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Study design Analysis of prospectively collected longitudinal web-based registry data. Objective To determine relative validity, responsiveness, and minimum clinically important difference (MCID) thresholds in patients undergoing surgery for intradural extramedullary (IDEM) spinal tumors. Summary of background data Patient-reported outcomes (PROs) are vital in establishing the value of care in spinal pathology. There is limited availability of prospective, quality studies reporting PROs for IDEM spine tumors. Methods . A total of 40 patients were analyzed. Baseline, postoperative 3-month, and 12-month PROs were recorded: Oswestry Disability Index or Neck disability Index (ODI/NDI), Quality of life EuroQol-5D (EQ-5D), Short Form-12 (SF-12), Numeric Rating Scale (NRS)-pain scores. Responders were defined as those who achieved a level of improvement one or two, after surgery, on health transition index (HTI) of SF-36. Receiver-operating characteristic curves were generated to assess the validity of PROs, and the difference between standardized response means (SRMs) in responders versus nonresponders was utilized to determine the relative responsiveness of each PRO measure. MCID thresholds were derived using previously reported minimal detectable change approach. Results A significant improvement across all PROs at 3-months and 12-months follow up was noted. The derived MCID thresholds were 13.9 points: ODI/NDI, 0.14 quality adjusted life years: EQ-5D, 2.8 points: SF-12PCS and 10.7 points: SF-12MCS, 1.9 points: NRS-back/neck pain, and 1.8 points: NRS-leg/arm pain. SF-12PCS was most accurate discriminator of meaningful improvement (area under the curve, AUC-0.83) and most responsive (SRM-1.36) to postoperative improvement. EQ-5D, ODI/NDI, NRS-pain scores were all accurate discriminator (AUC-0.7-0.8) and responsive measures (0.97-0.67) of meaningful postoperative improvement. SF-12MCS was neither a valid discriminator (AUC-0.48) nor a responsive measure (SRM: -1.5) of outcome. Conclusion Surgical resection of IDEM spinal tumors provides significant and sustained improvement in quality of life, general health, disability, and pain at 12-month after surgery. The surgically resected IDEM-specific clinically meaningful thresholds are reported. All the PROs reported in this study can accurately discriminate responders and nonresponder based on SF-36 HTI index except for SF-12 MCS. Level of evidence 3.

The hypoxia inducible factors (Hifs) are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1α in osteoanabolic signaling, we assessed the effect of Hif-1α loss-of-function on bone formation in response to intermittent parathyroid hormone (PTH). Mice lacking Hif-1α in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1α protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1α-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1α functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1α function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.

Foxo family transcription factors contribute to muscle atrophy by promoting transcription of the ubiquitin ligases muscle-specific RING finger protein and muscle atrophy F-box/atrogin-1. Foxo transcriptional effectiveness is largely determined by its nuclear-cytoplasmic distribution, with unphosphorylated Foxo1 transported into nuclei and phosphorylated Foxo1 transported out of nuclei. We expressed the fluorescent fusion protein Foxo1-green fluorescent protein (GFP) in cultured adult mouse flexor digitorum brevis muscle fibers and tracked the time course of the nuclear-to-cytoplasmic Foxo1-GFP mean pixel fluorescence ratio (N/C) in living fibers by confocal imaging. We previously showed that IGF-I, which activates the Foxo kinase Akt/PKB, caused a rapid marked decline in N/C, whereas inhibition of Akt caused a modest increase in N/C. Here we develop a two-state mathematical model for Foxo1 nuclear-cytoplasmic redistribution, where Foxo phosphorylation/dephosphorylation is assumed to be fast compared with nuclear influx and efflux. Cytoplasmic Foxo1-GFP mean pixel fluorescence is constant due to the much larger cytoplasmic than nuclear volume. Analysis of N/C time courses reveals that IGF-I strongly increased unidirectional nuclear efflux, indicating similarly increased fractional phosphorylation of Foxo1 within nuclei, and decreased unidirectional nuclear influx, indicating increased cytoplasmic fractional phosphorylation of Foxo1. Inhibition of Akt increased Foxo1 unidirectional nuclear influx, consistent with block of Foxo1 cytoplasmic phosphorylation, but did not decrease Foxo1 unidirectional nuclear efflux, indicating that Akt may not be involved in Foxo1 nuclear efflux under control conditions. New media change experiments show that cultured fibers release IGF-I-like factors, which maintain low nuclear Foxo1 in the medium. This study demonstrates the power of quantitative modeling of observed nuclear fluxes.

Current health care systems are rapidly transitioning from the "fee-for service" to the "pay-for performance" model. With this paradigm shift, the providers and payers are constantly striving to determine tools to provide cost-effective and high-quality patient care. Therefore, it is vital to account for the complications and their effects on the cost and quality of life. We set forth to determine the cost-utility associated with complications after lumbar spine surgery.Total 407 patients undergoing elective surgery for degenerative lumbar pathology enrolled in the prospective longitudinal registry were included in the study. PROs: Oswestry Disability Index (ODI), numeric rating scale-Back and leg pain (BP, LP), general health (SF-12), and quality-of-life scores EQ-5D were recorded at baseline and 2 years after surgery. Two-year back-related medical resource utilization, missed work, and health state values (quality-adjusted life-years [QALYs], calculated from the EQ-5D with US valuation using the time-weighted area under the curve approach) were assessed. Mean 2-year cost per QALY gained after surgery was assessed. The patients were divided into groups with and without complications to compare the QALYs gained and the cost-utility in these groups.Fourteen percent (n = 58) of patients developed complications within 90 days after surgery. Most frequent surgical complication was surgical site infection (4.2%, n = 17), 1.5% (n = 6) had deep surgical site infections. There was a significant improvement in pain (BP, LP), disability (ODI), and general health scores (EQ-5D and SF-12) in both groups at postoperative 2 years (P < .0001). Patients with complications had lower mean cumulative 2-year QALY gained compared with those without complications (0.49 vs 0.57, P = .36). Cost-per-QALYs gained in patients with and without complications was $70 822 vs $45 831 (P = .03).Lumbar surgery provided a significant improvement in outcomes and gain in health state utility regardless of the occurrence of complications within the 90-day global period. The cost-utility, which was higher in patients with complications, was $70 822, which is within the range of commonly accepted threshold of willingness to pay. Clearly, measures focused on prevention of complications to reduce the cost and increase cost-utility.