Christopher K. Kepler

Study Design.: Retrospective Cohort Study Objective.: The objective of the present investigation is to evaluate the association between perioperative SGLT2i use and short-term postoperative complications and long-term outcomes following ACDF. Summary of Background Data.: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a class of diabetic medications that provide cardiorenal benefits beyond glycemic control. Despite these benefits, SGLT2i use has been associated with a range of adverse effects. However, the literature remains limited regarding the impact of SGLT2i on perioperative recovery and complications in patients undergoing anterior cervical discectomy and fusion (ACDF). Methods.: A retrospective cohort study was conducted using the TriNetX database. Patients undergoing ACDF were identified and stratified by preoperative SGLT2i use. After 1:1 propensity score matching on demographics and comorbidities, 1,585 patients remained per cohort. Outcomes included postoperative events and long-term sequelae. Risk ratios (RR), 95% confidence intervals (CI), and P values were calculated; Kaplan–Meier curves were used to assess long-term event incidence. Results.: The SGLT2i cohort demonstrated lower rates of postoperative emergency department visits (1.3% vs. 2.2%; RR 0.59, 95% CI 0.34–0.99; P =0.047). At 1-year follow-up, patients receiving SGLT2i had lower rates of pseudoarthrosis (4.9% vs. 6.8%; RR 0.73, 95% CI 0.55–0.97; P =0.028). Reoperation rates at 5 years were also lower in the SGLT2i cohort (2.2% vs. 3.5%; RR 0.64, 95% CI 0.42–0.97; P =0.033). No significant differences were observed in ICU admission, surgical site infection, urinary tract infection, acute kidney injury, or readmission. Conclusion.: Preoperative SGLT2 inhibitor use was associated with reduced postoperative emergency department utilization and lower rates of early pseudarthrosis following ACDF, without an increased risk of short-term complications. Recognition of these risks should inform preoperative counselling, postoperative surveillance, and multidisciplinary care planning for patients undergoing ACDF.

Introduction: In modern healthcare systems, the role of advanced practice providers (APPs), including nurse practitioners (NP) and physician assistants (PA), has increased in many settings, in step with the increased demand for healthcare services. The purpose of the present investigation was to evaluate trends in the prevalence, reimbursement, and characteristics of care provided by APPs in the treatment of spinal disorders in the United States from 2013 to 2022. Methods: A retrospective cohort study using the publicly available Medicare Provider Utilization and Payment database from the Centers for Medicare and Medicare Services was conducted on diagnostic, procedural, and therapeutic services provided by advanced practice providers from 2013 to 2022. Provider-type and billing codes were used to identify healthcare professionals providing care for spine patients, such as ordering radiographs, assisting in surgical procedures, or performing office visits. Trends were analyzed using linear regression modeling with projections generated through 2030. Results: Over the study period, the number of surgeons involved in spine care decreased from 3953 (71.2%) in 2013 to 3951 (66.7%) in 2022. The number of APPs who billed for the care of spine patients increased 23.3% from 1600 in 2013 to 1974 in 2022. The most common services billed for by APPs included radiographs and office visits. There were increased odds (OR: 1.20, 95% CI, 1.03-1.41, P < 0.001) of a spine provider in rural areas being an APP versus spine surgeon. Forecasting analysis for 2030 demonstrated continuation of these trends regarding the number of providers, services, and geographic distribution. Discussion: Increased utilization of APPs in the care of patients with spinal pathology is likely to continue with the growing prevalence of patients with spinal disorders.

Extracellular matrix (ECM) dysregulation plays a significant role in the development of intervertebral disc disease (IVDD). The ECM around the chondrocytes in the nucleus pulposus (NP) is unique in that it contains ColVI. While linked to chondrocyte proliferation in cartilage, ColVI’s specific role in IVD degeneration is less clear. Our aim was to determine the expression of ColVI in NP cells from degenerative IVDs, along with the effects of soluble ColVI on NP cells. Thus, we compared the expression levels of ColVI in human degenerated IVD samples, along with the effect of soluble ColVI on primary human NP cells. A higher Pfirrmann grade was associated with increased COL6A1 mRNA expression, with a 4.4-fold increase in Pfirrmann grade IV (p = 0.024) and a 5.3-fold increase in grade V compared to grade III (p = 0.014). Soluble ColVI increased NP cell proliferation compared to untreated controls, from 1.204-fold for 5 µg/mL (p < 0.001) and 1.335-fold for 10 µg/mL (p = 0.001). The most upregulated gene was IGF-1 (7.9-fold increase). Co-treatment of NP cells with ColVI and an ERK inhibitor showed significantly less IGF-1 mRNA upregulation compared to ColVI treatment alone (6.2-fold vs. 12.4-fold; p = 0.009). Our findings suggest that degenerating discs are associated with COL6A1 upregulation by NP cells; moreover, the addition of soluble ColVI to NP cells increases NP cell proliferation and IGF-1 expression.

Objective: Low back pain (LBP) is common. Although imaging studies are widely used to evaluate back pain, the link between pain and intervertebral disc degeneration visualized on images is unclear. This study aims to discover novel biomarkers in patients with severe back pain. Design: Levels of 1512 serum proteins from 29 patients with LBP and 11 healthy controls were compared. Machine learning analyses were employed to identify proteins diagnostic of LBP, based on cumulative feature importance across five machine learning models with the highest performance. Proteins with highest feature importance and area under the receiver-operating characteristic curves (AUC) underwent pathway and network analyses. Results: Distinct serum biomarkers differentiating LBP patients from healthy controls were identified. Using Somascan proteomic analysis and machine learning methods, 37 significant biomarkers were highlighted. Notably, IL-19 and biglycan showed the strongest diagnostic potential (AUC 0.91 and 0.89, respectively). Pathway analyses implicate systemic processes in LBP pathology. Conclusions: IL-19 and biglycan showed promise as serum biomarkers in patients with severe LBP. Given the small sample size of this study, these findings are preliminary and require validation in larger, age- and sex-matched cohorts, with a confirmative, quantitative assay for key markers.

Purpose: Patients frequently utilize internet-based resources to seek information. Cervical disc replacement (CDR) is extensively marketed on the internet and patients may research their condition in preference to a fusion. Previous literature has recommended that the readability of patient education materials (PEM) should not exceed the 6th-grade(11–12 years old) United States reading level to optimize health literacy. This study aims to evaluate the readability of online patient education materials concerning cervical disc replacement. Methods: A Google search query was performed on March 1st, 2025 using the term” Cervical Disc Replacement patient information.” The first 25 websites meeting study inclusion criteria were analyzed for readability using Flesch-Kincaid, average reading level consensus, Gunning Fog, Coleman-Liau, SMOG, and Linsear Write indices. Descriptive statistics were reported. Results: The mean of the average reading levels by Flesch-Kincaid was 11.5 (1.29). The mean Flesch Kincaid Reading Ease score was 48.8 (8.12). The mean Gunning Fog Score was 12.9 (1.39), Flesch Kincaid grade level 10.6 (1.69), Coleman Liau 12.4 (1.48), SMOG 10.5 (1.3), Automated Readability Index 11.5 (2.12), Linear Write 69.4 (6.62). Zero PEMs were at or below the recommended sixth grade(11–12 years old) United States reading level. Four of the PEMs were considered general health information(GHI), twenty-one were considered clinical practice(CP). No differences were found between CP and GHI websites (P > 0.05). Conclusion: Creating appropriate patient education materials is integral to achieving optimal health literacy. The current readability of the most accessible PEMs related to CDR is inadequate. As it stands, many patients may not appropriately comprehend the description of their anticipated surgery.

Study Design.: Global cross-sectional survey. Objective.: To validate the hierarchical nature of the AO Spine Upper Cervical Spine Injury Classification (UCIC) across AO geographical regions/practice experience. Summary of Background Data.: To create a universally validated scheme with prognostic value, AO Spine established an upper cervical spine injury classification involving three elements: injury morphology (region: I—occipital condyle and craniocervical junction; II—C1 ring and C1-2 joint; III—C2 and C2-3 joint), and (subtype: A—isolated bony injury; B—bony/ligamentous injury; C—displaced/translational injury), neurological status [N0—intact; N1—transient deficit; N2—radiculopathy; N3—incomplete spinal cord injury (SCI); N4—complete SCI, and NX—unable to examine], and case-specific modifiers (M1—injuries at risk of nonunion; M2—injuries at risk of instability; M3—patient specific factors; M4—vascular injury). Materials and Methods.: Totally, 151 AO Spine members (orthopaedic and neurosurgery) were surveyed globally regarding the severity (zero—low severity to 100—high severity) of each UCIC variable. Primary outcomes were differences in perceived injury severity score (ISS) over various geographic/practice settings, level of experience, and subspecialty. Results.: One hundred forty-eight responses were received. There was an increase in median perceived severity as each anatomic region (I–III) progressed from types A to B to C. Neurological status progressed similarly, except N1 and N2 were perceived similarly. Modifier M2 was perceived more severely than M3. There were no differences in ISS among levels of surgeon experience. There were small geographic differences with respondents from North and Central and South America perceiving types IC (P=0.003), IIB (P=0.003), and IIIB (P=0.003) somewhat more severely than other regions. Neurosurgeons perceived types IB (P=0.002) and IIIB (P=0.026) as more severe than orthopaedic spine surgeons. Conclusions.: The AO Spine UCIC has overall excellent hierarchical progression in subtype ISS. These findings are consistent across geographic regions, spine subspecialty training and experience levels.

Study Design.: Global cross-sectional survey. Objective.: To determine the classification accuracy, interobserver reliability, and intraobserver reproducibility of the AO Spine Upper Cervical Injury Classification System based on an international group of AO Spine members. Summary of Background Data.: Previous upper cervical spine injury classifications have primarily been descriptive without incorporating a hierarchical injury progression within the classification system. Further, upper cervical spine injury classifications have focused on distinct anatomical segments within the upper cervical spine. The AO Spine Upper Cervical Injury Classification System incorporates all injuries of the upper cervical spine into a single classification system focused on a hierarchical progression from isolated bony injuries (type A) to fracture dislocations (type C). Methods.: A total of 275 AO Spine members participated in a validation aimed at classifying 25 upper cervical spine injuries through computed tomography scans according to the AO Spine Upper Cervical Classification System. The validation occurred on two separate occasions, three weeks apart. Descriptive statistics for percent agreement with the gold-standard were calculated and the Pearson χ² test evaluated significance between validation groups. Kappa coefficients (κ) determined the interobserver reliability and intraobserver reproducibility. Results.: The accuracy of AO Spine members to appropriately classify upper cervical spine injuries was 79.7% on assessment 1 (AS1) and 78.7% on assessment 2 (AS2). The overall intraobserver reproducibility was substantial (κ=0.70), while the overall interobserver reliability for AS1 and AS2 was substantial (κ=0.63 and κ=0.61, respectively). Injury location had higher interobserver reliability (AS1: κ = 0.85 and AS2: κ=0.83) than the injury type (AS1: κ=0.59 and AS2: 0.57) on both assessments. Conclusion.: The global validation of the AO Spine Upper Cervical Injury Classification System demonstrated substantial interobserver agreement and intraobserver reproducibility. These results support the universal applicability of the AO Spine Upper Cervical Injury Classification System. Level of Evidence: 4

Study Design. Laboratory study. Objective. To evaluate whether blockade of the Substance P (SP) NK1R attenuates its proinflammatory effect on human intervertebral disc cells (IVD), and to evaluate the signaling pathways associated with SP. Summary of Background Data. SP and its receptors are expressed in human IVD cells, and cause upregulation of inflammatory mediators; however, the effects of blocking these receptors have not been studied in human IVD cells. Methods. Human annulus fibrosus (AF) and nucleus pulposus (NP) cells were expanded in monolayer, and then suspended in alginate beads. The alginate beads were treated with culture medium first containing a high affinity NK1R antagonist (L-760735) at different concentrations, and then with medium containing both NK1R antagonist and SP at 2 concentrations. Ribonucleic acid was isolated and transcribed into cDNA. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to evaluate expression of interleukin (IL)-1β, IL-6, and IL-8. Western blot analysis was performed to examine levels of the phosphorylated p38 mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase 1/2 (ERK1/2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB p65). The cells were pretreated with specific inhibitors of p38 (SB203580), ERK1/2 (PD98059), and p65 (SM7368) and then stimulated with SP. Results. We detected expression of NK1R, neurokinin receptor 2 (NK2R), and neurokinin receptor 3 (NK3R) in AF and NP cells. Treatment of disc cells with the NK1R antagonist was able to suppress expression of IL-1β, IL-6, and IL-8 in a dose-dependent manner. SP stimulation increased phosphorylation of p38-MAPK and ERK1/2, but not of NFκB p65. This indicates that p38-MAPK and ERK1/2 control SP-induced cytokine expression independently from NF-kB p65. Inhibition of p38 and ERK1/2 activation reduced SP-induced IL-6 production in human disc cells. Conclusion. NK1R is responsible for the proinflammatory effect of SP on IVD cells and this effect can be blocked by preventing binding of SP to NK1R. This study shows for the first time that SP mediates signaling in disc cells through NK1R and that SP activates the proinflammatory p38-MAPK and ERK1/2 pathways. Level of Evidence: 4