The Combined Influence of Sleep Disturbance and Depression on 12-month Outcomes after Lumbar Spine Surgery.

STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: To examine the combined influence of preoperative sleep disturbance and depression on 12-month patient-reported outcomes after lumbar spine surgery (LSS). SUMMARY OF BACKGROUND DATA: Psychological and behavioral factors are considered major risk factors of poor outcome after LSS. However, there is a need to explore the combined effects of preoperative factors such as sleep disturbance and depression. Understanding the influence of sleep disturbance and depression can inform evidence-based preoperative assessment and shared-decision making of preoperative and postoperative treatment. METHODS: Data from 700 patients undergoing LSS were analyzed. Preoperative sleep disturbance and depression were assessed with PROMIS subscales. Established thresholds defined patients with moderate/severe symptoms. Outcomes for disability (Oswestry Disability Index) and back and leg pain (Numeric Rating Scales) were assessed preoperatively and at 12 months. Separate multivariable linear regressions examined the influence of each factor on 12-month outcomes with and without accounting for the other, and in combination as a 4-level variable: 1) moderate/severe sleep disturbance alone, 2) moderate/severe depression alone, 3) both moderate/severe sleep disturbance and depression, 4) no moderate/severe sleep disturbance or depression. RESULTS: Preoperative sleep disturbance and depression were associated with 12-month disability and pain (P<0.05). After accounting for depression, preoperative sleep disturbance remained associated with disability, while preoperative depression adjusting for sleep disturbance remained associated with all outcomes (P<0.05). Patients reporting both moderate/severe sleep disturbance and moderate/severe depression had 12.6 points higher disability and 1.5 points higher back and leg pain compared to patients without moderate/severe sleep disturbance or depression. CONCLUSION: The combination of sleep disturbance and depression impacts postoperative outcomes considerably. The high-risk group of patients with moderate/severe sleep disturbance and depression could benefit from targeted treatment strategies.

Impact of Racial/Ethnic Disparities on Patient Reported Outcomes Following Cervical Spine Surgery: QOD Analysis.

STUDY DESIGN: Retrospective analysis of data from the cervical module of a national spine registry, the Quality Outcomes Database (QOD). OBJECTIVE: To examine the association of race and ethnicity with patient-reported outcome measures (PROMs) at 1 year after cervical spine surgery. SUMMARY OF BACKGROUND DATA: Evidence suggests that Black individuals are 39% to 44% more likely to have postoperative complications and prolonged length of stay after cervical spine surgery compared to Whites. The long-term recovery assessed with PROMs after cervical spine surgery among Black, Hispanic and other non-Hispanic groups (i.e., Asian) remains unclear. METHODS: PROMs were used to assess disability (NDI) and neck/arm pain preoperatively and 1-year postoperative. Primary outcomes were disability and pain, and not being satisfied from pre-operative to 12-months after surgery. Multivariable logistic and proportional odds regression analyses were used to determine the association of racial/ethnic groups (Hispanic, non-Hispanic White (NHW), non-Hispanic Black (NHB), and non-Hispanic Asian (NHA)) with outcomes after covariate adjustment and to compute the odds of each racial/ethnic group achieving MCID 1-year postoperatively. RESULTS: Of the 14,429 participants, all had significant reductions in pain and disability, and 87% were satisfied at 1-year follow-up. Hispanic and NHB patients had higher odds of not being satisfied (40% and 80%) and having worse pain outcomes (30% to 70%) compared to NHW. NHB had 50% higher odds of worse disability scores compared to NHW. NHA reported similar disability and neck pain outcomes compared to NHW. CONCLUSIONS: Hispanic and non-Hispanic Black patients had worse patient-reported outcomes 1-year after cervical spine surgery compared to non-Hispanic White individuals, even after adjusting for potential confounders, yet there was no difference in disability and neck pain outcomes reported for non-Hispanic Asian patients. This study highlights the need to address inherent racial/ethnic disparities in recovery trajectories following cervical spine surgery. LEVEL OF EVIDENCE: 3.

Isoforms of the neuropeptide myosuppressin differentially modulate the cardiac neuromuscular system of the American lobster, Homarus americanus.

Post-translational modifications (PTMs) diversify peptide structure and allow for greater flexibility within signaling networks. The cardiac neuromuscular system of the American lobster, Homarus americanus, is made up of a central pattern generator, the cardiac ganglion (CG), and peripheral cardiac muscle. Together, these components produce flexible output in response to peptidergic modulation. Here, we examined the role of PTMs in determining the effects of a cardioactive neuropeptide, myosuppressin (pQDLDHVFLRFamide), on the whole heart, the neuromuscular junction/muscle, the isolated CG, and the neurons of the CG. Mature myosuppressin and noncyclized myosuppressin (QDLDHVFLRFamide) elicited similar and significant changes in whole heart contraction amplitude and frequency, stimulated muscle contraction amplitude and the bursting pattern of the intact and ligatured neurons of the ganglion. In the whole heart, nonamidated myosuppressin (pQDLDHVFLRFG) elicited only a small decrease in frequency and amplitude. In the absence of motor neuron input, nonamidated myosuppressin did not cause any significant changes in the amplitude of stimulated contractions. In the intact CG, nonamidated myosuppressin elicited a small but significant decrease in burst duration. Further analysis revealed a correlation between the extent of modulation elicited by nonamidated myosuppressin in the whole heart and the isolated, intact CG. When the neurons of the CG were physically decoupled, nonamidated myosuppressin elicited highly variable responses. Taken together, these data suggest that amidation, but not cyclization, is critical in enabling this peptide to exert its effects on the cardiac neuromuscular system.NEW & NOTEWORTHY Myosuppressin (pQDLDHVFLRFamide), a well-characterized crustacean neuropeptide, and its noncyclized (QDLDHVFLRFamide) and nonamidated (pQDLDHVFLRFG) isoforms alter the output of the cardiac neuromuscular system of the American lobster, Homarus americanus. Mature myosuppressin and noncyclized myosuppressin elicited similar and significant changes across all levels of the isolated system, whereas responses to nonamidated myosuppressin were significantly different from other isoforms and were highly variable. These data support the diversity of peptide action as a function of peptide structure.

Clinically Meaningful Improvement Following Cervical Spine Surgery: 30% Reduction Versus Absolute Point-change MCID Values.

STUDY DESIGN: Retrospective analysis of prospectively collected registry data. OBJECTIVE: The aim of this study was to compare the performance of 30% reduction to established absolute point-change values for measures of disability and pain in patients undergoing elective cervical spine surgery. SUMMARY OF BACKGROUND DATA: Recent studies recommend using a proportional change from baseline instead of an absolute point-change value to define minimum clinically important difference (MCID). METHODS: Analyses included 13,179 patients who underwent cervical spine surgery for degenerative disease between April 2013 and February 2018. Participants completed a baseline and 12-month follow-up assessment that included questionnaires to assess disability (Neck Disability Index [NDI]), neck and arm pain (Numeric Rating Scale [NRS-NP/AP], and satisfaction [NASS scale]). Participants were classified as met or not met 30% reduction from baseline in each of the respective measures. The 30% reduction in scores at 12 months was compared to a wide range of established absolute point-change MCID values using receiver-operating characteristic curves, area under the receiver-operating characteristic curve (AUROC), and logistic regression analyses. These analyses were conducted for the entire patient cohort, as well as for subgroups based on baseline severity and surgical approach. RESULTS: Thirty percent reduction in NDI and NRS-NP/AP scores predicted satisfaction with more accuracy than absolute point-change values for the total population and ACDF and posterior fusion procedures (P < 0.05). The largest AUROC differences, in favor of 30% reduction, were found for the lowest disability (ODI 0-20%: 16.8%) and bed-bound disability (ODI 81%-100%: 16.6%) categories. For pain, there was a 1.9% to 11% and 1.6% to 9.6% AUROC difference for no/mild neck and arm pain (NRS 0-4), respectively, in favor of a 30% reduction threshold. CONCLUSION: A 30% reduction from baseline is a valid method for determining MCID in disability and pain for patients undergoing cervical spine surgery.Level of Evidence: 3.

Differential neuropeptide modulation of premotor and motor neurons in the lobster cardiac ganglion.

The American lobster, Homarus americanus, cardiac neuromuscular system is controlled by the cardiac ganglion (CG), a central pattern generator consisting of four premotor and five motor neurons. Here, we show that the premotor and motor neurons can establish independent bursting patterns when decoupled by a physical ligature. We also show that mRNA encoding myosuppressin, a cardioactive neuropeptide, is produced within the CG. We thus asked whether myosuppressin modulates the decoupled premotor and motor neurons, and if so, how this modulation might underlie the role(s) that these neurons play in myosuppressin's effects on ganglionic output. Although myosuppressin exerted dose-dependent effects on burst frequency and duration in both premotor and motor neurons in the intact CG, its effects on the ligatured ganglion were more complex, with different effects and thresholds on the two types of neurons. These data suggest that the motor neurons are more important in determining the changes in frequency of the CG elicited by low concentrations of myosuppressin, whereas the premotor neurons have a greater impact on changes elicited in burst duration. A single putative myosuppressin receptor (MSR-I) was previously described from the Homarus nervous system. We identified four additional putative MSRs (MSR-II-V) and investigated their individual distributions in the CG premotor and motor neurons using RT-PCR. Transcripts for only three receptors (MSR-II-IV) were amplified from the CG. Potential differential distributions of the receptors were observed between the premotor and motor neurons; these differences may contribute to the distinct physiological responses of the two neuron types to myosuppressin.NEW & NOTEWORTHY Premotor and motor neurons of the Homarus americanus cardiac ganglion (CG) are normally electrically and chemically coupled, and generate rhythmic bursting that drives cardiac contractions; we show that they can establish independent bursting patterns when physically decoupled by a ligature. The neuropeptide myosuppressin modulates different aspects of the bursting pattern in these neuron types to determine the overall modulation of the intact CG. Differential distribution of myosuppressin receptors may underlie the observed responses to myosuppressin.

Why are patients dissatisfied after spine surgery when improvements in disability and pain are clinically meaningful?

BACKGROUND CONTEXT: Studies have found that most patients are satisfied after spine surgery, with rates ranging from 53% to 90%. Patient satisfaction appears to be closely related to achieving clinical improvement in pain and disability after surgery. While the majority of the literature has focused on patients who report both satisfaction and clinical improvement in disability and pain, there remains an important subpopulation of patients who have clinically relevant improvement but report being dissatisfied with surgery. PURPOSE: To examine why patients who achieve clinical improvement in disability or pain also report dissatisfaction at 1-year after spinal surgery. STUDY DESIGN: Retrospective analysis of prospective data from a national spine registry, the Quality Outcomes Database. PATIENT SAMPLE: There were 34,076 participants undergoing elective surgery for degenerative spine pathology who had clinical improvement in disability or pain. OUTCOME MEASURES: Satisfaction with surgery was assessed with 1-item from the North American Spine Society lumbar spine outcome assessment. Participants with answer choices other than "treatment met my expectations" were classified as dissatisfied. METHODS: Patients completed a baseline and 12-month postoperative assessment to evaluate disability, pain, and satisfaction. Clinical improvement was defined as patients who achieved a 30% or greater improvement in spine-related disability (Oswestry/Neck Disability Index) or extremity pain (11-point Numeric Rating Scale) from baseline to 12-month after surgery. A generalized linear mixed model was used to predict the odds of the patient being dissatisfied 1-year after surgery from demographic, clinical and surgical characteristics, postoperative complications and revision, and return to work and previous physical activity. Random effects were included to model the effect of both site and surgeon on dissatisfaction. Sensitivity analyses were conducted on samples who achieved 30% or greater improvement in (1) disability only, (2) axial (back/neck) pain only, (3) extremity (leg/arm)pain only, (4) both disability and axial pain, and (5) both disability and extremity pain. Results showed the same pattern of findings across all samples. RESULTS: Twenty-eight percent of patients were classified as dissatisfied with their spine surgery and 72% classified as satisfied. For patients with clinical improvement in disability or extremity pain at 1-year, significant predictors of higher odds of dissatisfaction included baseline psychological distress, current smoking status, workers compensation claim, lower education, higher ASA grade, lumbar versus cervical procedure, and increased axial pain, major complication within 30 days, and revision surgery within 12-months. The most important contributors to dissatisfaction were return to work and return to previous physical activity, with the odds of dissatisfaction being over 2 times and 4 times higher for these variables. Site and surgeon explained 3.8% of the variance in dissatisfaction, with more of the variance attributed to site than to surgeon. CONCLUSIONS: Several modifiable factors, including psychological distress, current smoking status, and failure to return to work and physical activity, helped explain why patients report being dissatisfied with surgery despite clinical improvement in disability or pain. The findings of this study have the potential to help providers identify at-risk patients, set realistic expectations during preoperative counseling, and implement postoperative management strategies. A multidisciplinary approach to rehabilitation that includes functional goal setting or restoration may help to improve patients psychological distress as well as return to work and previous physical activity after spine surgery.

Measuring clinically relevant improvement after lumbar spine surgery: is it time for something new?

BACKGROUND CONTEXT: Minimum clinically important difference (MCID) for patient-reported outcome measures is commonly used to assess clinical improvement. However, recent literature suggests that an absolute point-change may not be an effective or reliable marker of response to treatment for patients with low or high baseline patient-reported outcome scores. The multitude of established MCIDs also makes it difficult to compare outcomes across studies and different spine surgery procedures. PURPOSE: To determine whether a 30% reduction from baseline in disability and pain is a valid method for determining clinical improvement after lumbar spine surgery. STUDY DESIGN: Retrospective analysis of prospective data from a national spine registry, the Quality Outcomes Database. PATIENT SAMPLE: There were 23,280 participants undergoing elective lumbar spine surgery for degenerative disease who completed a baseline and follow-up assessment at 12 months. OUTCOME MEASURES: Patient-reported disability (Oswestry Disability Index [ODI]), back and leg pain (11-point Numeric Rating Scale [NRS]), and satisfaction (NASS scale). METHODS: Patients completed baseline and a 12-month postoperative assessment to evaluate the outcomes of disability, pain, and satisfaction. The change in ODI and NRS pain scores was categorized as met (≥30%) or not met (<30%) percent reduction MCID. The 30% reduction from baseline was compared with a wide range of well-established absolute point-change MCID values. The relationship between 30% reduction and absolute change values and satisfaction were primarily compared using receiver operating characteristic (ROC) curves, area under the curve (AUROC), and logistic regression analyses. Analyses were conducted for overall scores and for disability and pain severity categories and by surgical procedure. RESULTS: Thirty percent reduction in ODI and back and leg pain predicted satisfaction with more accuracy than absolute point-change values for the total population and across all procedure categories (p<.001), except for when compared with the highest absolute point-change threshold for leg pain (3.5-point reduction). The largest AUROC differences, in favor of 30% reduction, were found for the lowest disability (ODI 0-20%: 21.8%) and bed-bound disability (ODI 81%-100%: 13.9%) categories. For pain, there was a 3.4%-12.4% and 1.3%-9.8% AUROC difference for no/mild back and leg pain (NRS 0-4), respectively, in favor of a 30% reduction threshold. CONCLUSIONS: A 30% reduction MCID either outperformed or was similar to absolute point-change MCID values. Results indicate that a 30% reduction (baseline to 12 months after surgery) in disability and pain is a valid method for determining clinically relevant improvement in a broad spine surgery population. Furthermore, a 30% reduction was most accurate for patients in the lowest and highest disability and lowest pain severity categories. A 30% reduction MCID allows for a standard cut-off for disability and pain that can be used to compare outcomes across various spine surgery procedures.

To what extent may peptide receptor gene diversity/complement contribute to functional flexibility in a simple pattern-generating neural network?

Peptides are known to contribute to central pattern generator (CPG) flexibility throughout the animal kingdom. However, the role played by receptor diversity/complement in determining this functional flexibility is not clear. The stomatogastric ganglion (STG) of the crab, Cancer borealis, contains CPGs that are models for investigating peptidergic control of rhythmic behavior. Although many Cancer peptides have been identified, their peptide receptors are largely unknown. Thus, the extent to which receptor diversity/complement contributes to modulatory flexibility in this system remains unresolved. Here, a Cancer mixed nervous system transcriptome was used to determine the peptide receptor complement for the crab nervous system as a whole. Receptors for 27 peptide families, including multiple receptors for some groups, were identified. To increase confidence in the predicted sequences, receptors for allatostatin-A, allatostatin-B, and allatostatin-C were cloned, sequenced, and expressed in an insect cell line; as expected, all three receptors trafficked to the cell membrane. RT-PCR was used to determine whether each receptor was expressed in the Cancer STG. Transcripts for 36 of the 46 identified receptors were amplified; these included at least one for each peptide family except RYamide. Finally, two peptides untested on the crab STG were assessed for their influence on its motor outputs. Myosuppressin, for which STG receptors were identified, exhibited clear modulatory effects on the motor patterns of the ganglion, while a native RYamide, for which no STG receptors were found, elicited no consistent modulatory effects. These data support receptor diversity/complement as a major contributor to the functional flexibility of CPGs.

Comparing different chronic preoperative opioid use definitions on outcomes after spine surgery.

BACKGROUND CONTEXT: No consensus exists for defining chronic preoperative opioid use. Most spine studies rely solely on opioid duration to stratify patients into preoperative risk categories. PURPOSE: The purpose of this study is to compare established opioid definitions that contain both duration and dosage to opioid models that rely solely on duration, including the CDC Guideline for Prescribing Opioids for Chronic Pain, in patients undergoing spine surgery. STUDY DESIGN: This was a retrospective cohort study that used opioid data from the Tennessee Controlled Substance Monitoring Database and prospective clinical data from a single-center academic spine registry. PATIENT SAMPLE: The study cohort consisted of 2,373 patients who underwent elective spine surgery for degenerative conditions between January 2011 and February 2017 and who completed a follow-up assessment at 12 months after surgery. OUTCOME MEASURES: Postoperative opioid use and patient-reported satisfaction (NASS Satisfaction Scale), disability (Oswestry/Neck Disability Index), and pain (Numeric Rating Scale) at 12 month follow-up. METHODS: Six different chronic preoperative opioid use variables were created based on the number of times a prescription was filled and/or daily morphine milligram equivalent for the one year before surgery. These variables defined chronic opioid use as 1) most days for > 3 months (CDC), 2) continuous use for ≥ 6 months (Schoenfeld), 3) >4,500 mg for at least 9 months (Svendsen wide), 4) >9,000 mg for 12 months (Svendsen intermediary), 5) >18,000 mg for 12 months (Svendsen strict), 6) low-dose chronic (1-36 mg for >91 days), medium-dose chronic (36-120 mg for >91 days), and high-dose chronic (>120 mg for >91 days) (Edlund). Multivariable regression models yielding C-index and R2 values were used to compare chronic preoperative opioid use definitions by postoperative outcomes, adjusting for type of surgery. RESULTS: Chronic preoperative opioid use was reported in 470 to 725 (19.8% to 30.6%) patients, depending on definition. The Edlund definition, accounting for duration and dosage, had the highest predictive ability for postoperative opioid use (77.5%), followed by Schoenfeld (75.7%), CDC (72.6%), and Svendsen (59.9% to 72.5%) definitions. A combined Edlund and Schoenfeld duration and dosage definition in post-hoc analysis, that included 3 and 6 month duration cut-offs, performed the best overall with a C-index of 78.4%. Both Edlund and Schoenfeld definitions explained similar amounts of variance in satisfaction, disability, and pain (4.2% to 8.5%). Svendsen and CDC definitions demonstrated poorer performance for patient-reported outcomes (1.4% to 7.2%). CONCLUSIONS: The Edlund definition is recommended for identifying patients at highest risk for postoperative opioid use. When opioid dosage is unavailable, the Schoenfeld definition is a reasonable choice with similar predictive ability. For patient-reported outcomes, either the Edlund or Schoenfeld definition is recommended. Future work should consider combing dosage and duration, with 3 and 6 month cutoffs, into chronic opioid use definitions.

AMGSEFLamide, a member of a broadly conserved peptide family, modulates multiple neural networks in Homarus americanus.

Recent genomic/transcriptomic studies have identified a novel peptide family whose members share the carboxyl terminal sequence -GSEFLamide. However, the presence/identity of the predicted isoforms of this peptide group have yet to be confirmed biochemically, and no physiological function has yet been ascribed to any member of this peptide family. To determine the extent to which GSEFLamides are conserved within the Arthropoda, we searched publicly accessible databases for genomic/transcriptomic evidence of their presence. GSEFLamides appear to be highly conserved within the Arthropoda, with the possible exception of the Insecta, in which sequence evidence was limited to the more basal orders. One crustacean in which GSEFLamides have been predicted using transcriptomics is the lobster, Homarus americanus Expression of the previously published transcriptome-derived sequences was confirmed by reverse transcription (RT)-PCR of brain and eyestalk ganglia cDNAs; mass spectral analyses confirmed the presence of all six of the predicted GSEFLamide isoforms - IGSEFLamide, MGSEFLamide, AMGSEFLamide, VMGSEFLamide, ALGSEFLamide and AVGSEFLamide - in H. americanus brain extracts. AMGSEFLamide, of which there are multiple copies in the cloned transcripts, was the most abundant isoform detected in the brain. Because the GSEFLamides are present in the lobster nervous system, we hypothesized that they might function as neuromodulators, as is common for neuropeptides. We thus asked whether AMGSEFLamide modulates the rhythmic outputs of the cardiac ganglion and the stomatogastric ganglion. Physiological recordings showed that AMGSEFLamide potently modulates the motor patterns produced by both ganglia, suggesting that the GSEFLamides may serve as important and conserved modulators of rhythmic motor activity in arthropods.