Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors.

A significant unmet need for patients with multiple sclerosis (MS) is the lack of U.S. Food and Drug Administration (FDA)-approved remyelinating therapies. We have identified a compelling remyelinating agent, bazedoxifene (BZA), a European Medicines Agency (EMA)-approved (and FDA-approved in combination with conjugated estrogens) selective estrogen receptor (ER) modulator (SERM) that could move quickly from bench to bedside. This therapy stands out as a tolerable alternative to previously identified remyelinating agents and other candidates within this family. Using an unbiased high-throughput screen, with subsequent validation in both murine and human oligodendrocyte precursor cells (OPCs) and coculture systems, we find that BZA enhances differentiation of OPCs into functional oligodendrocytes. Using an in vivo murine model of focal demyelination, we find that BZA enhances OPC differentiation and remyelination. Of critical importance, we find that BZA acts independently of its presumed target, the ER, in both in vitro and in vivo systems. Using a massive computational data integration approach, we independently identify six possible candidate targets through which SERMs may mediate their effect on remyelination. Of particular interest, we identify EBP (encoding 3ß-hydroxysteroid-Δ8,Δ7-isomerase), a key enzyme in the cholesterol biosynthesis pathway, which was previously implicated as a target for remyelination. These findings provide valuable insights into the implications for SERMs in remyelination for MS and hormonal research at large.SIGNIFICANCE STATEMENT Therapeutics targeted at remyelination failure, which results in axonal degeneration and ultimately disease progression, represent a large unmet need in the multiple sclerosis (MS) population. Here, we have validated a tolerable European Medicines Agency-approved (U.S. Food and Drug Administration-approved in combination with conjugated estrogens) selective estrogen receptor (ER) modulator (SERM), bazedoxifene (BZA), as a potent agent of oligodendrocyte precursor cell (OPC) differentiation and remyelination. SERMs, which were developed as nuclear ER-α and ER-ß agonists/antagonists, have previously been implicated in remyelination and neuroprotection, following a heavy focus on estrogens with underwhelming and conflicting results. We show that nuclear ERs are not required for SERMs to mediate their potent effects on OPC differentiation and remyelination in vivo and highlight EBP, an enzyme in the cholesterol biosynthesis pathway that could potentially act as a target for SERMs.

Movement if Life-Optimizing Patient Access to Total Joint Arthroplasty: Alcohol and Substance Abuse Disparities.

Alcohol use disorders (AUDs) and substance use disorders (SUDs) place patients undergoing total joint arthroplasty at notable risk for complications. AUD and SUD disproportionately affect vulnerable communities and often coexist. Following is a discussion of the presence of these disorders in vulnerable populations and approaches to screening for them to optimize care and reduce the risks of joint arthroplasty surgery. 25.1% of American adults report binge drinking in the past year, and 5.8% of American adults carry a diagnosis of AUD. Alcohol consumption and AUD disproportionately affect American Indians/Alaskan Natives, and heavy episodic drinking is highest in Latinx and American Indians. AUD is higher in those who are unemployed, have lower education level, and those who are single/divorced. Alcohol use in the preoperative period is associated with difficulty maintaining blood pressure during surgery, infections, wound disruptions, and increased length of stay. In addition, patients with AUD or unhealthy alcohol use have a greater comorbidity burden, including liver disease and dementia, that predisposes them to poor surgical outcomes. Optimization in these vulnerable populations include proper screening, cessation programs, psychosocial interventions, assessment of support systems, and pharmacologic interventions. 38% of adults battle a drug use disorder. Twenty-one million Americans have at least one addiction, but only 10% receive treatment. Rates of opioid use and opioid-related deaths have continued to rise. Recreational drug use is highest in American Indians. Marijuana use is highest in Black and Latinx lesbian, gay, and bisexual women. Overall, substance use is associated with depression and anxiety; discrimination based on race, ethnicity, sex, or sexual preference is also deeply interwoven with depression, anxiety, and substance use. Preoperative use of opioids is the number one predictor of prolonged chronic postoperative opioid use. Optimization in these vulnerable groups begins with appropriate screening, followed by psychosocial interventions, social work and substance abuse counseling, and pharmacologic therapies.

Movement Is Life-Optimizing Patient Access to Total Joint Arthroplasty: Obesity Disparities.

Thirty five percent of the American population is considered obese (body mass index [BMI] > 30). Obesity disproportionately affects African Americans, Hispanics, and women. Obesity is associated with postoperative complications, including wound complications, infections, and revision total joint arthroplasty (including total hip arthroplasty and total knee arthroplasty). Current BMI benchmarks (many institutions rely on a BMI of 40) selectively preclude patients from having surgery. Patients in these underserved populations can be optimized through the lens of shared decision making through the assessment of food security (eg, food deserts and food swamps), ability to afford healthy food, knowledge of social safety net and community resources to access healthy food, nutrition and weight loss referrals to programs that accept all forms of insurance, weight loss measurements as a percentage of body weight lost instead of BMI cutoffs, pharmacologic modalities, and bariatric surgery.

Movement is Life-Optimizing Patient Access to Total Joint Arthroplasty: Housing Security and Discharge Planning Disparities.

Patients undergoing total joint arthroplasty should be screened for housing insecurity. Housing insecurity in the United States ranges from 10% to 15%, which is predisposed to those who are low-income, racial minorities, and unmarried. Osteoarthritic pain has a notable effect on function and quality of life and may prevent many individuals from continuing with their jobs. There is an inexorable, cyclic, structurally reinforced relationship between housing and health: where chronic illness affects housing security leading to issues with access to care and ultimately issues with health status. Housing insecurity is currently an imposed barrier to surgery. However, creative solutions exist to address housing insecurity, such as insurance company waivers, community resources (eg, churches) and organizations (eg, Meals on Wheels), halfway houses, and temporary housing (eg, hotels). Optimization for discharge planning in these vulnerable populations includes short-term stay in rehabilitation or skilled nursing facilities, home health services, or outpatient therapy.

Movement Is Life-Optimizing Patient Access to Total Joint Arthroplasty: Mental Health Disparities.

Mental illness affects 20.6% of American adults. The lifetime prevalence of depression and anxiety is 17% and 29%, respectively. In particular, women suffer more from mental illness than men. Racial and ethnic minorities experience disproportionate discrimination, which has been linked to depression, anxiety, and psychological distress. African Americans are more likely to be chronically depressed, have higher levels of impairment and more severe symptoms, and often have challenges accessing treatment. Poor mental health is associated with low socioeconomic status, prolonged hospital stays, psychosis, postoperative anemia, infection, and pulmonary embolism. For total hip and knee arthroplasty, mental health conditions have been linked to higher hospital charges, higher rates of nonroutine discharges, and an increased Charlson Comorbidity Index. Mechanisms to address mental health are varied and range from psychosocial to pharmacologic modalities. Optimization in these vulnerable patients includes appropriate preoperative screening, assessment of support systems, identifying resources, and providing a safe discharge plan.

Secret shopper studies: an unorthodox design that measures inequities in healthcare access.

Secret shopper studies are particularly potent study designs that allow for the gathering of objective data for a variety of research hypotheses, including but not limited to, healthcare delivery, equity of healthcare, and potential barriers to care. Of particular interest during the COVID-19 pandemic, secret shopper study designs allow for the gathering of data over the phone. However, there is a dearth of literature available on appropriate methodological practices for these types of studies. To make these study designs more widely accessible, here we outline the case for using the secret shopper methodology and detail best practices for designing and implementing them.

Computer-Assisted Navigation for Complex Revision of Unstable Total Hip Replacement in a Patient With Post-traumatic Arthritis.

Imageless computer-assisted navigation (CAN) excels in the post-traumatic arthritis and complex revision case setting when altered anatomy and landmarks are inaccurate references for cup positioning. We describe the case of an adult male patient who suffered an acetabular fracture which was treated nonoperatively. He subsequently developed post-traumatic arthritis and underwent an anterior approach total hip arthroplasty 25 years later. Postoperatively, he developed recurrent hip instability due to malpositioned components. We describe the use of imageless CAN during revision total hip arthroplasty to correct malpositioned components, with 3-year follow-up without dislocation. In these complex cases, CAN reduces the risk of component malpositioning and joint instability.

Operative Techniques to Reduce Hip and Knee Arthroplasty Complications in Morbidly Obese Patients.

Obesity, defined as a body mass index (BMI) >30, is associated with an increased likelihood of osteoarthritis and need for total joint arthroplasty (TJA). Unfortunately, the morbidly obese population has a higher risk of postoperative complications. For some surgeons, patient selection criteria for TJA includes BMI<40. The associated risks are recognized by The American Association of Hip And Knee Surgeons, and many surgeons follow these guidelines. Importantly, as obese patients have been demonstrated to have equal or greater gains in functional outcomes and quality of life metrics, it is important for obese patients to have access to TJA. Through a comprehensive literature review and structured interviews with leading surgeons in the field, we provide guidance for orthopedic surgeons treating patients with BMI>40 to minimize risks, including tailored preoperative, intraoperative, and postoperative considerations.

Comparing Outcomes in Cemented and Press-Fit Hemiarthroplasty.

INTRODUCTION: Arthroplasty has become the standard of care for displaced femoral neck fractures in the geriatric cohort. However, details regarding optimal implant design and fixation strategy continue to be debated. We sought to determine whether cemented or press-fit hemiarthroplasties were more advantageous in terms of revision surgery, contralateral hip fractures, hospital length of stay, mortality rates, and survival. METHODS: All geriatric fragility hip fractures at a level 1 trauma center (2014 to 2019) were retrospectively reviewed for the fracture pattern, fixation methodology, and outcome, yielding 707 femoral neck fractures treated with hemiarthroplasty (309 cemented and 398 press fit). The final follow-up was either date of death or final encounter. Major end points were revision surgery, contralateral fracture, and death. A Z-score test of two proportions was used for dichotomous variables, and a two-tailed t -test was used for continuous variables. Cox proportional hazard was used for revision surgery-free survival between groups, adjusting for age, sex, and American Society of Anesthesiologists status. RESULTS: Patients who underwent press-fit hemiarthroplasty had a significantly higher rate of revision surgery (7.8% vs 3.9%; P = 0.006). Press-fit cases had a trend toward a decreased risk of contralateral fracture (13% vs 9.8%; P = 0.12), although this did not reach significance. Both groups had similar length of stay ( P = 0.08) and death rates ( P = 0.39). Of those who died, there was a trend toward longer survival in patients who received a press-fit hemiarthroplasty (413 vs 615 days; P < 0.001). There was a trend toward longer survival without repeat surgery in the cemented group without reaching significance (hazard ratio, 0.66 [0.34 to 1.23]; P = 0.201). CONCLUSION: In this study, we found a markedly longer survival time after press-fit hemiarthroplasty, which we believe reflects surgeons' tendencies to cement the femoral prosthesis in patients with more comorbidities. However, press-fit hemiarthroplasties were more likely to result in repeat procedures on the same hip. Displaced geriatric femoral neck fractures may benefit from a cemented rather than press-fit hemiarthroplasty.

Total Joint Arthroplasty Direct-to-Consumer Advertising by Medical Device Companies Lacks Patient Diversity.

Background: Obese and African American populations suffer from higher incidence of hip and knee osteoarthritis, yet African Americans are less likely to undergo total hip and knee arthroplasty (TJA). Patient interest in TJA is a necessary first step for surgery. Medical device company direct-to-consumer advertising for TJA represents 1 potential factor driving disparities in utilization. Here we analyze demographics of models represented in medical device company direct-to-consumer TJA advertisements to understand whether advertisement content correlates with the population in need. Methods: We analyzed medical device company pamphlets, websites, and banner and video advertisements of the top 4 medical device companies in US arthroplasty sales, collected via ad-specific search engine and direct correspondence. Variables include model race, sex, age, and weight. Pearson likelihood ratio tests were used to compare categorical variables. Results: Of the 116 advertisements collected, the model featured in the advertisement was white in 69.8%. The proportion of white models differed across medical device companies (company C, 75%) (P < .001) and advertisement type (video, 81.8%) (P < .001). Only 2.6% of advertisements featured obese models. Neither company C nor D, nor pamphlet or website advertisements used obese models. Conclusions: Direct-to-consumer advertising from the top 4 orthopedic US medical device companies does not represent the population in need: While TJA remains underutilized by African American/Hispanic patients, models were overwhelmingly white. While obese patients are known to need TJA, patients in the advertisements were overwhelmingly not obese. We advocate for medical device companies to refocus their advertising strategies to target diverse patients in need of TJA. Level of evidence: III (retrospective cohort study).

Jump in Elective Total Hip and Knee Arthroplasty Numbers at Age 65 Years: Evidence for Moral Hazard?

INTRODUCTION: Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are outstanding options for many older patients at the discretion of the patient and the surgeon. As patients turn 65 years, greater than 98% of the US population becomes eligible for Medicare, and this represents a time of changing healthcare coverage for many. METHODS: Patients undergoing elective TKA and THA were abstracted from the 2012 to 2018 National Surgical Quality Improvement Program database. Incidences of TKA and THA (combined and separate) were plotted and assessed by age. To assess factors associated with who "delayed" surgery until 65 years, demographic and preoperative characteristics, and postoperative adverse events were compared for the 2 years above and the 2 years below the 65-year-old mark with multivariate analysis. Significance was set at P < 0.05. RESULTS: In total, 515,139 TKA and THA patients were identified (62.04% TKA and 37.95% THA). When the number of procedures was plotted by age, a discontinuity in the bell-shaped curve was noted at age 65 years. Highlighting this finding, the changes in percent population between 63 and 64 years was -1.52%, between 64 and 65 years was +15.36%, and between 65 and 66 years was -2.32%. Relative to those who were 63 and 64 years (n = 36,511), those who were 65 and 66 years (n = 41,671) were more likely to be female, be non-Hispanic White, have a lower body mass index, and have a lower functional status but were not different in the preoperative American Society of Anesthesiologists class. CONCLUSION: In this large national sample, there was a clear step increase in undergoing TKA or THA once patients reached the age of 65 years (Medicare eligibility). This discontinuity in the bell-shaped curve may be evidence for a moral hazard in healthcare markets. Although factors in decision-making were not assessed, there were demographic factors associated with this step finding.

A hormonal therapy for menopausal women with MS: A phase Ib/IIa randomized controlled trial.

INTRODUCTION: Most women develop MS before menopause. Menopausal hot flashes can worsen MS symptoms, and could be relieved with hormone therapy. Our objective was to evaluate feasibility, tolerability and symptom response of Duavee® (bazedoxifene + conjugated estrogen) in a Phase Ib/IIa double-blind randomized controlled clinical trial. METHODS: We randomized 24 peri/postmenopausal women with MS and symptomatic hot flashes 1:1 to Duavee® versus placebo. Evaluations occurred at baseline and 2 months. RESULTS: Groups were balanced for age (mean 51.2 ± 3.6 years), EDSS [median 3 (IQR:2.5, 4.5)], and MS duration. 21/24 participants completed the study. FEASIBILITY: Enrollment was protracted (34 months), partially due to concerns about hormone therapy safety. TOLERABILITY: treatment group participants reported greater satisfaction and fewer missed doses; one participant (placebo) developed new MRI lesions; liver function testing remained normal for all patients. SYMPTOMS: Hot Flash Related Daily Interference scale at 2 months was lower in treatment vs. placebo group [median (IQR) of 4 (0.5, 14) vs. 9 (0, 33)]. Between-group differences were not statistically significant. CONCLUSION: Despite perceived benefits in MS, estrogens have perceived risks that represent a hurdle to enrollment. With appropriate education and screening of participants, the favorable study retention (87%) and treatment satisfaction observed in the current study support the feasibility of a longer, powered trial to evaluate whether a proven treatment for menopausal symptoms, Duavee®, could also improve MS-related function in menopausal women with MS.

Experience-dependent myelination following stress is mediated by the neuropeptide dynorphin.

Emerging evidence implicates experience-dependent myelination in learning and memory. However, the specific signals underlying this process remain unresolved. We demonstrate that the neuropeptide dynorphin, which is released from neurons upon high levels of activity, promotes experience-dependent myelination. Following forced swim stress, an experience that induces striatal dynorphin release, we observe increased striatal oligodendrocyte precursor cell (OPC) differentiation and myelination, which is abolished by deleting dynorphin or blocking its endogenous receptor, kappa opioid receptor (KOR). We find that dynorphin also promotes developmental OPC differentiation and myelination and demonstrate that this effect requires KOR expression specifically in OPCs. We characterize dynorphin-expressing neurons and use genetic sparse labeling to trace their axonal projections. Surprisingly, we find that they are unmyelinated normally and following forced swim stress. We propose a new model whereby experience-dependent and developmental myelination is mediated by unmyelinated, neuropeptide-expressing neurons that promote OPC differentiation for the myelination of neighboring axons.

Centers for Medicare & Medicaid Services' 2018 Removal of Total Knee Arthroplasty From the Inpatient-only List Led to Broad Changes in Hospital Length of Stays.

INTRODUCTION: Centers for Medicare & Medicaid Services (CMS) removed total knee arthroplasty (TKA) from the "inpatient-only" list from January 1, 2018. The impact of this change on actual hospital length of stay (LOS) and patient coding is of interest. METHODS: Patients undergoing TKA were abstracted from the 2015 to 2018 National Surgical Quality Improvement Program database. Patient characterization as "inpatient" or "outpatient" and actual LOS were assessed. Ordinal and categorical data comparisons were done with Pearson chi-squared tests. Continuous variables were tested for normality, and nonparametric analyses were conducted using the Mann-Whitney test. Significance was set at P < 0.05. RESULTS: In total, 125,613 TKA patients from 2017 to 2018 were identified (232,269 TKA patients from 2015 to 2018). Most patients undergoing TKA were of Medicare eligibility (≥65 years old; 60.78% in 2017 and 62.42% in 2018). Overall, LOS decreased significantly from 2017 to 2018 (2.31 ± 1.56 days versus 2.05 ± 1.57 days; P < 0.001), and more patients were discharged the same day (5.09% versus 2.28%; P < 0.001). In 2017, patients were coded as "outpatient" 1.66% of the time (those with LOS = 0 days were 22.85%, LOS = 1 day were 1.80%, LOS = 2 days were 0.79%, and LOS ≥3 days were 0.85%). In 2018, patients were coded as "outpatient" 17.14% of the time (those with LOS = 0 days were 78.2%, LOS = 1 day were 29.75%, LOS = 2 days were 6.96%, and LOS ≥3 days were 3.05%). This represented a significant change for each LOS day (P < 0.001). These results remained true when stratifying by Medicare eligibility (P < 0.001 for those <65 years old and those ≥65 years old). DISCUSSION: After the 2018 removal of TKA from the CMS "inpatient-only" list, patients were more likely to be discharged the same day and be considered "outpatients." Patients with more prolonged LOS and those younger than 65 years were more likely to have been coded as "outpatient" in 2018 compared with 2017. These data demonstrate that national changes in CMS policies can have broad impact on overall practice patterns. LEVEL OF EVIDENCE: Retrospective cohort study.

Clusters of Injuries From Motorcycle Collisions: Exploratory Factor Analysis of a Single Institution Trauma Registry.

Objective With the goal of guiding acute management of associated injuries motorcycle trauma patients, this study aims to identify patterns of associated injuries after motorcycle collisions using exploratory factor analysis. Methods We conducted a retrospective review at a Level 1 trauma center of all patients who presented after motorcycle collisions resulting in trauma system activations between July 2, 2002 and December 31, 2013. We performed exploratory factor analysis on this dataset to identify sets of injuries that cluster together. Results We identified 1,050 patients who presented for trauma after a motorcycle collision. These patients had 3,101 injuries, including 1,694 fractures. Using exploratory factor analysis, we developed a model with four latent factors that explained approximately half of the variance in injuries. These factors were defined by: head and cervical spine injuries; extremity injuries; abdomen, pelvis and upper extremity injuries; and shoulder girdle and thorax injuries. We also found a novel injury pattern relationship between forearm shaft/wrist and lower extremity injuries. Conclusions Motorcycle trauma results in distinct clusters of associated injuries likely due to common motorcycle collision patterns, most notably a novel relationship between forearm shaft/wrist and lower extremity injuries that merits further exploration, and could play a role during secondary survey.

High-risk motor vehicle drivers engage in more risk behaviors than motorcyclists.

OBJECTIVE: The purpose of this study was to characterize and compare risk behaviors between motorcyclists and motor vehicle drivers who were involved in accidents and required hospitalization. The study focused on patients who were recently involved in motorcycle collisions (MCCs) and motor vehicle collisions (MVCs). METHODS: We identified 63 patients involved in MCCs and 39 patients involved in MVCs who were admitted to our level-1 trauma center from April 2014 to September 2015. These 102 patients completed a questionnaire designed to evaluate risky driving behaviors. Pearson's chi-squared tests and unpaired two-tailed t-tests were used to evaluate categorical and normally distributed continuous variables, respectively. Multivariable linear regression was used to analyze predictors of risk behavior. Significance was set at p < 0.05. RESULTS: When compared to patients involved in an MCC, patients involved in MVCs were more likely to be female (p = 0.007), drive more frequently (p < 0.001), and never perceive the risk of an accident (p = 0.036). MVC patients were more likely to have admitted to substance use on the day of the accident (p = 0.030), historically drive under the influence of drugs (p = 0.031), drive while tired (p < 0.001), drive while text messaging (p < 0.001), and speed while overtaking vehicles (p = 0.011). Overall, MVC patients engaged in more risk behaviors (3.3 ± 1.3 vs. 2.0 ± 1.5; p < 0.001) and were more likely to engage in multiple risk behaviors (p < 0.001). MVCs were associated with increased risk behavior, even after controlling for protective behaviors, driving history, and demographics (p = 0.045). CONCLUSIONS: Within our cohort of trauma patients at our institution, motor vehicle drivers were more likely than motorcyclists to engage in any one risk behavior and engage in a higher number of risk behaviors. In addition, motor vehicle drivers perceived their risk of a potential accident as lower than riding a motorcycle. Education initiatives should focus on motor vehicle driver safety interventions that reduce risk behaviors.

Motorcycle crashes and upper extremity trauma.

OBJECTIVES: Upper extremity injuries following motorcycle crashes (MCC) incur increased healthcare costs and rehabilitation needs. We aim to characterize the epidemiology of MCC upper extremity injuries and identify factors that influence the severity of and cost of care for upper extremity injuries. METHODS: We performed a retrospective cohort analysis of 571 patients with upper extremity injuries after MCC at a level 1 trauma center from 2002 to 2013. We collected data pertaining to demographics, helmet use, toxicology, bony injury, Injury Severity Score (ISS), Glasgow Coma Scale (GCS), hospital length of stay (LOS), and cost. Continuous variables were compared using t-test or Wilcoxon rank test, depending on data distribution, and dichotomous variables were compared using Pearson's chi-squared or Fisher's exact tests. Regression models were used to evaluate the effect of intoxication or helmets on injury location, severity, cost of care, and LOS. RESULTS: The incidence of MCC upper extremity injury was 47.5%, with hand and forearm fractures the most common injuries (25.5% and 24.7% of total injuries). Intoxicated patients were more likely to have a high cost of care (p = 0.012), extended LOS (p = 0.038), plastic surgery involvement in their care (p = 0.038), but fewer upper extremity bony injuries (p = 0.019). Non-helmeted patients sustained less upper extremity bony injuries (p < 0.001) and upper extremity soft tissue injuries (p = 0.001), yet more severe injuries (ISS ≥ 30, p = 0.006 and GCS < 9, p < 0.01) than helmeted patients. CONCLUSION: Upper extremity injuries are common in motorcyclists. Despite vital protection for the brain and maxillofacial injury, helmeted MCC patients have an increased incidence of upper extremity injuries compared to non-helmeted patients, but overall have less severe injuries. Intoxicated patients have fewer upper extremity bony injuries, but the higher cost of care, and extended LOS. Therefore, even with the increased risk of injury helmets may expose to the upper extremity, helmets reduced overall morbidity and mortality. In addition to mandatory helmet laws, we advocate for further development of safety equipment focusing specifically on the prevention of upper extremity injuries.

The Effect of Feedback on Surgeon Performance: A Narrative Review.

Surgeons play a critical role in the healthcare community and provide a service that can tremendously impact patients' livelihood. However, there are relatively few means for monitoring surgeons' performance quality and seeking improvement. Surgeon-level data provide an important metric for quality improvement and future training. A narrative review was conducted to analyze the utility of providing surgeons direct feedback on their individual performance. The articles selected identified means of collecting surgeon-specific data, suggested ways to report this information, identified pertinent gaps in the field, and concluded the results of giving feedback to surgeons. There is a relative sparsity of data pertaining to the effect of providing surgeons with information regarding their individual performance. However, the literature available does suggest that providing surgeons with individualized feedback can help make meaningful improvements in the quality of practice and can be done in a way that is safe for the surgeons' reputation.

Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery.

Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.