Like-minded sources on Facebook are prevalent but not polarizing.

Many critics raise concerns about the prevalence of 'echo chambers' on social media and their potential role in increasing political polarization. However, the lack of available data and the challenges of conducting large-scale field experiments have made it difficult to assess the scope of the problem1,2. Here we present data from 2020 for the entire population of active adult Facebook users in the USA showing that content from 'like-minded' sources constitutes the majority of what people see on the platform, although political information and news represent only a small fraction of these exposures. To evaluate a potential response to concerns about the effects of echo chambers, we conducted a multi-wave field experiment on Facebook among 23,377 users for whom we reduced exposure to content from like-minded sources during the 2020 US presidential election by about one-third. We found that the intervention increased their exposure to content from cross-cutting sources and decreased exposure to uncivil language, but had no measurable effects on eight preregistered attitudinal measures such as affective polarization, ideological extremity, candidate evaluations and belief in false claims. These precisely estimated results suggest that although exposure to content from like-minded sources on social media is common, reducing its prevalence during the 2020 US presidential election did not correspondingly reduce polarization in beliefs or attitudes.

The effects of Facebook and Instagram on the 2020 election: A deactivation experiment.

We study the effect of Facebook and Instagram access on political beliefs, attitudes, and behavior by randomizing a subset of 19,857 Facebook users and 15,585 Instagram users to deactivate their accounts for 6 wk before the 2020 U.S. election. We report four key findings. First, both Facebook and Instagram deactivation reduced an index of political participation (driven mainly by reduced participation online). Second, Facebook deactivation had no significant effect on an index of knowledge, but secondary analyses suggest that it reduced knowledge of general news while possibly also decreasing belief in misinformation circulating online. Third, Facebook deactivation may have reduced self-reported net votes for Trump, though this effect does not meet our preregistered significance threshold. Finally, the effects of both Facebook and Instagram deactivation on affective and issue polarization, perceived legitimacy of the election, candidate favorability, and voter turnout were all precisely estimated and close to zero.

Single cell RNA sequencing reveals emergent notochord-derived cell subpopulations in the postnatal nucleus pulposus.

Intervertebral disc degeneration is a leading cause of chronic low back pain. Cell-based strategies that seek to treat disc degeneration by regenerating the central nucleus pulposus (NP) hold significant promise, but key challenges remain. One of these is the inability of therapeutic cells to effectively mimic the performance of native NP cells, which are unique amongst skeletal cell types in that they arise from the embryonic notochord. In this study, we use single cell RNA sequencing to demonstrate emergent heterogeneity amongst notochord-derived NP cells in the postnatal mouse disc. Specifically, we established the existence of progenitor and mature NP cells, corresponding to notochordal and chondrocyte-like cells, respectively. Mature NP cells exhibited significantly higher expression levels of extracellular matrix (ECM) genes including aggrecan, and collagens II and VI, along with elevated transforming growth factor-beta and phosphoinositide 3 kinase-protein kinase B signaling. Additionally, we identified Cd9 as a novel surface marker of mature NP cells, and demonstrated that these cells were localized to the NP periphery, increased in numbers with increasing postnatal age, and co-localized with emerging glycosaminoglycan-rich matrix. Finally, we used a goat model to show that Cd9+ NP cell numbers decrease with moderate severity disc degeneration, suggesting that these cells are associated with maintenance of the healthy NP ECM. Improved understanding of the developmental mechanisms underlying regulation of ECM deposition in the postnatal NP may inform improved regenerative strategies for disc degeneration and associated low back pain.

A decade-long longitudinal survey shows that the Supreme Court is now much more conservative than the public.

Has the US Supreme Court become more conservative than the public? We introduce results of three surveys conducted over the course of a decade that ask respondents about their opinions on the policy issues before the court. Using these data, we show that the gap between the court and the public has grown since 2020, with the court moving from being quite close to the average American to a position that is more conservative than the majority of Americans. Second, in contrast to findings showing consistency in the public's approval of or deference to the court, we find that the public's expectations of the court vary significantly over time and in tandem with changes in the court's composition and recent rulings. Even so, many members of the public currently underestimate the court's conservative leaning. Third, we find that respondents' perceptions of the court's ideology relative to their own are associated with support for institutional changes but with important differences between Democrats and Republicans. The fact that so many people currently underestimate how conservative the court is implies that support for proposed changes to the court may be weaker than it would be if people knew with greater accuracy the court's conservative nature.

Outcomes from 871,441 Consecutive Surgical Procedures without Overlap or with Maximally Permissible Non-Concurrent Overlap.

OBJECTIVE: To isolate the impact of subsumed surgery (a shorter procedure completed entirely during overlapping non-critical portions of a longer antecedent procedure) on patient outcomes. SUMMARY BACKGROUND DATA: The American College of Surgeons recently recommended the elimination of "concurrent surgery" with overlap during a procedure's critical portions. Guidelines for non-concurrent overlap have been established, but the safety of subsumed surgery remains to be examined. METHODS: All consecutive procedures from 2013 to 2021 within a multihospital academic medical center were included (n=871,441). Simple logistic regression was performed to compare postoperative events between patients undergoing non-overlap surgery (n=533,032) and completely subsumed surgery (n=11,319). Thereafter, coarsened exact matching was used to match patients with non-overlap and subsumed surgery 1:1 on CPT code, 18 demographic features, baseline health characteristics, and procedural variables (n=7,146). Exact-matched cases were subsequently limited to pairs performed by the same surgeon (n=5,028). Primary outcomes included 30-day readmission, ED visits, and reoperations. RESULTS: Univariate analysis suggested that subsumed surgery had a higher 30-day risk of readmission (OR 1.55, P<0.0001), ED evaluation (OR 1.19, P<0.0001), and reoperation (OR 1.98, P<0.0001). When comparison was limited to the exact same procedure and patients were matched on demographics and health characteristics, there were no outcome differences between patients with subsumed surgery and non-overlapping surgery, even when limiting analyses to the same surgeon. CONCLUSIONS: Similar surgeries for similar patients result in similar outcomes whether there is completely subsumed or no overlap. Individual surgeons performing a specific procedure have no outcome differences with subsumed and non-overlapping cases.

A Randomized Controlled Trial to Assess the Impact of Enhanced Recovery After Surgery on Patients Undergoing Elective Spine Surgery.

OBJECTIVE: To conduct a prospective, randomized controlled trial (RCT) of an enhanced recovery after surgery (ERAS) protocol in an elective spine surgery population. BACKGROUND: Surgical outcomes such as length of stay (LOS), discharge disposition, and opioid utilization greatly contribute to patient satisfaction and societal healthcare costs. ERAS protocols are multimodal, patient-centered care pathways shown to reduce postoperative opioid use, reduced LOS, and improved ambulation; however, prospective ERAS data are limited in spine surgery. METHODS: This single-center, institutional review board-approved, prospective RCT-enrolled adult patients undergoing elective spine surgery between March 2019 and October 2020. Primary outcomes were perioperative and 1-month postoperative opioid use. Patients were randomized to ERAS (n=142) or standard-of-care (SOC; n=142) based on power analyses to detect a difference in postoperative opioid use. RESULTS: Opioid use during hospitalization and the first postoperative month was not significantly different between groups (ERAS 112.2 vs SOC 117.6 morphine milligram equivalent, P =0.76; ERAS 38.7% vs SOC 39.4%, P =1.00, respectively). However, patients randomized to ERAS were less likely to use opioids at 6 months postoperatively (ERAS 11.4% vs SOC 20.6%, P =0.046) and more likely to be discharged to home after surgery (ERAS 91.5% vs SOC 81.0%, P =0.015). CONCLUSION: Here, we present a novel ERAS prospective RCT in the elective spine surgery population. Although we do not detect a difference in the primary outcome of short-term opioid use, we observe significantly reduced opioid use at 6-month follow-up as well as an increased likelihood of home disposition after surgery in the ERAS group.

The impact of gender on long-term outcomes following supratentorial brain tumor resection.

PURPOSE: Gender is a known social determinant of health which has been linked disparities in medical care. This study intends to assess the impact of gender on 90-day and long-term morbidity and mortality outcomes following supratentorial brain tumor resection in a coarsened-exact matched population. MATERIALS AND METHODS: A total of 1970 consecutive patients at a single, university-wide health system undergoing supratentorial brain tumor resection over a six-year period (09 June 2013 to 26 April 2019) were analyzed retrospectively. Coarsened Exact Matching was employed to match patients on key demographic factors including history of prior surgery, smoking status, median household income, American Society of Anesthesiologists (ASA) grade, and Charlson Comorbidity Index (CCI), amongst others. Primary outcomes assessed included readmission, ED visit, unplanned reoperation, and mortality within 90 days of surgery. Long-term outcomes such as mortality and unplanned return to surgery during the entire follow-up period were also recorded. RESULTS: Whole-population regression demonstrated significantly increased mortality throughout the entire follow-up period for the male cohort (p = 0.004, OR = 1.32, 95% CI = 1.09 - 1.59); however, no significant difference was found after coarsened exact matching was performed (p = 0.08). In both the whole-population regression and matched-cohort analysis, no significant difference was observed between gender and readmission, ED visit, unplanned reoperation, or mortality in the 90-day post-operative window, in addition to return to surgery after throughout the entire follow-up period. CONCLUSION: After controlling for confounding variables, female birth gender did not significantly predict any difference in morbidity and mortality outcomes following supratentorial brain tumor resection. Difference between mortality outcomes in the pre-matched population versus the matched cohort suggests the need to better manage the underlying health conditions of male patients in order to prevent future disparities.

The role of socioeconomic status on outcomes following cerebellopontine angle tumor resection.

PURPOSE: It is well documented that the interaction between many social factors can affect clinical outcomes. However, the independent effects of economics on outcomes following surgery are not well understood. The goal of this study is to investigate the role socioeconomic status has on postoperative outcomes in a cerebellopontine angle (CPA) tumor resection population. MATERIALS AND METHODS: Over 6 years (07 June 2013 to 24 April 2019), 277 consecutive CPA tumor cases were reviewed at a single, multihospital academic medical center. Patient characteristics obtained included median household income, Charlson Comorbidity Index (CCI), race, BMI, tobacco use, amongst 23 others. Outcomes studied included readmission, ED evaluation, unplanned return to surgery (during and after index admission), return to surgery after index admission, and mortality within 90 days, in addition to reoperation and mortality throughout the entire follow-up period. Univariate analysis was conducted amongst the entire population with significance set at a p value <0.05. The population was divided into quartiles based on median household income and univariate analysis conducted between the lowest (Q1) and highest (Q4) socioeconomic quartiles, with significance set at a p value <0.05. Stepwise regression was conducted to determine the correlations amongst study variables and identify confounding factors. RESULTS: Regression analysis of 273 patients did not find household income to be associated with any of the long-term outcomes assessed. Similarly, a Q1 vs Q4 comparison did not yield significantly different odds of outcomes assessed. CONCLUSION: Although not statistically significant, the odds ratios suggest socioeconomic status may have a clinically significant effect on postsurgical outcomes. Further studies in larger, matched populations are necessary to validate these findings.

Matched analysis of patient gender and meningioma resection outcomes.

PURPOSE: Gender is a known social determinant of health (SDOH) that has been linked to neurosurgical outcome disparities. To improve quality of care, there exists a need to investigate the impact of gender on procedure-specific outcomes. The objective of this study was to assess the role of gender on short- and long-term outcomes following resection of meningiomas - the most common benign brain neoplasm of adulthood - between exact matched patient cohorts. MATERIAL AND METHODS: All consecutive patients undergoing supratentorial meningioma resection (n = 349) at a single, university-wide health system over a 6-year period were analyzed retrospectively. Coarsened exact matching was employed to match patients on numerous key characteristics related to outcomes. Primary outcomes included readmission, ED visit, reoperation, and mortality within 30 and 90 days of surgery. Mortality and reoperation were also assessed during the entire follow-up period. Outcomes were compared between matched female and male cohorts. RESULTS: Between matched cohorts, no significant difference was observed in morbidity or mortality at 30 days (p = 0.42-0.75), 90-days (p = 0.23-0.69), or throughout the follow-up period (p = 0.22-0.45). Differences in short-term mortality could not be assessed due to the low number of mortality events. CONCLUSIONS: After matching on characteristics known to impact outcomes and when isolated from other SDOHs, gender does not independently affect morbidity and mortality following meningioma resection. Further research on the role of other SDOHs in this population is merited to better understand underlying drivers of disparity.

Impact of Reduced Preincision Antibiotic Infusion Time on Surgical Site Infection Rates: A Retrospective Cohort Study.

OBJECTIVE: Our objective was to determine the impact of total preincision infusion time on surgical site infections (SSIs) and establish an optimal time threshold for subsequent prospective study. BACKGROUND: SSIs remain a major cause of morbidity. Although regulated, the total time of infusion of preincision antibiotics varies widely. Impact of infusion time on SSI risk is poorly understood. METHODS: All consecutive patients (n = 46,791) undergoing inpatient surgical intervention were retrospectively enrolled (2014-2015) and monitored for 1 year. Primary outcomes: the presence of SSI infection as predicted by reduced preoperative antibiotic infusion time. SECONDARY OUTCOMES: preintervention compliance, the impact of a quality improvement algorithm to optimize infusion time compliance. Multivariate logistic regression of the retrospective cohort demonstrated predictors of infection. Receiver-operating characteristic analysis demonstrated the timing threshold predictive of infection. Cost impact of avoidable infections was analyzed. RESULTS: Only 36.1% of patients received preincision infusion of vancomycin in compliance with national and institutional standards (60-120 min). Cephalosporin infusion times were 53 times more likely to be compliant [odds ratio (OR) 53.33, P < 0.001]. Vancomycin infusion times that were not compliant with national standards (less than standard 60-120 min) did not predict infection. However, significantly noncompliant, reduced preincision infusion time, significantly predicted SSI (<24.6 min infusion, AUC = 0.762). Vancomycin infusion, initiated too close to surgical incision, predicted increased SSI (OR = 4.281, P < 0.001). Implementation of an algorithm to improve infusion time, but not powered to demonstrate infection /reduction, improved vancomycin infusion start time (257% improvement, P < 0.001) and eliminated high-risk infusions (sub-24.6 min). CONCLUSIONS: Initially, vancomycin infusion rarely met national guidelines; however, minimal compliance breach was not associated with SSI implications. The retrospective data here suggest a critical infusion time for infection reduction (24.6 min before incision). Prospective implementation of an algorithm led to 100% compliance. These data suggest that vancomycin administration timing should be studied prospectively.

The LACE + index as a predictor of 90-day urologic surgery outcomes.

PURPOSE: This study assessed the ability of the LACE + [Length of stay, Acuity of admission, Charlson Comorbidity Index (CCI) score, and Emergency department visits in the past 6 months] index to predict adverse outcomes after urologic surgery. METHODS: LACE + scores were retrospectively calculated for all consecutive patients (n = 9824) who received urologic surgery at one multi-center health system over 2 years (2016-2018). Coarsened exact matching was employed to sort patient data before analysis; matching criteria included duration of surgery, BMI, and race among others. Outcomes including unplanned hospital readmission, emergency room visits, and reoperation were compared for patients with different LACE + quartiles. RESULTS: 722 patients were matched between Q1 and Q4; 1120 patients were matched between Q2 and Q4; 2550 patients were matched between Q3 and Q4. Higher LACE + score significantly predicted readmission within 90 days (90D) of discharge for Q1 vs Q4 and Q2 vs Q4. Increased LACE + score also significantly predicted 90D emergency room visits for Q1 vs Q4, Q2 vs Q4, and Q3 vs Q4. LACE + score was also significantly predictive of 90D reoperation for Q1 vs Q4. LACE + score did not predict 90D reoperation for Q2 vs Q4 or Q3 vs Q4 or 90D readmission for Q3 vs. Q4. CONCLUSION: These results suggest that LACE + may be a suitable prediction model for important patient outcomes after urologic surgery.

Reduction of Postoperative Opioid Use After Elective Spine and Peripheral Nerve Surgery Using an Enhanced Recovery After Surgery Program.

OBJECTIVE: Enhanced recovery after surgery (ERAS) pathways have previously been shown to be feasible and safe in elective spinal procedures. As publications on ERAS pathways have recently emerged in elective neurosurgery, long-term outcomes are limited. We report on our 18-month experience with an ERAS pathway in elective spinal surgery. METHODS: A historical cohort of 149 consecutive patients was identified as the control group, and 1,141 patients were prospectively enrolled in an ERAS protocol. The primary outcome was the need for opioid use one month postoperation. Secondary outcomes were opioid and nonopioid consumption on postoperative day (POD) 1, opioid use at three and six months postoperation, inpatient pain scores, patient satisfaction scores, postoperative Foley catheter use, mobilization/ambulation on POD0-1, length of stay, complications, and intensive care unit admissions. RESULTS: There was significant reduction in use of opioids at one, three, and six months postoperation (38.6% vs 70.5%, P < 0.001, 36.5% vs 70.9%, P < 0.001, and 23.6% vs 51.9%, P = 0.008) respectively. Both groups had similar surgical procedures and demographics. PCA use was nearly eliminated in the ERAS group (1.4% vs 61.6%, P < 0.001). ERAS patients mobilized faster on POD0 compared with control (63.5% vs 20.7%, P < 0.001). Fewer patients in the ERAS group required postoperative catheterization (40.7% vs 32.7%, P < 0.001). The ERAS group also had decreased length of stay (3.4 vs 3.9 days, P = 0.020). CONCLUSIONS: ERAS protocols for all elective spine and peripheral nerve procedures are both possible and effective. This standardized approach to patient care decreases opioid usage, eliminates the use of PCAs, mobilizes patients faster, and reduces length of stay.

Association of Overlapping, Nonconcurrent, Surgery With Patient Outcomes at a Large Academic Medical Center: A Coarsened Exact Matching Study.

OBJECTIVE: Assess the safety of overlapping surgery before implementation of new recommendations and regulations. BACKGROUND: Overlapping surgery is a longstanding practice that has not been well studied. There remains a need to analyze data across institutions and specialties to draw well-informed conclusions regarding appropriate application of this practice. METHODS: Coarsened exact matching was used to assess the impact of overlap on outcomes amongst all surgical interventions (n = 61,524) over 1 year (2014) at 1 health system. Overlap was categorized as: any, beginning, or end overlap. Study subjects were matched 1:1 on 11 variables. Serious unanticipated events were studied including unplanned return to operating room, readmission, and mortality. RESULTS: In all, 8391 patients (13.6%) had any overlap and underwent coarsened exact matching. For beginning/end overlap, matched groups were created (total matched population N = 4534/3616 patients, respectively). Any overlap did not predict unanticipated return to surgery (9.8% any overlap vs 10.1% no overlap; P = 0.45). Further, any overlap did not predict an increase in reoperation, readmission, or emergency room (ER) visits at 30 or 90 days (30D reoperation 3.6% vs 3.7%; P = 0.83, 90D reoperation 3.8% vs 3.9%; P = 0.84) (30D readmission 9.9% vs 10.2%; P = 0.45, 90D readmissions 6.9% vs 7.0%; P = 0.90) (30D ER 5.4% vs 5.6%; P = 0.60, 90D ER 4.8% vs 4.7%; P = 0.71). In addition, any overlap was not associated with mortality over the surgical follow-up period (90D mortality 1.7% vs 2.1%; P = 0.06). Beginning/end overlap had results similar to any overlap. CONCLUSION: Overlapping, nonconcurrent surgery is not associated with an increase in reoperation, readmission, ER visits, or unanticipated return to surgery.

Human Disc Nucleotomy Alters Annulus Fibrosus Mechanics at Both Reference and Compressed Loads.

Nucleotomy is a common surgical procedure and is also performed in ex vivo mechanical testing to model decreased nucleus pulposus (NP) pressurization that occurs with degeneration. Here, we implement novel and noninvasive methods using magnetic resonance imaging (MRI) to study internal 3D annulus fibrosus (AF) deformations after partial nucleotomy and during axial compression by evaluating changes in internal AF deformation at reference loads (50 N) and physiological compressive loads (∼10% strain). One particular advantage of this methodology is that the full 3D disc deformation state, inclusive of both in-plane and out-of-plane deformations, can be quantified through the use of a high-resolution volumetric MR scan sequence and advanced image registration. Intact grade II L3-L4 cadaveric human discs before and after nucleotomy were subjected to identical mechanical testing and imaging protocols. Internal disc deformation fields were calculated by registering MR images captured in each loading state (reference and compressed) and each condition (intact and nucleotomy). Comparisons were drawn between the resulting three deformation states (intact at compressed load, nucleotomy at reference load, nucleotomy at compressed load) with regard to the magnitude of internal strain and direction of internal displacements. Under compressed load, internal AF axial strains averaged -18.5% when intact and -22.5% after nucleotomy. Deformation orientations were significantly altered by nucleotomy and load magnitude. For example, deformations of intact discs oriented in-plane, whereas deformations after nucleotomy oriented axially. For intact discs, in-plane components of displacements under compressive loads oriented radially outward and circumferentially. After nucleotomy, in-plane displacements were oriented radially inward under reference load and were not significantly different from the intact state at compressed loads. Re-establishment of outward displacements after nucleotomy indicates increased axial loading restores the characteristics of internal pressurization. Results may have implications for the recurrence of pain, design of novel therapeutics, or progression of disc degeneration.

Folk-economic beliefs as moral intuitions.

Although Boyer & Petersen's (B&P's) cataloguing of and evolutionary explanations for folk-economic beliefs is important and valuable, the authors fail to connect their theories to existing explanations for why people do not think like economists. For instance, people often have moral intuitions akin to principles of fairness and justice that conflict with utilitarian approaches to resource allocation.

Chronic Opioid Usage in Surgical Patients in a Large Academic Center.

OBJECTIVE: The objective of this study is to investigate the prevalence and disparity of chronic opioid usage in surgical patients and the potential risk factors associated with chronic opioid usage. BACKGROUND: Chronic opioid usage is common in surgical patients; however, the characteristics of opioid usage in surgical patients is unclear. In this study, we hypothesize that the prevalence of chronic opioid usage in surgical patients is high, and that significant disparities may exist among different surgical populations. METHODS: Data of opioid usage in outpatients among different surgical services were extracted from the electronic medical record database. Patient demographics, clinical characteristics of sex, age, race, body mass index (BMI), specialty visited, duration of opioid use, and opioid type were collected. Chronic opioid users were defined as patients who had been recorded as taking opioids for at least 90 days determined by the first and last visit dates under opioid usage during the investigation. RESULTS: There were 79,123 patients included in this study. The average prevalence is 9.2%, ranging from 4.4% to 23.8% among various specialties. The prevalence in orthopedics (23.8%), neurosurgery (18.7%), and gastrointestinal surgery (14.4%) ranked in the top three subspecialties. Major factors influencing chronic opioid use include age, Ethnicitiy, Subspecialtiy, and multiple specialty visits. Approximately 75% of chronic users took opioids that belong to the category II Drug Enforcement Administration classification. CONCLUSIONS: Overall prevalence of chronic opioid usage in surgical patients is high with widespread disparity among different sex, age, ethnicity, BMI, and subspecialty groups. Information obtained from this study provides clues to reduce chronic opioid usage in surgical patients.

Imaging Surveillance in Patients After a Benign Fine-Needle Aspiration Biopsy of the Thyroid: Associated Cost and Incidence of Subsequent Cancer.

OBJECTIVE: The objective of our study was to determine patterns and cost of imaging tumor surveillance in patients after a benign fine-needle aspiration (FNA) biopsy of the thyroid in a large teaching hospital as well as the rate of subsequent cancer detection. MATERIALS AND METHODS: This cohort study was approved by the appropriate institutional review board and complied with HIPAA. All patients who had a benign thyroid FNA biopsy between January 1, 1999, and December 31, 2003, were identified from an institutional pathology database. We gathered information from electronic medical records on imaging tumor surveillance and subsequent cancer detection. Cost was determined using the facility total relative value unit and the 2014 Hospital Outpatient Prospective Payment System conversion factor. RESULTS: Between January 1, 1999, and December 31, 2003, 1685 patients had a benign thyroid FNA biopsy, 800 (47.5%) of whom underwent follow-up imaging. These patients underwent 2223 thyroid ultrasound examinations, 606 ultrasound-guided thyroid FNA biopsies, 78 thyroid scintigraphy examinations, 168 neck CTs, and 53 neck MRIs at a cost of $529,874, $176,157, $39,622, $80,580, and $53,114, respectively, for a total cost of $879,347 or $1099 per patient. The mean length of follow-up was 7.3 years, during which time 19 (2.4%) patients were diagnosed with thyroid cancer at a cost of $46,281 per cancer. Seventeen (89.5%) were diagnosed with papillary carcinoma and two (10.5%) with Hurthle cell carcinoma. CONCLUSION: Over a 5-year period, about half of the patients who had a benign thyroid FNA biopsy underwent follow-up imaging at considerable cost with a small rate of subsequent malignancy.

Pathogenesis and treatment of spine disease in the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS) are a family of lysosomal storage disorders characterized by deficient activity of enzymes that degrade glycosaminoglycans (GAGs). Skeletal disease is common in MPS patients, with the severity varying both within and between subtypes. Within the spectrum of skeletal disease, spinal manifestations are particularly prevalent. Developmental and degenerative abnormalities affecting the substructures of the spine can result in compression of the spinal cord and associated neural elements. Resulting neurological complications, including pain and paralysis, significantly reduce patient quality of life and life expectancy. Systemic therapies for MPS, such as hematopoietic stem cell transplantation and enzyme replacement therapy, have shown limited efficacy for improving spinal manifestations in patients and animal models. Therefore, there is a pressing need for new therapeutic approaches that specifically target this debilitating aspect of the disease. In this review, we examine how pathological abnormalities affecting the key substructures of the spine - the discs, vertebrae, odontoid process and dura - contribute to the progression of spinal deformity and symptomatic compression of neural elements. Specifically, we review current understanding of the underlying pathophysiology of spine disease in MPS, how the tissues of the spine respond to current clinical and experimental treatments, and discuss future strategies for improving the efficacy of these treatments.

Delayed hypertrophic differentiation of epiphyseal chondrocytes contributes to failed secondary ossification in mucopolysaccharidosis VII dogs.

Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient ß-glucuronidase activity, which leads to the accumulation of incompletely degraded glycosaminoglycans (GAGs). MPS VII patients present with severe skeletal abnormalities, which are particularly prevalent in the spine. Incomplete cartilage-to-bone conversion in MPS VII vertebrae during postnatal development is associated with progressive spinal deformity and spinal cord compression. The objectives of this study were to determine the earliest postnatal developmental stage at which vertebral bone disease manifests in MPS VII and to identify the underlying cellular basis of impaired cartilage-to-bone conversion, using the naturally-occurring canine model. Control and MPS VII dogs were euthanized at 9 and 14 days-of-age, and vertebral secondary ossification centers analyzed using micro-computed tomography, histology, qPCR, and protein immunoblotting. Imaging studies and mRNA analysis of bone formation markers established that secondary ossification commences between 9 and 14 days in control animals, but not in MPS VII animals. mRNA analysis of differentiation markers revealed that MPS VII epiphyseal chondrocytes are unable to successfully transition from proliferation to hypertrophy during this critical developmental window. Immunoblotting demonstrated abnormal persistence of Sox9 protein in MPS VII cells between 9 and 14 days-of-age, and biochemical assays revealed abnormally high intra and extracellular GAG content in MPS VII epiphyseal cartilage at as early as 9 days-of-age. In contrast, assessment of vertebral growth plates and primary ossification centers revealed no significant abnormalities at either age. The results of this study establish that failed vertebral bone formation in MPS VII can be traced to the failure of epiphyseal chondrocytes to undergo hypertrophic differentiation at the appropriate developmental stage, and suggest that aberrant processing of Sox9 protein may contribute to this cellular dysfunction. These results also highlight the importance of early diagnosis and therapeutic intervention to prevent the progression of debilitating skeletal disease in MPS patients.