Patterns of Opioid and Benzodiazepine Use in Opioid-Naïve Patients with Newly Diagnosed Low Back and Lower Extremity Pain.

BACKGROUND: The morbidity and mortality associated with opioid and benzodiazepine co-prescription is a pressing national concern. Little is known about patterns of opioid and benzodiazepine use in patients with acute low back pain or lower extremity pain. OBJECTIVE: To characterize patterns of opioid and benzodiazepine prescribing among opioid-naïve, newly diagnosed low back pain (LBP) or lower extremity pain (LEP) patients and to investigate the relationship between benzodiazepine prescribing and long-term opioid use. DESIGN/SETTING: We performed a retrospective analysis of a commercial database containing claims for more than 75 million enrollees in the USA. PARTICIPANTS: Participants were adult patients newly diagnosed with LBP or LEP between 2008 and 2015 who did not have a red flag diagnosis, had not received an opioid prescription in the 6 months prior to diagnosis, and had 12 months of continuous enrollment after diagnosis. MAIN OUTCOMES AND MEASURES: Among patients receiving at least one opioid prescription within 12 months of diagnosis, we defined discrete patterns of benzodiazepine prescribing-continued use, new use, stopped use, and never use. We tested the association of these prescription patterns with long-term opioid use, defined as six or more fills within 12 months. RESULTS: We identified 2,497,653 opioid-naïve patients with newly diagnosed LBP or LEP. Between 2008 and 2015, 31.9% and 11.5% of these patients received opioid and benzodiazepine prescriptions, respectively, within 12 months of diagnosis. Rates of opioid prescription decreased from 34.8% in 2008 to 27.0% in 2015 (P < 0.001); however, prescribing of benzodiazepines only decreased from 11.6% in 2008 to 10.8% in 2015. Patients with continued or new benzodiazepine use consistently used more opioids than patients who never used or stopped using benzodiazepines during the study period (one-way ANOVA, P < 0.001). For patients with continued and new benzodiazepine use, the odds ratio of long-term opioid use compared with those never prescribed a benzodiazepine was 2.99 (95% CI, 2.89-3.08) and 2.68 (95% CI, 2.62-2.75), respectively. LIMITATIONS: This study used administrative claims analyses, which rely on accuracy and completeness of diagnostic, procedural, and prescription codes. CONCLUSION: Overall opioid prescribing for low back pain or lower extremity pain decreased substantially during the study period, indicating a shift in management within the medical community. Rates of benzodiazepine prescribing, however, remained at approximately 11%. Concurrent prescriptions of benzodiazepines and opioids after LBP or LEP diagnosis were associated with increased risk of long-term opioid use.

Notch1 maintains dormancy of olfactory horizontal basal cells, a reserve neural stem cell.

The remarkable capacity of the adult olfactory epithelium (OE) to regenerate fully both neurosensory and nonneuronal cell types after severe epithelial injury depends on life-long persistence of two stem cell populations: the horizontal basal cells (HBCs), which are quiescent and held in reserve, and mitotically active globose basal cells. It has recently been demonstrated that down-regulation of the ΔN form of the transcription factor p63 is both necessary and sufficient to release HBCs from dormancy. However, the mechanisms by which p63 is down-regulated after acute OE injury remain unknown. To identify the cellular source of potential signaling mechanisms, we assessed HBC activation after neuron-only and sustentacular cell death. We found that ablation of sustentacular cells is sufficient for HBC activation to multipotency. By expression analysis, next-generation sequencing, and immunohistochemical examination, down-regulation of Notch pathway signaling is coincident with HBC activation. Therefore, using HBC-specific conditional knockout of Notch receptors and overexpression of N1ICD, we show that Notch signaling maintains p63 levels and HBC dormancy, in contrast to its suppression of p63 expression in other tissues. Additionally, Notch1, but not Notch2, is required to maintain HBC dormancy after selective neuronal degeneration. Taken together, our data indicate that the activation of HBCs observed after tissue injury or sustentacular cell ablation is caused by the reduction/elimination of Notch signaling on HBCs; elimination of Jagged1 expressed by sustentacular cells may be the ligand responsible.

Canonical Notch Signaling Directs the Fate of Differentiating Neurocompetent Progenitors in the Mammalian Olfactory Epithelium.

The adult olfactory epithelium (OE) has the remarkable capacity to regenerate fully both neurosensory and non-neuronal cell types after severe epithelial injury. Lifelong persistence of two stem cell populations supports OE regeneration when damaged: the horizontal basal cells (HBCs), dormant and held in reserve; and globose basal cells, a heterogeneous population most of which are actively dividing. Both populations regenerate all cell types of the OE after injury, but the mechanisms underlying neuronal versus non-neuronal lineage commitment after recruitment of the stem cell pools remains unknown. We used both retroviral transduction and mouse lines that permit conditional cell-specific genetic manipulation as well as the tracing of progeny to study the role of canonical Notch signaling in the determination of neuronal versus non-neuronal lineages in the regenerating adult OE. Excision of either Notch1 or Notch2 genes alone in HBCs did not alter progenitor fate during recovery from epithelial injury, whereas conditional knock-out of both Notch1 and Notch2 together, retroviral transduction of progenitors with a dominant-negative form of MAML (mastermind-like), or excision of the downstream cofactor RBPJ caused progeny to adopt a neuronal fate exclusively. Conversely, we show that overexpressing the Notch1-intracellular domain (N1ICD) either genetically or by transduction blocks neuronal differentiation completely. However, N1ICD overexpression requires both alleles of the canonical cofactor RBPJ to specify downstream lineage. Together, our results suggest that canonical RBPJ-dependent Notch signaling through redundant Notch1 and Notch2 receptors is both necessary and sufficient for determining neuronal versus non-neuronal differentiation in the regenerating adult OE.SIGNIFICANCE STATEMENT Despite the substantial reconstitution of the olfactory epithelium and its population of sensory neurons after injury, disruption and exhaustion of neurogenesis is a consequence of aging and a cause of olfactory dysfunction. Understanding the mechanisms underlying the generation of replacement neurons and non-neuronal cells is critical to any therapeutic strategy aimed at rebuilding a functional neuroepithelium. The results shown here demonstrate that canonical Notch signaling determines the balance between neurons and non-neuronal cells during restoration of the epithelium after injury. Moreover, the complexities of the multiple Notch pathways impinging on that decision are dissected in detail. Finally, RBPJ, the canonical Notch transcriptional cofactor, exhibits a heretofore unreported haploinsufficiency in setting the balance among the regenerating populations.

The Neuroregenerative Capacity of Olfactory Stem Cells Is Not Limitless: Implications for Aging.

The olfactory epithelium (OE) of vertebrates is a highly regenerative neuroepithelium that is maintained under normal conditions by a population of stem and progenitor cells, globose basal cells (GBCs), which also contribute to epithelial reconstitution after injury. However, aging of the OE often leads to neurogenic exhaustion, the disappearance of both GBCs and olfactory sensory neurons (OSNs). Aneuronal tissue may remain as olfactory, with an uninterrupted sheet of apically arrayed microvillar-capped sustentacular cell, or may undergo respiratory metaplasia. We have generated a transgenic mouse model for neurogenic exhaustion using olfactory marker protein-driven Tet-off regulation of the A subunit of Diphtheria toxin such that the death of mature OSNs is accelerated. At as early as 2 months of age, the epithelium of transgenic mice, regardless of sex, recapitulates what is seen in the aged OE of humans and rodents. Areas of the epithelium completely lack neurons and GBCs; whereas the horizontal basal cells, a reserve stem cell population, show no evidence of activation. Surprisingly, other areas that were olfactory undergo respiratory metaplasia. The impact of accelerated neuronal death and reduced innervation on the olfactory bulb (OB) was also examined. Constant neuronal turnover leaves glomeruli shrunken and affects the dopaminergic interneurons in the periglomerular layer. Moreover, the acceleration of OSN death can be reversed in those areas where some GBCs persist. However, the projection onto the OB recovers incompletely and the reinnervated glomeruli are markedly altered. Therefore, the capacity for OE regeneration is tempered when GBCs disappear.SIGNIFICANCE STATEMENT A large percentage of humans lose or suffer a significant decline in olfactory function as they age. Therefore, quality of life suffers and safety and nutritional status are put at risk. With age, the OE apparently becomes incapable of fully maintaining the neuronal population of the epithelium despite its well known capacity for recovering from most forms of injury when younger. Efforts to identify the mechanism by which olfactory neurogenesis becomes exhausted with age require a powerful model for accelerating age-related tissue pathology. The current OMP-tTA;TetO-DTA transgenic mouse model, in which olfactory neurons die when they reach maturity and accelerated death can be aborted to assess the capacity for structural recovery, satisfies that need.

Transcription factor p63 controls the reserve status but not the stemness of horizontal basal cells in the olfactory epithelium.

Adult tissue stem cells can serve two broad functions: to participate actively in the maintenance and regeneration of a tissue or to wait in reserve and participate only when activated from a dormant state. The adult olfactory epithelium, a site for ongoing, life-long, robust neurogenesis, contains both of these functional stem cell types. Globose basal cells (GBCs) act as the active stem cell population and can give rise to all the differentiated cells found in the normal tissue. Horizontal basal cells (HBCs) act as reserve stem cells and remain dormant unless activated by tissue injury. Here we show that HBC activation following injury by the olfactotoxic gas methyl bromide is coincident with the down-regulation of protein 63 (p63) but anticipates HBC proliferation. Gain- and loss-of-function studies show that this down-regulation of p63 is necessary and sufficient for HBC activation. Moreover, activated HBCs give rise to GBCs that persist for months and continue to act as bona fide stem cells by participating in tissue maintenance and regeneration over the long term. Our analysis provides mechanistic insight into the dynamics between tissue stem cell subtypes and demonstrates that p63 regulates the reserve state but not the stem cell status of HBCs.

Early Therapy Intensity Level (TIL) Predicts Mortality in Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Outcome from spontaneous intracerebral hemorrhage (sICH) may depend on patient-care variability. We developed as ICH-specific therapy intensity level (TIL) metric using evidence-based elements in a high severity sICH cohort. METHODS: This is a cohort study of 170 patients with sICH and any intraventricular hemorrhage treated in 2 academic neuroICUs. Pre-defined quality indicators were identified based on current guidelines, scientific evidence, and likelihood of care documentation in first 72 h of hospital admission. We assessed performance on each indicator and association with discharge mortality. Significant indicators were aggregated to develop a TIL score. The predictive validity of the best fit TIL score was tested with threefold cross-validation of multivariate logistic regression models of in-hospital survival and good outcome (modified Rankin score 0-3). RESULTS: Median ICH score was 3; discharge mortality was 51.2%. Five/19 tested variables were significantly associated with lower discharge mortality: no DNR/withdrawal of treatment within 24 h of admission, target glucose within 4 h of high glucose, no recurrent hyperpyrexia, clinical reversal of herniation/intracranial pressure >20 mmHg within 60 min of detection, and reversal of INR (<1.4) within 2 h of first elevation. One point was given for each or if not applicable. Median TIL score was significantly higher in survivors versus non-survivors (5[1] vs. 3[1]; P < 0.001). A 4-point aggregated TIL score was most predictive of discharge survival (area under receiving operating characteristic curve 0.85, 95% CI 0.80-0.90) and good outcome (AUC 0.84) and was an independent predictor of both (survival: OR 7.10; 95% CI 3.57-14.11; P < 0.001; good outcome: OR 3.10; 95% CI 1.06-8.79; P < 0.001). CONCLUSION: A simplified TIL score using evidenced-based patient-care parameters within first 3 days of admission after sICH was significantly associated with early mortality and good outcome. The next step is prospective validation of the simplified TIL score in a large clinical trial.

Graduate medical education in humanism and professionalism: a needs assessment survey of pediatric gastroenterology fellows.

The deterioration of humanism and professionalism during graduate medical training is an acknowledged concern, and programs are required to provide professionalism education for pediatric fellows. We conducted a needs assessment survey in a national sample of 138 first- and second-year gastroenterology fellows (82% response rate). Most believed that present humanism and professionalism education met their needs, but this education was largely informal (eg, role modeling). Areas for formal education desired by >70% included competing demands of clinical practice versus research, difficult doctor-patient relationships, depression/burnout, angry parents, medical errors, work-life balance, and the patient illness experience. These results may guide curricula to formalize humanism and professionalism education in pediatric gastroenterology fellowships.

Determinants of external ventricular drain placement and associated outcomes in patients with spontaneous intraventricular hemorrhage.

BACKGROUND: External ventricular drain (EVD) usage in patients with intraventricular hemorrhage (IVH) is variable in current practice and in clinical trials, and its impact on outcome remains controversial. The objective of this study was to identify the clinical predictors of EVD utilization, and associated outcome in adults with spontaneous IVH with or without intracerebral hemorrhage (ICH). METHODS: Retrospective review of 183 consecutive IVH patients admitted to a University Hospital between 2003 and 2010. Clinical and radiographic data were analyzed for associations between EVD placement and mortality, poor outcome, and improvement in Glasgow Coma Scale score (GCS) using multivariate logistic regression models. RESULTS: Average age was 62 ± 15.6 years, and average ICH and IVH volumes were 35.8 ± 40.9 cc and 19.7 ± 25.3 cc, respectively. Independent predictors of EVD placement within first 5 days of admission were GCS ≤ 8 (OR 11.5; P < 0.001), Graeb score >5 (OR 4.6; P = 0.001), and non-lobar ICH ≤ 30 cc (OR 9.7; P < 0.001). Median GCS increased from 5 (IQR 3-7) 48 h post-EVD (P < 0.001). EVD placement was an independent predictor of reduced mortality (OR 0.31; P = 0.04) and modified Rankin score 0-3 (OR 15.7; P = 0.01) at hospital discharge. In patients with hydrocephalus on presentation, EVD was associated with reduced mortality for patients with GCS > 3 after controlling for ICH and IVH severity (OR 0.02; P = 0.01). CONCLUSIONS: Patients with lower GCS, higher IVH severity, and lower ICH volume are more likely to have an EVD placed. EVD placement is associated with reduced mortality and improved short-term outcomes in patients with IVH after adjusting for known severity factors. EVD use should be protocolized in clinical trials of ICH management where IVH is included.

Using Machine Learning Models to Identify Factors Associated With 30-Day Readmissions After Posterior Cervical Fusions: A Longitudinal Cohort Study.

OBJECTIVE: Readmission rates after posterior cervical fusion (PCF) significantly impact patients and healthcare, with complication rates at 15%-25% and up to 12% 90-day readmission rates. In this study, we aim to test whether machine learning (ML) models that capture interfactorial interactions outperform traditional logistic regression (LR) in identifying readmission-associated factors. METHODS: The Optum Clinformatics Data Mart database was used to identify patients who underwent PCF between 2004-2017. To determine factors associated with 30-day readmissions, 5 ML models were generated and evaluated, including a multivariate LR (MLR) model. Then, the best-performing model, Gradient Boosting Machine (GBM), was compared to the LACE (Length patient stay in the hospital, Acuity of admission of patient in the hospital, Comorbidity, and Emergency visit) index regarding potential cost savings from algorithm implementation. RESULTS: This study included 4,130 patients, 874 of which were readmitted within 30 days. When analyzed and scaled, we found that patient discharge status, comorbidities, and number of procedure codes were factors that influenced MLR, while patient discharge status, billed admission charge, and length of stay influenced the GBM model. The GBM model significantly outperformed MLR in predicting unplanned readmissions (mean area under the receiver operating characteristic curve, 0.846 vs. 0.829; p < 0.001), while also projecting an average cost savings of 50% more than the LACE index. CONCLUSION: Five models (GBM, XGBoost [extreme gradient boosting], RF [random forest], LASSO [least absolute shrinkage and selection operator], and MLR) were evaluated, among which, the GBM model exhibited superior predictive performance, robustness, and accuracy. Factors associated with readmissions impact LR and GBM models differently, suggesting that these models can be used complementarily. When analyzing PCF procedures, the GBM model resulted in greater predictive performance and was associated with higher theoretical cost savings for readmissions associated with PCF complications.

Lean principles optimize on-time vascular surgery operating room starts and decrease resident work hours.

OBJECTIVE: Lean process improvement techniques are used in industry to improve efficiency and quality while controlling costs. These techniques are less commonly applied in health care. This study assessed the effectiveness of Lean principles on first case on-time operating room starts and quantified effects on resident work hours. METHODS: Standard process improvement techniques (DMAIC methodology: define, measure, analyze, improve, control) were used to identify causes of delayed vascular surgery first case starts. Value stream maps and process flow diagrams were created. Process data were analyzed with Pareto and control charts. High-yield changes were identified and simulated in computer and live settings prior to implementation. The primary outcome measure was the proportion of on-time first case starts; secondary outcomes included hospital costs, resident rounding time, and work hours. Data were compared with existing benchmarks. RESULTS: Prior to implementation, 39% of first cases started on time. Process mapping identified late resident arrival in preoperative holding as a cause of delayed first case starts. Resident rounding process inefficiencies were identified and changed through the use of checklists, standardization, and elimination of nonvalue-added activity. Following implementation of process improvements, first case on-time starts improved to 71% at 6 weeks (P = .002). Improvement was sustained with an 86% on-time rate at 1 year (P < .001). Resident rounding time was reduced by 33% (from 70 to 47 minutes). At 9 weeks following implementation, these changes generated an opportunity cost potential of $12,582. CONCLUSIONS: Use of Lean principles allowed rapid identification and implementation of perioperative process changes that improved efficiency and resulted in significant cost savings. This improvement was sustained at 1 year. Downstream effects included improved resident efficiency with decreased work hours.

Identification of Factors Associated With 30-day Readmissions After Posterior Lumbar Fusion Using Machine Learning and Traditional Models: A National Longitudinal Database Study.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: To identify the factors associated with readmissions after PLF using machine learning and logistic regression (LR) models. SUMMARY OF BACKGROUND DATA: Readmissions after posterior lumbar fusion (PLF) place significant health and financial burden on the patient and overall health care system. MATERIALS AND METHODS: The Optum Clinformatics Data Mart database was used to identify patients who underwent posterior lumbar laminectomy, fusion, and instrumentation between 2004 and 2017. Four machine learning models and a multivariable LR model were used to assess factors most closely associated with 30-day readmission. These models were also evaluated in terms of ability to predict unplanned 30-day readmissions. The top-performing model (Gradient Boosting Machine; GBM) was then compared with the validated LACE index in terms of potential cost savings associated with the implementation of the model. RESULTS: A total of 18,981 patients were included, of which 3080 (16.2%) were readmitted within 30 days of initial admission. Discharge status, prior admission, and geographic division were most influential for the LR model, whereas discharge status, length of stay, and prior admissions had the greatest relevance for the GBM model. GBM outperformed LR in predicting unplanned 30-day readmission (mean area under the receiver operating characteristic curve 0.865 vs. 0.850, P <0.0001). The use of GBM also achieved a projected 80% decrease in readmission-associated costs relative to those achieved by the LACE index model. CONCLUSIONS: The factors associated with readmission vary in terms of predictive influence based on standard LR and machine learning models used, highlighting the complementary roles these models have in identifying relevant factors for the prediction of 30-day readmissions. For PLF procedures, GBM yielded the greatest predictive ability and associated cost savings for readmission. LEVEL OF EVIDENCE: 3.

Systemic hematologic status following intraventricular recombinant tissue-type plasminogen activator for intraventricular hemorrhage: the CLEAR IVH Study Group.

BACKGROUND AND PURPOSE: This is the first prospective evaluation of changes in systemic hematologic status following administration of intraventricular recombinant tissue-type plasminogen activator in patients with intraventricular hemorrhage (IVH). METHODS: Laboratory data from subjects enrolled onto the Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) Trials were analyzed. We analyzed pre- and post- recombinant tissue-type plasminogen activator dosing coagulation parameters. Longer-term changes in hematologic status were studied in subjects who received the study agent after blood clot in the third/fourth ventricles had resolved radiologically. RESULTS: Plasma fibrinogen increased significantly in both treatment groups. Dosing did not have a significant impact on any systemic coagulation parameters in either treatment group. CONCLUSIONS: Intraventricular recombinant tissue-type plasminogen activator is unlikely to impact systemic coagulation or to compound the effects of systemic anticoagulation for deep venous thrombosis prophylaxis. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00650858.

Timing of Adjuvant Radiation Therapy and Risk of Wound-Related Complications Among Patients With Spinal Metastatic Disease.

STUDY DESIGN: This was an epidemiological study using national administrative data from the MarketScan database. OBJECTIVE: To investigate the impact of early versus delayed adjuvant radiotherapy (RT) on wound healing following surgical resection for spinal metastatic disease. METHODS: We queried the MarketScan database (2007-2016), identifying patients with a diagnosis of spinal metastasis who also underwent RT within 8 weeks of surgery. Patients were categorized into "Early RT" if they received RT within 4 weeks of surgery and as "Late RT" if they received RT between 4 and 8 weeks after surgery. Descriptive statistics and hypothesis testing were used to compare baseline characteristics and wound complication outcomes. RESULTS: A total of 540 patients met the inclusion criteria: 307 (56.9%) received RT within 4 weeks (Early RT) and 233 (43.1%) received RT within 4 to 8 weeks (Late RT) of surgery. Mean days to RT for the Early RT cohort was 18.5 (SD, 6.9) and 39.7 (SD, 7.6) for the Late RT cohort. In a 90-day surveillance period, n = 9 (2.9%) of Early RT and n = 8 (3.4%) of Late RT patients developed wound complications (P = .574). CONCLUSIONS: When comparing patients who received RT early versus delayed following surgery, there were no significant differences in the rates of wound complications. Further prospective studies should aim to identify optimal patient criteria for early postoperative RT for spinal metastases.

Postoperative Complication Burden, Revision Risk, and Health Care Use in Obese Patients Undergoing Primary Adult Thoracolumbar Deformity Surgery.

STUDY DESIGN: This is a retrospective cohort study using a nationally representative administrative database. OBJECTIVE: To identify the impact of obesity on postoperative outcomes in patients undergoing thoracolumbar adult spinal deformity (ASD) surgery. BACKGROUND: The obesity rate in the United States remains staggering, with approximately one-third of all Americans being overweight or obese. However, the impact of elevated body mass index on spine surgery outcomes remains unclear. METHODS: We queried the MarketScan database to identify patients who were diagnosed with a spinal deformity and underwent ASD surgery from 2007 to 2016. Patients were then stratified by whether or not they were diagnosed as obese at index surgical admission. Propensity score matching (PSM) was then utilized to mitigate intergroup differences between obese and nonobese patients. Patients <18 years and those with any prior history of trauma or tumor were excluded from this study. Baseline demographics and comorbidities, postoperative complication rates, and short- and long-term reoperation rates were determined. RESULTS: A total of 7423 patients met the inclusion criteria of this study, of whom 597 (8.0%) were obese. Initially, patients with obesity had a higher 90-day postoperative complication rate than nonobese patients (46.1% vs 40.8%, P < .05); however, this difference did not remain after PSM. Revision surgery rates after 2 years were similar across the 2 groups following primary surgery (obese, 21.4%, vs nonobese, 22.0%; P = .7588). Health care use occurred at a higher rate among obese patients through 2 years of long-term follow-up (obese, $152 930, vs nonobese, $140 550; P < .05). CONCLUSION: Patients diagnosed with obesity who underwent ASD surgery did not demonstrate increased rates of complications, reoperations, or readmissions. However, overall health care use through 2 years of follow-up after index surgery was higher in the obesity cohort.

Single-Stage Versus Multistage Surgical Management of Single- and Two-Level Lumbar Degenerative Disease.

OBJECTIVE: To determine postoperative complications and quality outcomes of single-stage and multistage surgical management for lumbar degenerative disease (LDD). METHODS: This retrospective cohort study using a national administrative database identified patients who underwent surgery for LDD between 2007 and 2016. Patients were stratified based on whether their surgeon chose to perform single-stage or multistage LDD surgery, and these cohorts were mutually exclusive. Propensity score matching was used to mitigate intergroup differences between single-stage and multistage patients. Patients who underwent ≥3 levels of surgical correction, who were <18 years old, or who had any prior history of trauma or tumor were excluded from the study. Baseline comorbidities, postoperative complication rates, and reoperation rates were determined. RESULTS: Primary surgery for LDD was performed in 47,190 patients; 9438 (20%) of these patients underwent multistage surgery. After propensity score matching, baseline covariates of the 2 cohorts were similar. The complication rate was 6.1% in the single-stage cohort and 11.0% in the multistage cohort. Rates of posthemorrhagic anemia, infection, wound complication, deep vein thrombosis, and hematoma all were higher in the multistage cohort. Length of stay, revisions, and readmissions were also significantly higher in the multistage cohort. Through 2 years of follow-up, multistage surgery was associated with higher payments throughout the 2-year follow-up period ($57,036 vs. $39,318, P < 0.05). CONCLUSIONS: Single-stage surgery for LDD demonstrated improved outcomes and lower health care utilization. Spine surgeons should carefully consider single-stage surgery when treating patients with LDD requiring <3 levels of correction.

Activating a Reserve Neural Stem Cell Population In Vitro Enables Engraftment and Multipotency after Transplantation.

The olfactory epithelium (OE) regenerates after injury via two types of tissue stem cells: active globose cells (GBCs) and dormant horizontal basal cells (HBCs). HBCs are roused to activated status by OE injury when P63 levels fall. However, an in-depth understanding of activation requires a system for culturing them that maintains both their self-renewal and multipotency while preventing spontaneous differentiation. Here, we demonstrate that mouse, rat, and human HBCs can be cultured and passaged as P63+ multipotent cells. HBCs in vitro closely resemble HBCs in vivo based on immunocytochemical and transcriptomic comparisons. Genetic lineage analysis demonstrates that HBCs in culture arise from both tissue-derived HBCs and multipotent GBCs. Treatment with retinoic acid induces neuronal and non-neuronal differentiation and primes cultured HBCs for transplantation into the lesioned OE. Engrafted HBCs generate all OE cell types, including olfactory sensory neurons, confirming that HBC multipotency and neurocompetency are maintained in culture.

The relationship between surgical site drains and reoperation for wound-related complications following posterior cervical spine surgery: a multicenter retrospective study.

OBJECTIVEUse of surgical site drains following posterior cervical spine surgery is variable, and its impact on outcomes remains controversial. Studies of drain use in the lumbar spine have suggested that drains are not associated with reduction of reoperations for wound infection or hematoma. There is a paucity of studies examining this relationship in the cervical spine, where hematomas and infections can have severe consequences. This study aims to examine the relationship between surgical site drains and reoperation for wound-related complications following posterior cervical spine surgery.METHODSThis study is a multicenter retrospective review of 1799 consecutive patients who underwent posterior cervical decompression with instrumentation at 4 tertiary care centers between 2004 and 2016. Demographic and perioperative data were analyzed for associations with drain placement and return to the operating room.RESULTSOf 1799 patients, 1180 (65.6%) had a drain placed. Multivariate logistic regression analysis identified history of diabetes (OR 1.37, p = 0.03) and total number of levels operated (OR 1.32, p < 0.001) as independent predictors of drain placement. Rates of reoperation for any surgical site complication were not different between the drain and no-drain groups (4.07% vs 3.88%, p = 0.85). Similarly, rates of reoperation for surgical site infection (1.61% vs 2.58%, p = 0.16) and hematoma (0.68% vs 0.48%, p = 0.62) were not different between the drain and no-drain groups. However, after adjusting for history of diabetes and the number of operative levels, patients with drains had significantly lower odds of returning to the operating room for surgical site infection (OR 0.48, p = 0.04) but not for hematoma (OR 1.22, p = 0.77).CONCLUSIONSThis large study characterizes current practice patterns in the utilization of surgical site drains during posterior cervical decompression and instrumentation. Patients with drains placed did not have lower odds of returning to the operating room for postoperative hematoma. However, the authors' data suggest that patients with drains may be less likely to return to the operating room for surgical site infection, although the absolute number of infections in the entire population was small, limiting the analysis.

Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency.

Adult neurogenesis in the olfactory epithelium is often depicted as a unidirectional pathway during homeostasis and repair. We challenge the unidirectionality of this model by showing that epithelial injury unlocks the potential for Ascl1+ progenitors and Neurog1+ specified neuronal precursors to dedifferentiate into multipotent stem/progenitor cells that contribute significantly to tissue regeneration in the murine olfactory epithelium (OE). We characterize these dedifferentiating cells using several lineage-tracing strains and single-cell mRNA-seq, and we show that Sox2 is required for initiating dedifferentiation and that inhibition of Ezh2 promotes multipotent progenitor expansion. These results suggest that the apparent hierarchy of neuronal differentiation is not irreversible and that lineage commitment can be overridden following severe tissue injury. We elucidate a previously unappreciated pathway for endogenous tissue repair by a highly regenerative neuroepithelium and introduce a system to study the mechanisms underlying plasticity in the OE that can be adapted for other tissues.

Stem and progenitor cells of the mammalian olfactory epithelium: Taking poietic license.

The capacity of the olfactory epithelium (OE) for lifelong neurogenesis and regeneration depends on the persistence of neurocompetent stem cells, which self-renew as well as generating all of the cell types found within the nasal epithelium. This Review focuses on the types of stem and progenitor cells in the epithelium and their regulation. Both horizontal basal cells (HBCs) and some among the population of globose basal cells (GBCs) are stem cells, but the two types plays vastly different roles. The GBC population includes the basal cells that proliferate in the uninjured OE and is heterogeneous with respect to transcription factor expression. From upstream in the hierarchy to downstream, GBCs encompass 1) Sox2+ /Pax6+ stem-like cells that are totipotent and self-renew over the long term, 2) Ascl1+ transit-amplifying progenitors with a limited capacity for expansive proliferation, and 3) Neurog1+ /NeuroD1+ immediate precursor cells that make neurons directly. In contrast, the normally quiescent HBCs are activated to multipotency and proliferate when sustentacular cells are killed, but not when only OSNs die, indicating that HBCs are reserve stem cells that respond to severe epithelial injury. The master regulator of HBC activation is the ΔN isoform of the transcription factor p63; eliminating ΔNp63 unleashes HBC multipotency. Notch signaling, via Jagged1 ligand on Sus cells and Notch1 and Notch2 receptors on HBCs, is likely to play a major role in setting the level of p63 expression. Thus, ΔNp63 becomes a potential therapeutic target for reversing the neurogenic exhaustion characteristic of the aged OE. J. Comp. Neurol. 525:1034-1054, 2017. © 2016 Wiley Periodicals, Inc.

Unilateral Pedicle Screw Fixation is Associated with Reduced Cost and Similar Outcomes in Selected Patients Undergoing Minimally Invasive Transforaminal Lumbar Interbody Fusion for L4-5 Degenerative Spondylolisthesis.

STUDY DESIGN: Retrospective study of 24 patients who underwent either a bilateral or unilateral TLIF procedure for the treatment of degenerative spondylolisthesis. OBJECTIVE: To analyze differences in cost and outcome between patients undergoing minimally invasive transforaminal lumbar interbody fusion (mi-TLIF) with unilateral or bilateral pedicle screw fixation for L4-5 degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: Lumbar fusion surgeries, including the TLIF procedure, have been shown to be an effective treatment for leg and low back pain caused by degenerative spondylolisthesis. Some studies have shown TLIF surgeries to be cost-effective, but there is still a paucity of data and no consensus. Unilateral TLIFs can provide the same benefits as bilateral TLIFs, but come with additional benefits of a less invasive surgery. METHODS: We retrospectively analyzed a consecutive series of patients with L4-5 degenerative stenosis and spondylolisthesis who either received a unilateral or bilateral mi-TLIF, paying particular attention to hospital cost and clinical outcome. Of the 33 patients eligible for analysis, we were able to obtain appropriate clinical and radiographic follow-up data on 24 patients (72.7%), 14 patients who underwent unilateral fixation, and 10 patients who underwent bilateral fixation. RESULTS: The cohorts were similar with regard to age, comorbidities, and demographics. Most patients reported good or excellent results, and there were no significant differences between the cohorts with regard to clinical outcome. There was one interbody graft extrusion in the unilateral cohort that required explantation, but no other hardware failures. Hospital cost was significantly lower in the unilateral cohort, and hardware savings accounted for only part of the difference. CONCLUSION: Unilateral pedicle screw fixation is an acceptable surgical strategy in patients with stable L4-5 degenerative spondylolisthesis undergoing mi-TLIF. In our series, unilateral fixation led to significant hospital cost savings without compromising clinical or radiographic outcomes.