activated macrophages (CD68) in plaque tissue. Carotid sections incubated with 3'-aza-2'-[18F]fluorofolic acid displayed increased accumulation in atherosclerotic plaques through in vitro autoradiography. Specific binding of the radiotracer correlated with FR-β-expressing macrophages. These results demonstrate high FR-β expression in atherosclerotic lesions of human carotid tissue correlating with CD68-positive macrophages. Areas of high 3'-aza-2'-[18F]fluorofolic acid binding within the lesions represented FR-β-expressing macrophages. Selectively targeting FR-β-positive macrophages through folate-based radiopharmaceuticals may be useful for noninvasive imaging of plaque inflammation.

Objective. The purpose of this study was to evaluate a new questionnaire to assess outcomes related to the midline anterior lumbar approach and to identify risk factors for negative patient responses. Methods. A retrospective review of 58 patients who underwent anterior lumbar surgery at a single institution for either degenerative disc disease or spondylolisthesis in 2009 was performed. The outcome measures included our newly developed Anterior Lumbar Surgery Questionnaire (ALSQ), ODI, and EQ-5D. Results. There were 58 patients available for followup, 27 women and 31 men. The average age at surgery was 50.8 years, with an average followup of 2.92 years. The average change in ODI was 34.94 (22.7) and EQ-5D was 0.28 (0.29). The rate of complications with the anterior approach was 10.3% and there was one male patient (3.2%) with retrograde ejaculation. Determination of the effectiveness of the new ALSQ revealed that it significantly correlated to the EQ-5D and ODI (P < 0.05). Smoking was associated with a negative response on thirteen questions. BMP use was not associated with a negative response on any sexual function questions. Conclusions. Our new Anterior Lumbar Surgery Questionnaire determines patient perceived complications related to the midline anterior lumbar surgical approach.

Background: The folate receptor (FR) is a well-established target for tumor imaging and therapy. To date, only a few 18 F-folate conjugates via 18 F-prosthetic group labeling for positron emission tomography (PET) imaging have been developed. To some extent, they all lack the optimal balance between efficient radiochemistry and favorable in vivo characteristics., Methods: A new clickable olate precursor was synthesized by regioselective coupling of folic acid to 11-azido-3,6,9-trioxaundecan-1-amine at the γ-position of the glutamic acid residue. The non-radioactive reference compound was synthesized via copper-catalyzed azide-alkyne cycloaddition of 3-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)prop-1-yne and γ-(11-azido-3,6,9-trioxaundecanyl)folic acid amide. The radiosynthesis was accomplished in two steps: at first a 18 F-fluorination of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl-4-methylbenzenesulfonate, followed by a 18 F-click reaction with the γ-azido folate. The in vitro, ex vivo, and in vivo behaviors of the new 18 F-folate were investigated using FR-positive human KB cells in displacement assays and microPET studies using KB tumor-bearing mice., Results: The new 18 F-folate with oligoethylene spacers showed reduced lipophilicity in respect to the previously developed 18 F-click folate with alkyl spacers and excellent affinity (Ki = 1.6 nM) to the FR. Combining the highly efficient 18 F-click chemistry and a polar oligoethylene-based 18 F-prosthetic group facilitated these results. The overall radiochemical yield of the isolated and formulated product averages 8.7%. In vivo PET imaging in KB tumor-bearing mice showed a tumor uptake of 3.4% ID/g tissue, which could be reduced by FR blockade with native folic acid. Although the new 18 F-oligoethyleneglycole (OEG)-folate showed reduced hepatobiliary excretion over time, a distinct unspecific abdominal background was still observed., Conclusions: A new 18 F-folate was developed, being available in very high radiochemical yields via a fast and convenient two-step radiosynthesis. The new 18 F-OEG-folate showed good in vivo behavior and lines up with several recently evaluated 18 F-labeled folates.

Unlabelled: The aim of this study was to characterize the different phenotypes of osteosarcoma by PET, comparing the uptake of 3 tracers ((18)F-FDG, (18)F-fluoromisonidazole [(18)F-FMISO], and (18)F-fluoride) in preclinical mouse models that reflect the heterogeneity of the human disease., Methods: Mouse LM8 osteosarcoma, human 143B, and Caprin-1 stably overexpressing SaOS-2 cells were injected intratibially in C3H and severe-combined immunodeficient mice. PET imaging with (18)F-FDG, (18)F-FMISO, and (18)F-fluoride was performed in these mouse models, and a ratio between the standardized uptake value of the primary tumor and a control area of bone was calculated and compared among the models. Histology and immunohistochemistry were performed to confirm the PET findings., Results: The pattern of tracer uptake differed among the primary tumors of the 3 models in accordance with the histology and immunohistochemistry on primary tumor sections. The osteolytic tumors in the 143B model showed the highest uptake of (18)F-FDG, an indicator of glucose metabolism, which was significantly higher (P < 0.05) than in the SaOS-2/Caprin-1 model and correlated with the percentage of Ki67-positive cells in the primary tumors. Hypoxia, indicated by (18)F-FMISO accumulation, was higher in the SaOS-2/Caprin-1 and 143B cell line-derived tumors (P < 0.01). Finally (18)F-fluoride, a marker of bone remodeling, correlated with the osteoblastic phenotype. The SaOS-2/Caprin-1 cell-derived tumors showed a significantly higher uptake than the moderately osteoblastic LM8 (P < 0.05) and the osteolytic 143B (P < 0.01) cell line-derived tumors., Conclusion: Differential PET imaging with tracers indicating metabolic activity, hypoxia, or bone remodeling will be helpful for the characterization of different osteosarcoma phenotypes and subsequent evaluation of more specific treatment modalities targeting the processes that are predominant in each specific tumor type or subtype.

Elastin is considered as a key player in human vascular diseases and it might contribute to the development of atherosclerosis. The elastin binding radiotracer, [(18)F]AlF-NOTA-EBM ([(18)F]2), was evaluated in a wild type mouse to determine its in vivo distribution and on human carotid atherosclerotic plaque tissues to assess its utility as a PET imaging agent for visualizing human atherosclerotic plaque lesions. The free ligand NOTA-EBM, which served as the precursor, was obtained in 25% chemical yield. The radiosynthesis of [(18)F]2 was accomplished by coordination of Al(18)F to NOTA-EBM in 8-13% decay corrected radiochemical yield (n = 7) and specific radioactivity of 59 ± 12 GBq/μmol. A dynamic in vivo PET scan in a healthy wild type mouse (C57BL/6) showed high accumulation of radioactivity in heart and lungs, organs reported to have high elastin content. Excretion of [(18)F]2 proceeded via the renal pathway and through the hepatobiliary system as indicated by a high uptake of radioactivity in the liver, intestines and gall bladder. In vitro autoradiography on human atherosclerotic plaque sections showed a heterogeneous distribution of [(18)F]2 with an elevated accumulation in stable and vulnerable atherosclerotic plaques compared to control samples of normal arteries. However, there was no statistical significance between the different plaque phenotypes and control samples. Competition experiments with 10.000-fold excess of free ligand NOTA-EBM resulted in a marked decrease of radioactivity accumulation, consistent with a target-specific ligand.

Background: The increased prevalence of spinal fusion surgery has created an industry focus on bone graft alternatives. While autologous bone graft remains the gold standard, the complications and morbidity from harvesting autologous bone drives the search for reliable and safe bone graft substitutes. With the recent information about the adverse events related to bone morhogenetic protein use, it is appropriate to review the literature about the numerous products that are not solely bone morphogenetic protein., Purpose: The purpose of this literature review is to determine the recommendations for use of non-bone morphogenetic protein bone graft alternatives in the most common spine procedures based on a quantifiable grading system., Study Design: Systematic literature review., Methods: A literature search of MEDLINE (1946-2012), CINAHL (1937-2012), and the Cochrane Central Register of Controlled Trials (1940-April 2012) was performed, and this was supplemented by a hand search. The studies were then evaluated based on the Guyatt criteria for quality of the research to determine the strength of the recommendation., Results: In this review, more than one hundred various studies on the ability of bone graft substitutes to create solid fusions and good patient outcomes are detailed., Conclusion: The recommendations for use of bone graft substitutes and bone graft extenders are based on the strength of the studies and given a grade.

Background: Mass spectrometry-based metabolomics analyses have the potential to complement sequence-based methods of genome annotation, but only if raw mass spectral data can be linked to specific metabolic pathways. In untargeted metabolomics, the measured mass of a detected compound is used to define the location of the compound in chemical space, but uncertainties in mass measurements lead to "degeneracies" in chemical space since multiple chemical formulae correspond to the same measured mass. We compare two methods to eliminate these degeneracies. One method relies on natural isotopic abundances, and the other relies on the use of stable-isotope labeling (SIL) to directly determine C and N atom counts. Both depend on combinatorial explorations of the "chemical space" comprised of all possible chemical formulae comprised of biologically relevant chemical elements., Results: Of 1532 metabolic pathways curated in the MetaCyc database, 412 contain a metabolite having a chemical formula unique to that metabolic pathway. Thus, chemical formulae alone can suffice to infer the presence of some metabolic pathways. Of 248,928 unique chemical formulae selected from the PubChem database, more than 95% had at least one degeneracy on the basis of accurate mass information alone. Consideration of natural isotopic abundance reduced degeneracy to 64%, but mainly for formulae less than 500 Da in molecular weight, and only if the error in the relative isotopic peak intensity was less than 10%. Knowledge of exact C and N atom counts as determined by SIL enabled reduced degeneracy, allowing for determination of unique chemical formula for 55% of the PubChem formulae., Conclusions: To facilitate the assignment of chemical formulae to unknown mass-spectral features, profiling can be performed on cultures uniformly labeled with stable isotopes of nitrogen (15N) or carbon (13C). This makes it possible to accurately count the number of carbon and nitrogen atoms in each molecule, providing a robust means for reducing the degeneracy of chemical space and thus obtaining unique chemical formulae for features measured in untargeted metabolomics having a mass greater than 500 Da, with relative errors in measured isotopic peak intensity greater than 10%, and without the use of a chemical formula generator dependent on heuristic filtering. These chemical formulae can serve as indicators for the presence of particular metabolic pathways.

Stable isotope probing (SIP) has been used to track nutrient flows in microbial communities, but existing protein-based SIP methods capable of quantifying the degree of label incorporation into peptides and proteins have been demonstrated only by targeting usually less than 100 proteins per sample. Our method automatically (i) identifies the sequence of and (ii) quantifies the degree of heavy atom enrichment for thousands of proteins from microbial community proteome samples. These features make our method suitable for comparing isotopic differences between closely related protein sequences, and for detecting labeling patterns in low-abundance proteins or proteins derived from rare community members. The proteomic SIP method was validated using proteome samples of known stable isotope incorporation levels at 0.4%, ∼50%, and ∼98%. The method was then used to monitor incorporation of (15)N into established and regrowing microbial biofilms. The results indicate organism-specific migration patterns from established communities into regrowing communities and provide insights into metabolism during biofilm formation. The proteomic SIP method can be extended to many systems to track fluxes of (13)C or (15)N in microbial communities.

Unlabelled: Bombesin is a peptide exhibiting high affinity for the gastrin-releasing peptide receptor (GRPr), which is highly overexpressed on prostate cancer cells. In the present study, we developed an (18)F-labeled bombesin analog, (18)F-BAY 86-4367, which is currently being clinically tested for use in PET of prostate cancer., Methods: In vitro pharmacologic studies were performed to characterize the nonradioactive ((19)F) standard of the bombesin analog for binding affinity and selectivity for GRPr. The stability of (18)F-BAY 86-4367 was determined in murine and human plasma. In vivo, the tumor-targeting potential and pharmacokinetic profile of the (18)F tracer were analyzed with biodistribution experiments and PET studies of prostate tumor-bearing mice., Results: The nonradioactive ((19)F) standard of the bombesin analog showed subnanomolar and GRPr-selective binding affinity. The stability of the tracer in murine and human plasma was found to be high. In 2 prostate cancer xenograft models (PC-3 and LNCaP), (18)F-BAY 86-4367 showed more specific and effective GRPr-based targeting in vivo than the benchmark radiotracers (18)F-fluoroethylcholine and (18)F-FDG. In addition, rapid tumor targeting and fast renal excretion (∼70%) and hepatobiliary excretion (∼10%) were identified in both xenograft models. Furthermore, PET studies provided clear and specific visualization of PC-3 tumors in mice., Conclusion: Favorable preclinical data showing specific and effective tumor targeting by (18)F-BAY 86-4367 suggest that a clinical trial be undertaken to test its diagnostic utility in PET for prostate carcinoma patients.

The strong overexpression or complete deletion of a gene gives only limited information about its control over a certain phenotype or pathway. Gene function studies based on these methods are therefore incomplete. To effect facile manipulation of gene expression across a full continuum of possible expression levels, we recently created a library of mutant promoters. Here, we provide the detailed characterization of our yeast promoter collection comprising 11 mutants of the strong constitutive Saccharomyces cerevisiae TEF1 promoter. The activities of the mutant promoters range between about 8% and 120% of the activity of the unmutated TEF1 promoter. The differences in reporter gene expression in the 11 mutants were independent of the carbon source used, and real-time PCR confirmed that these differences were due to varying levels of transcription (i.e., caused by varying promoter strengths). In addition to a CEN/ARS plasmid-based promoter collection, we also created promoter replacement cassettes. They enable genomic integration of our mutant promoter collection upstream of any given yeast gene, allowing detailed genotype-phenotype characterizations. To illustrate the utility of the method, the GPD1 promoter of S. cerevisiae was replaced by five TEF1 promoter mutants of different strengths, which allowed analysis of the impact of glycerol 3-phosphate dehydrogenase activity on the glycerol yield.