An extensive proteostatic network comprised of molecular chaperones and protein clearance mechanisms functions collectively to preserve the integrity and resiliency of the proteome. The efficacy of this network deteriorates during aging, coinciding with many clinical manifestations, including protein aggregation diseases of the nervous system. A decline in proteostasis can be delayed through the activation of cytoprotective transcriptional responses, which are sensitive to environmental stress and internal metabolic and physiological cues. The homeodomain-interacting protein kinase (hipk) family members are conserved transcriptional co-factors that have been implicated in both genotoxic and metabolic stress responses from yeast to mammals. We demonstrate that constitutive expression of the sole Caenorhabditis elegans Hipk homolog, hpk-1, is sufficient to delay aging, preserve proteostasis, and promote stress resistance, while loss of hpk-1 is deleterious to these phenotypes. We show that HPK-1 preserves proteostasis and extends longevity through distinct but complementary genetic pathways defined by the heat shock transcription factor (HSF-1), and the target of rapamycin complex 1 (TORC1). We demonstrate that HPK-1 antagonizes sumoylation of HSF-1, a post-translational modification associated with reduced transcriptional activity in mammals. We show that inhibition of sumoylation by RNAi enhances HSF-1-dependent transcriptional induction of chaperones in response to heat shock. We find that hpk-1 is required for HSF-1 to induce molecular chaperones after thermal stress and enhances hormetic extension of longevity. We also show that HPK-1 is required in conjunction with HSF-1 for maintenance of proteostasis in the absence of thermal stress, protecting against the formation of polyglutamine (Q35::YFP) protein aggregates and associated locomotory toxicity. These functions of HPK-1/HSF-1 undergo rapid down-regulation once animals reach reproductive maturity. We show that HPK-1 fortifies proteostasis and extends longevity by an additional independent mechanism: induction of autophagy. HPK-1 is necessary for induction of autophagosome formation and autophagy gene expression in response to dietary restriction (DR) or inactivation of TORC1. The autophagy-stimulating transcription factors pha-4/FoxA and mxl-2/Mlx, but not hlh-30/TFEB or the nuclear hormone receptor nhr-62, are necessary for extended longevity resulting from HPK-1 overexpression. HPK-1 expression is itself induced by transcriptional mechanisms after nutritional stress, and post-transcriptional mechanisms in response to thermal stress. Collectively our results position HPK-1 at a central regulatory node upstream of the greater proteostatic network, acting at the transcriptional level by promoting protein folding via chaperone expression, and protein turnover via expression of autophagy genes. HPK-1 therefore provides a promising intervention point for pharmacological agents targeting the protein homeostasis system as a means of preserving robust longevity.

Study Design:Retrospective cohort study.Objective:To determine if patients fused with multi-rod constructs to the pelvis have a lower incidence of lumbosacral rod failure and pseudarthrosis than those fused with dual-rod constructs.Methods:We performed a retrospective review of consecutive adult spinal deformity patients who underwent long fusion to the pelvis. Inclusion criteria were >5 levels, primary fusion or revision for L5-S1 pseudarthrosis, and minimum 1-year follow-up. Revision patients with indications other than L5-S1 pseudarthrosis were excluded. One-year follow-up plain radiographs were reviewed for rod integrity, and computed tomography scan (CT) was obtained whenever rod breakage was observed. Dual-rod and multi-rod (3 or 4 rods) cohorts were statistically compared.Results:There were 31 patients with 15 in the dual-rod group and 16 in the multi-rod group, with average ages of 68 ± 9 and 63 ± 12 years, respectively. No patients in the multi-rod group experienced rod fracture, whereas 6 in the dual-rod group fractured a rod (P = .007), with 4 occurring at the lumbosacral junction (P = .04). CT scan in the 4 lumbosacral rod fracture cases, and surgical exploration in 3, confirmed pseudarthrosis and hypertrophic nonunion at the L5-S1 junction.Conclusion:Patients with dual-rod constructs had a statistically greater incidence of lumbosacral pseudarthrosis with implant failure than those with multi-rod constructs. CT and surgical exploration showed hypertrophic nonunion as opposed to oligo- or atrophic nonunion. This suggests that mechanical instability, not biology, is the main reason for failure, and could be addressed with the use of multi-rods.

Study Design:Retrospective study.Objective:To determine the presence of any potential associations between anesthesia time with postoperative outcome and complications following elective anterior cervical discectomy and fusion (ACDF).Methods:Patients who underwent elective ACDF were identified in the American College of Surgeons National Quality Improvement Program database. Patient demographics, medical comorbidities, and perioperative and postoperative complications up to 30 days were analyzed by univariate and multivariate analysis.Results:A total of 3801 patients undergoing elective ACDF were identified. Patients were subdivided into quintiles of anesthesia time: Group 1, 48 to 129 minutes (n = 761, 20%); Group 2, 129 to 156 minutes (n = 760, 20%); Group 3, 156 to 190 minutes (n = 760, 20%); Group 4, 190 to 245 minutes (n = 760, 20%); and Group 5, 245 to 1025 minutes (n = 760, 20%). Univariate analysis showed significantly higher rates of any complication (P < .0001), pulmonary complication (P < .0001), intra-/postoperative blood transfusions (P < .0001), sepsis (P = .017), wound complications (P = .002), total length of stay >5 days (P < .0001), and return to operating room (P = .006) in the highest quintile compared to those of other groups. Multivariate regression analysis revealed that prolonged anesthesia was an independent factor for increased odds of overall complications (odds ratio [OR] = 2.71, P = .012), venous thromboembolism (OR = 2.69, P = .011), and return to the operating room (OR = 2.92, P = .004). The 2 groups with the longest anesthesia durations (quintiles 4 and 5) had increased total length of stay more than 5 days (for quintile 4, OR = 3.10, P = .0004; for quintile 5, OR = 3.61, P < .0001).Conclusion:Prolonged anesthesia duration is associated with increased odds of complication, venous thromboembolism, increased length of stay, and return to the operating room.

Study Design:Retrospective case series.Objective:To investigate which sagittal parameters contribute to a normal sagittal vertical axis (SVA) when there is a pelvic incidence-lumbar lordosis (PI-LL) mismatch >10° following adult spinal deformity (ASD) correction.Methods:We performed a retrospective review of ASD patients with >5 levels fused. Sagittal measurements between cohorts of postoperative PI-LL >10° and PI-LL<10° were compared. We correlated SVA to pelvic tilt (PT), thoracic kyphosis (TK), PI-LL, cervical lordosis (CL), and correlated the pre- to postoperative change in SVA to change in PT, change in TK, change in PI-LL, and change in CL. We also correlated SVA and the change in SVA to combined parameters of ((PI-LL) − PT + TK).Results:We analyzed 52 patients with a mean age of 59 ± 16 years. In patients with a postoperative SVA <5cm, a smaller TK was seen when PI-LL >10° than when PI-LL<10° (15.45° vs 33.04°, P = .0004). Additionally, PT was larger when PI-LL >10° than when PI-LL <10° (25.73° vs 19.07°, P = .006). SVA correlated better with ((PI-LL) − PT + TK) (R 2 = 0.51) than with PI-LL alone (R 2 = 0.33). Lastly, there was no significant correlation between change in pre- to postoperative SVA with change in TK for all cases (P = .73), but in cases where change in PI-LL was <10°, there was a significant correlation between change in TK and change in SVA (P = .009).Conclusion:Our results demonstrate that PT and TK, and not just PI-LL, play an important role in maintaining sagittal balance when there is a PI-LL mismatch >10°.

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