CD4 T cells restricted to DRB1*15:01 recognize two Epstein-Barr virus glycoproteins capable of intracellular antigen presentation.

Both genetic and environmental factors contribute to multiple sclerosis (MS) risk. Infection with the Epstein-Barr virus (EBV) is the strongest environmental risk factor, and HLA-DR15 is the strongest genetic risk factor for MS. We employed computational methods and in vitro assays for CD4 T cell activation to investigate the DR15-restricted response to EBV. Using a machine learning-based HLA ligand predictor, the EBV glycoprotein B (gB) was predicted to be enriched in epitopes restricted to presentation by DRB1*15:01. In DR15-positive individuals, two epitopes comprised the major CD4 T cell response to gB. Surprisingly, the expression of recombinant gB in a DR15-homozygous B cell line or primary autologous B cells elicited a CD4 T cell response, indicating that intracellular gB was loaded onto HLA class II molecules. By deleting the signal sequence of gB, we determined that this pathway for direct activation of CD4 T cells was dependent on trafficking to the endoplasmic reticulum (ER) within the B cell. We screened seven recombinant EBV antigens from the ER compartment for immune responses in DR15-negative vs. DR15-homozygous individuals. In addition to gB, gH was a key CD4 T cell target in individuals homozygous for DR15. Compared to non-DR15 controls, DR15-homozygotes had significantly higher T cell responses to both gB and gH but not to EBV latent or lytic antigens overall. Responses to gB and gH were slightly elevated in DR15 homozygotes with MS. Our results link MS environmental and genetic risk factors by demonstrating that HLA-DR15 dictates CD4 T cell immunity to EBV antigens.

Effectiveness of immunotherapies in relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can cause optic neuritis, transverse myelitis, or acute disseminated encephalomyelitis (ADEM). Immunotherapy is often used for relapsing disease, but there is variability in treatment decisions. OBJECTIVE: The objective was to determine the annualized relapse rates (ARRs) and incidence rate ratios (IRRs) compared to pre-treatment and relapse-freedom probabilities among patients receiving steroids, B-cell depletion (BCD), intravenous immunoglobulin (IVIG), and mycophenolate mofetil (MMF). METHODS: Retrospective cohort study of patients with relapsing MOGAD treated at Mass General Brigham. ARRs and IRRs compared to pre-treatment, and relapse-freedom probability and odds ratio for relapse-freedom compared to prednisone were calculated. RESULTS: A total of 88 patients met the inclusion criteria. The ARR on IVIG was 0.13 (95% confidence interval (CI) = 0.06-0.27) and the relapse-freedom probability after at least 6 months of therapy was 72%. The ARR on BCD was 0.51 (95% CI = 0.34-0.77), and the relapse-freedom probability was 33%. The ARR on MMF was 0.32 (95% CI = 0.19-0.53) and the relapse-freedom probability was 49%. In pediatric-onset disease, MMF had the lowest ARRs (0.15, 95% CI = 0.07-0.33). CONCLUSION: IVIG had the lowest ARRs and IRRs compared to pre-treatment and the highest relapse-freedom odds ratio compared to prednisone, while BCD had the lowest. In pediatric-onset MOGAD, MMF had the lowest ARRs.

Intravenous immunoglobulin treatment for acute attacks in myelin oligodendrocyte glycoprotein antibody disease.

BACKGROUND: The potential therapeutic benefit of intravenous immunoglobulins (IVIGs) for acute attacks of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is unknown. OBJECTIVE: The objective was to describe the outcomes of IVIG treatment for acute MOGAD attacks. METHODS: A retrospective observational study involving seven tertiary neuroimmunology centers. Data collection included patients' demographics, Expanded Disability Status Scale (EDSS), and visual acuity (VA) before the attack, at the nadir of the attack before IVIG treatment, and at follow-up visits ⩾3 months after treatment. RESULTS: Thirty-nine patients were included, of which 21 (53.8%) were female. The median age was 23 years (range 5-74 years), and the median disease duration was 4 months (range 0-93 months). The most common type of attack treated with IVIG was isolated optic neuritis (ON) (unilateral n = 14, bilateral n = 5, associated with transverse myelitis (TM), n = 1), followed by acute disseminated encephalomyelitis (ADEM) (n = 8), multifocal (n = 7), TM (n = 3), brainstem (n = 1), and other encephalitis (n = 1). A significant improvement in both the EDSS and VA measures was observed at follow-up compared to the time of IVIG treatment initiation (p < 0.0001 for both outcome measures). CONCLUSION: IVIG may be an effective treatment option for acute MOGAD attacks. Further prospective studies are warranted to validate our results.

Protocol for a single patient therapy plan: A randomised, double-blind, placebo-controlled N-of-1 trial to assess the efficacy of cannabidiol in patients with intractable epilepsy.

AIM: This paper describes the use of the single patient therapy plan (SPTP). The SPTP has been designed to assess the efficacy at an individual level of a commercially available cannabinoid product, cannabidiol, in reducing seizure frequency in paediatric patients with intractable epilepsy. METHODS: The SPTP is a randomised, double-blind, placebo-controlled N-of-1 trial designed to assess the efficacy of treatment in a neurology outpatient setting. The primary objective of the SPTP is to assess the efficacy of cannabidiol in reducing seizure frequency in each patient with intractable epilepsy, with change in seizure frequency being the primary outcome of interest. The analysis adopts a Bayesian approach, which provides results in the form of posterior probabilities that various levels of benefit (based on the primary outcome measure, seizure frequency) have been achieved under active treatment compared to placebo, accompanied by decision rules that provide thresholds for deciding whether treatment has been successful in the individual patient. The SPTP arrangement is most accurately considered part of clinical practice rather than research, since it is aimed at making clinical treatment decisions for individual patients and is not testing a hypothesis or collecting aggregate data. Therefore, Human Research Ethics Committee approval was considered not to be required, although it is recommended that hospital Clinical Ethics Committees provide ethical oversight. CONCLUSION: These SPTP resources are made available so that they may inform clinical practice in the treatment of severe epilepsy or adapted for use in other conditions.

Compliance with results reporting at ClinicalTrials.gov.

BACKGROUND: The Food and Drug Administration Amendments Act (FDAAA) mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results. METHODS: Using an algorithm based on input from the National Library of Medicine, we identified trials that were likely to be subject to FDAAA provisions (highly likely applicable clinical trials, or HLACTs) from 2008 through 2013. We determined the proportion of HLACTs that reported results within the 12-month interval mandated by the FDAAA or at any time during the 5-year study period. We used regression models to examine characteristics associated with reporting at 12 months and throughout the 5-year study period. RESULTS: From all the trials at ClinicalTrials.gov, we identified 13,327 HLACTs that were terminated or completed from January 1, 2008, through August 31, 2012. Of these trials, 77.4% were classified as drug trials. A total of 36.9% of the trials were phase 2 studies, and 23.4% were phase 3 studies; 65.6% were funded by industry. Only 13.4% of trials reported summary results within 12 months after trial completion, whereas 38.3% reported results at any time up to September 27, 2013. Timely reporting was independently associated with factors such as FDA oversight, a later trial phase, and industry funding. A sample review suggested that 45% of industry-funded trials were not required to report results, as compared with 6% of trials funded by the National Institutes of Health (NIH) and 9% of trials that were funded by other government or academic institutions. CONCLUSIONS: Despite ethical and legal obligations to disclose findings promptly, most HLACTs did not report results to ClinicalTrials.gov in a timely fashion during the study period. Industry-funded trials adhered to legal obligations more often than did trials funded by the NIH or other government or academic institutions. (Funded by the Clinical Trials Transformation Initiative and the NIH.).

Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection.

The MHC class I D(k) molecule supplies vital host resistance during murine cytomegalovirus (MCMV) infection. Natural killer (NK) cells expressing the Ly49G2 inhibitory receptor, which specifically binds D(k), are required to control viral spread. The extent of D(k)-dependent host resistance, however, differs significantly amongst related strains of mice, C57L and MA/My. As a result, we predicted that relatively small-effect modifier genetic loci might together shape immune cell features, NK cell reactivity, and the host immune response to MCMV. A robust D(k)-dependent genetic effect, however, has so far hindered attempts to identify additional host resistance factors. Thus, we applied genomic mapping strategies and multicolor flow cytometric analysis of immune cells in naive and virus-infected hosts to identify genetic modifiers of the host immune response to MCMV. We discovered and validated many quantitative trait loci (QTL); these were mapped to at least 19 positions on 16 chromosomes. Intriguingly, one newly discovered non-MHC locus (Cmv5) controlled splenic NK cell accrual, secondary lymphoid organ structure, and lymphoid follicle development during MCMV infection. We infer that Cmv5 aids host resistance to MCMV infection by expanding NK cells needed to preserve and protect essential tissue structural elements, to enhance lymphoid remodeling and to increase viral clearance in spleen.

Factors associated with reporting results for pulmonary clinical trials in ClinicalTrials.gov.

Background/aims The Food and Drug Administration Amendments Act mandates that applicable clinical trials report basic summary results to the ClinicalTrials.gov database within 1 year of trial completion or termination. We aimed to determine the proportion of pulmonary trials reporting basic summary results to ClinicalTrials.gov and assess factors associated with reporting. Methods We identified pulmonary clinical trials subject to the Food and Drug Administration Amendments Act (called highly likely applicable clinical trials) that were completed or terminated between 2008 and 2012 and reported results by September 2013. We estimated the cumulative percentage of applicable clinical trials reporting results by pulmonary disease category. Multivariable Cox regression modeling identified characteristics independently associated with results reporting. Results Of 1450 pulmonary highly likely applicable clinical trials, 380 (26%) examined respiratory neoplasms, 238 (16%) asthma, 175 (12%) chronic obstructive pulmonary disease, and 657 (45%) other respiratory diseases. Most (75%) were pharmaceutical highly likely applicable clinical trials and 71% were industry-funded. Approximately 15% of highly likely applicable clinical trials reported results within 1 year of trial completion, while 55% reported results over the 5-year study period. Earlier phase highly likely applicable clinical trials were less likely to report results compared to phase 4 highly likely applicable clinical trials (phases 1/2 and 2 (adjusted hazard ratio 0.41 (95% confidence interval: 0.31-0.54)), phases 2/3 and 3 (adjusted hazard ratio 0.55 (95% confidence interval: 0.42-0.72)) and phase not applicable (adjusted hazard ratio 0.43 (95% confidence interval: 0.29-0.63)). Pulmonary highly likely applicable clinical trials without Food and Drug Administration oversight were less likely to report results compared with those with oversight (adjusted hazard ratio 0.65 (95% confidence interval: 0.51-0.83)). Conclusion A total of 15% of pulmonary clinical highly likely applicable clinical trials report basic summary results to ClinicalTrials.gov within 1 year of trial completion. Strategies to improve reporting are needed within the pulmonary community.

The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy.

There is growing evidence that macroautophagic cargo is not limited to bulk cytosol in response to starvation and can occur selectively for substrates, including aggregated proteins. It remains unclear, however, whether starvation-induced and selective macroautophagy share identical adaptor molecules to capture their cargo. Here, we report that Alfy, a phosphatidylinositol 3-phosphate-binding protein, is central to the selective elimination of aggregated proteins. We report that the loss of Alfy inhibits the clearance of inclusions, with little to no effect on the starvation response. Alfy is recruited to intracellular inclusions and scaffolds a complex between p62(SQSTM1)-positive proteins and the autophagic effectors Atg5, Atg12, Atg16L, and LC3. Alfy overexpression leads to elimination of aggregates in an Atg5-dependent manner and, likewise, to protection in a neuronal and Drosophila model of polyglutamine toxicity. We propose that Alfy plays a key role in selective macroautophagy by bridging cargo to the molecular machinery that builds autophagosomes.

Balancing Justice and Welfare Needs in Family Group Conferences for Children with Harmful Sexual Behavior: The HSB-FGC Framework.

In England and Wales, family group conferences (FGCs) are most often found either in the field of youth justice or in the field of child protection, and consequently often have priorities in line with either one of the two systems. On the one hand, FGCs are a restorative justice tool to address offending behavior and hold young perpetrators to account, while giving victims the possibility of contributing to the justice process. On the other hand, FGCs address safeguarding concerns and are used to plan for child safety and protection. In cases where a young person has sexually harmed another young person, that is, has perpetrated harmful sexual behavior (HSB), all young people involved will have both justice and welfare needs. FGCs are emerging as promising mechanisms in such cases, not only because of their ability to deal with both sets of needs for both young people but also because of their potential to address more holistic needs. However, HSB cases are often complex and sensitive, and are not without risk. Drawing on their experiences in research and practice, the authors explore how the holistic needs of both the harmed and harming individual can be balanced within a risk managed HSB-FGC framework.

Regional Variation in Out-of-Hospital Cardiac Arrest Survival in the United States.

BACKGROUND: Although previous studies have shown marked variation in out-of-hospital cardiac arrest survival across US regions, factors underlying this survival variation remain incompletely explained. METHODS AND RESULTS: Using data from the Cardiac Arrest Registry to Enhance Survival, we identified 96 662 adult patients with out-of-hospital cardiac arrest in 132 US counties. We used hierarchical regression models to examine county-level variation in rates of survival and survival with functional recovery (defined as Cerebral Performance Category score of 1 or 2) and examined the contribution of demographics, cardiac arrest characteristics, bystander cardiopulmonary resuscitation, automated external defibrillator use, and county-level sociodemographic factors in survival variation across counties. A total of 9317 (9.6%) patients survived to discharge, and 7176 (7.4%) achieved functional recovery. At a county level, there was marked variation in rates of survival to discharge (range, 3.4%-22.0%; median odds ratio, 1.40; 95% confidence interval, 1.32-1.46) and survival with functional recovery (range, 0.8%-21.0%; median odds ratio, 1.53; 95% confidence interval, 1.43-1.62). County-level rates of bystander cardiopulmonary resuscitation and automated external defibrillator use were positively correlated with both outcomes (P<0.0001 for all). Patient demographic and cardiac arrest characteristics explained 4.8% and 27.7% of the county-level variation in survival, respectively. Additional adjustment of bystander cardiopulmonary resuscitation and automated external defibrillator explained 41% of the survival variation, and this increased to 50.4% after adjustment of county-level sociodemographic factors. Similar findings were noted in analyses of survival with functional recovery. CONCLUSIONS: Although out-of-hospital cardiac arrest survival varies significantly across US counties, a substantial proportion of the variation is attributable to differences in bystander response across communities.

Cardiac arrest and clinical characteristics, treatments and outcomes among patients hospitalized with ST-elevation myocardial infarction in contemporary practice: A report from the National Cardiovascular Data Registry.

BACKGROUND: Cardiac arrest (CA) is a major complication of patients with ST-elevation myocardial infarction (STEMI). Its prevalence and prognostic impact in contemporary US practice has not been well assessed. METHODS: We evaluated STEMI patients included in the National Cardiovascular Data Registry (NCDR) Acute Coronary Treatment Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG) from 4/1/11 to 6/30/12. Patient clinical characteristics, treatments, and inhospital outcomes were compared by the presence or absence of CA on first medical contact-either before hospital arrival or upon presentation to the ACTION hospital. RESULTS: Of the 49,279 STEMI patients included, 3,716 (7.5%) had CA. Cardiac arrest patients were more likely to have heart failure (15.5% vs 6.9%) and shock (42.9% vs 4.9%) on presentation and higher median (25th and 75th percentiles) ACTION Registry-GWTG mortality risk scores (42 [32, 54] vs 32 [26, 38]) than non-CA patients (all P < .001). Primary percutaneous coronary intervention was performed in most patients with and without CA (76.7% vs 79.1%). Inhospital mortality was significantly higher in patients with than without CA (28.8% vs 4.0%; P < .001), both in patients who presented with cardiogenic shock (46.9% vs 27.1%; P < .001) and those without shock (15.4% vs 2.9%; P < .001). The ACTION Registry-GWTG inhospital mortality model underestimated mortality risk in CA patients; however, prediction significantly improved after adding CA to the model. CONCLUSIONS: Almost 8% of STEMI patients present with CA. More than 25% die during the hospitalization, despite high use of primary percutaneous coronary intervention. Cardiogenic shock and CA frequently coexist. Our results suggest that development of systems of care and treatments for both STEMI and CA is needed to reduce the high mortality in these patients.

Ethical and regulatory issues of pragmatic cluster randomized trials in contemporary health systems.

Cluster randomized trials randomly assign groups of individuals to examine research questions or test interventions and measure their effects on individuals. Recent emphasis on quality improvement, comparative effectiveness, and learning health systems has prompted expanded use of pragmatic cluster randomized trials in routine health-care settings, which in turn poses practical and ethical challenges that current oversight frameworks may not adequately address. The 2012 Ottawa Statement provides a basis for considering many issues related to pragmatic cluster randomized trials but challenges remain, including some arising from the current US research and health-care regulations. In order to examine the ethical, regulatory, and practical questions facing pragmatic cluster randomized trials in health-care settings, the National Institutes of Health Health Care Systems Research Collaboratory convened a workshop in Bethesda, Maryland, in July 2013. Attendees included experts in clinical trials, patient advocacy, research ethics, and research regulations from academia, industry, the National Institutes of Health Collaboratory, and other federal agencies. Workshop participants identified substantial barriers to implementing these types of cluster randomized trials, including issues related to research design, gatekeepers and governance in health systems, consent, institutional review boards, data monitoring, privacy, and special populations. We describe these barriers and suggest means for understanding and overcoming them to facilitate pragmatic cluster randomized trials in health-care settings.

The Food and Drug Administration and pragmatic clinical trials of marketed medical products.

Pragmatic clinical trials can help answer questions of comparative effectiveness for interventions routinely used in medical practice. Pragmatic clinical trials may examine outcomes of one or more marketed medical products, and they are heterogeneous in design and risk. The Food and Drug Administration is charged with protecting the rights, safety, and welfare of individuals enrolled in clinical investigations, as well as assuring the integrity of the data upon which approval of medical products is made. The Food and Drug Administration has broad jurisdiction over drugs and medical devices (whether or not they are approved for marketing), and as such, clinical investigations of these products are subject to applicable Food and Drug Administration regulations. While many pragmatic clinical trials will meet the criteria for an exemption from the requirements for an investigational new drug application or investigational device exemption, in general, all clinical investigations of medical products that fall under Food and Drug Administration jurisdiction must adhere to regulations for informed consent and review by an institutional review board. We are concerned that current Food and Drug Administration requirements for obtaining individual informed consent may deter or delay the conduct of pragmatic clinical trials intended to develop reliable evidence of comparative safety and effectiveness of approved medical products that are regulated by the Food and Drug Administration. Under current regulations, there are no described mechanisms to alter or waive informed consent to make it less burdensome or more practicable for low-risk pragmatic clinical trials. We recommend that the Food and Drug Administration establish a risk-based approach to obtaining informed consent in pragmatic clinical trials that would facilitate the conduct of pragmatic clinical trials without compromising the protection of enrolled individuals or the integrity of the resulting data.

Association of Bystander and First-Responder Intervention With Survival After Out-of-Hospital Cardiac Arrest in North Carolina, 2010-2013.

IMPORTANCE: Out-of-hospital cardiac arrest is associated with low survival, but early cardiopulmonary resuscitation (CPR) and defibrillation can improve outcomes if more widely adopted. OBJECTIVE: To examine temporal changes in bystander and first-responder resuscitation efforts before arrival of the emergency medical services (EMS) following statewide initiatives to improve bystander and first-responder efforts in North Carolina from 2010-2013 and to examine the association between bystander and first-responder resuscitation efforts and survival and neurological outcome. DESIGN, SETTINGS, AND PARTICIPANTS: We studied 4961 patients with out-of-hospital cardiac arrest for whom resuscitation was attempted and who were identified through the Cardiac Arrest Registry to Enhance Survival (2010-2013). First responders were dispatched police officers, firefighters, rescue squad, or life-saving crew trained to perform basic life support until arrival of the EMS. EXPOSURES: Statewide initiatives to improve bystander and first-responder interventions included training members of the general population in CPR and in use of automated external defibrillators (AEDs), training first responders in team-based CPR including AED use and high-performance CPR, and training dispatch centers in recognition of cardiac arrest. MAIN OUTCOMES AND MEASURES: The proportion of bystander and first-responder resuscitation efforts, including the combination of efforts between bystanders and first responders, from 2010 through 2013 and the association between these resuscitation efforts and survival and neurological outcome. RESULTS: The combination of bystander CPR and first-responder defibrillation increased from 14.1% (51 of 362; 95% CI, 10.9%-18.1%) in 2010 to 23.1% (104 of 451; 95% CI, 19.4%-27.2%) in 2013 (P < .01). Survival with favorable neurological outcome increased from 7.1% (82 of 1149; 95% CI, 5.8%-8.8%) in 2010 to 9.7% (129 of 1334; 95% CI, 8.2%-11.4%) in 2013 (P = .02) and was associated with bystander-initiated CPR. Adjusting for age and sex, bystander and first-responder interventions were associated with higher survival to hospital discharge. Survival following EMS-initiated CPR and defibrillation was 15.2% (30 of 198; 95% CI, 10.8%-20.9%) compared with 33.6% (38 of 113; 95% CI, 25.5%-42.9%) following bystander-initiated CPR and defibrillation (odds ratio [OR], 3.12; 95% CI, 1.78-5.46); 24.2% (83 of 343; 95% CI, 20.0%-29.0%) following bystander CPR and first-responder defibrillation (OR, 1.70; 95% CI, 1.06-2.71); and 25.2% (109 of 432; 95% CI, 21.4%-29.6%) following first-responder CPR and defibrillation (OR, 1.77; 95% CI, 1.13-2.77). CONCLUSIONS AND RELEVANCE: Following a statewide educational intervention on rescusitation training, the proportion of patients receiving bystander-initiated CPR and defibrillation by first responders increased and was associated with greater likelihood of survival. Bystander-initiated CPR was associated with greater likelihood of survival with favorable neurological outcome.

Slit/Robo-mediated chemorepulsion of vagal sensory axons in the fetal gut.

BACKGROUND: The vagus nerve descends from the brain to the gut during fetal life to reach specific targets in the bowel wall. Vagal sensory axons have been shown to respond to the axon guidance molecule netrin and to its receptor, deleted in colorectal cancer (DCC). As there are regions of the gut wall into which vagal axons do and do not extend, it is likely that a combination of attractive and repellent cues are involved in how vagal axons reach specific targets. We tested the hypothesis that Slit/Robo chemorepulsion can contribute to the restriction of vagal sensory axons to specific targets in the gut wall. RESULTS: Transcripts encoding Robo1 and Robo2 were expressed in the nodose ganglia throughout development and mRNA encoding the Robo ligands Slit1, Slit2, and Slit3 were all found in the fetal and adult bowel. Slit2 protein was located in the outer gut mesenchyme in regions that partially overlap with the secretion of netrin-1. Neurites extending from explanted nodose ganglia were repelled by Slit2. CONCLUSIONS: These observations suggest that vagal sensory axons are responsive to Slit proteins and are thus repelled by Slits secreted in the gut wall and prevented from reaching inappropriate targets.

Advances in the long-term treatment of neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune neuroinflammatory disorder with a prevalence of 1-5/100,000 globally, characterized by attacks of the central nervous system including but not limited to optic neuritis, transverse myelitis and brainstem lesions, including area postrema lesions. These autoimmune attacks can lead to irreversible damage if left untreated, therefore strategies have been developed to prevent relapses. Initial off-label treatments have achieved variable levels of success in relapse prevention, but improved relapse prevention and quality of life remain a goal in the field. A better understanding of the underlying pathophysiology of NMOSD over the last 10 years has led to newer, more specific approaches in treatment, culminating in the first FDA approved treatments in the disease. In this review, we will discuss the seminal trials of PREVENT or Eculizumab in the treatment of aquaporin-4 (AQP4)-IgG positive NMOSD, N-Momentum or Inebilizumab in the study of NMOSD (both AQP4-IgG positive and negative) and SAkura Sky and SAkuraStar which studied satralizumab in AQP4-IgG seropositive and seronegative NMOSD patients. We will also discuss the extension trials of each of these medications and what lead to their approval in AQP4-IgG seropositive NMOSD patients. We will then examine treatments in the pipeline for adult and pediatric NMOSD patients and conclude with discussions on treatment considerations in pregnant patients and how to approach treatment of NMOSD patients during COVID.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare central nervous system inflammatory disorder caused by the aquaporin-4 antibody (AQP-4 IgG) labeling and immune system attack of astrocytes, and later downstream loss of myelin, the protective sheath surrounding neurons. It occurs in approximately 1-5 individuals per 100,000 globally and is characterized by attacks of the central nervous system including but not limited to optic neuritis, transverse myelitis and brainstem lesions, including area postrema lesions. These autoimmune attacks can lead to irreversible damage if left untreated, therefore strategies have been developed to prevent additional attacks. Initial off-label treatments have achieved variable levels of success in relapse prevention, but improved immune attack prevention and quality of life remain a goal in the field. A better understanding of the underlying causes of NMOSD over the last 10 years has led to newer, more specific approaches in treatment, culminating in the first FDA approved treatments in the disease. In this review, we will discuss the trials PREVENT or Eculizumab in the treatment of aquaporin-4 (AQP4)-IgG positive NMOSD, N-Momentum or Inebilizumab in the study of NMOSD (both AQP4-IgG positive and negative) and SAkura Sky and SAkuraStar which studied satralizumab in AQP4-IgG seropositive and seronegative NMOSD patients. We will also discuss the extension trials of each of these medications and what lead to their approval in AQP4-IgG seropositive NMOSD patients. We will then examine treatments in the pipeline for adult and pediatric NMOSD patients and conclude with discussions on treatment considerations in pregnant patients and how to approach treatment of NMOSD patients during COVID.

An evaluation of ravulizumab for the treatment of neuromyelitis optica spectrum disorder.

INTRODUCTION: Following the CHAMPION-NMOSD trial, the FDA recently granted approval for ravulizumab, a humanized monoclonal antibody against complement C5 protein in AQP-4 seropositive neuromyelitis optica spectrum disorder (NMOSD). Similar to eculizumab, ravulizumab offers near complete prevention of NMOSD relapses, but has a longer half-life, providing decreased infusion frequency and increased convenience for patients. While targeting the complement pathway has clear advantages, patients are at risk for infection with encapsulated organisms, in particular Neisseria meningitidis. AREAS COVERED: In this paper, we discuss the details of the CHAMPION-NMOSD trial and discuss challenges in meningitis prevention and strategies for switching therapies. EXPERT OPINION: Ravulizumab improves on eculizumab's success as a highly effective NMOSD therapy by decreasing infusion frequency, thereby increasing patient convenience. We predict ravulizumab will eventually replace eculizumab, but may not have a similar impact on inebelizumab or satralizumab. Patients taking C5 complement inhibitors have an increased risk of serious meningococcal infections, such as invasive meningococcal disease (IMD), and have incomplete protection against IMD despite immunization. Thus, we recommend that in addition to standard pre-immunizations against Neisseria meningitidis, patients should also be assessed for starting on appropriate antibiotic prophylaxis against IMD, based on local resistance patterns.

Predictors of relapsing disease course following index event in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune disease that can present as a monophasic or relapsing disease course. Here, we investigate the predictors of developing relapsing disease with a focus on the index event. METHODS: MOGAD patients followed at Massachusetts General Hospital and Brigham and Women's Hospital were included. Data on demographic, clinical, and laboratory features were collected. Time-to-event survival analysis was performed using a Cox proportional hazards model. Univariate and multivariate regression analyses were performed. RESULTS: We included 124 patients with a diagnosis of MOGAD of which 62.1% (n = 77) were female. The median (IQR) onset age and follow-up time were 31 (16, 45), and 4.08 (2.2, 7.9) years respectively. In total, 40.3% (n = 50) of patients remained monophasic and, 59.7% (n = 74) developed a relapsing course. The median (IQR) time between the index event and the second attack was 3(2, 13.7) months. Starting maintenance therapy following the index event was associated with decreased risk of relapsing disease (HR:0.26; 95%CI: 0.12, 0.54; P < 0.001). Maintenance therapy with intravenous immunoglobulin (HR:0.1; 95% CI:0.01, 0.78, P = 0.02), rituximab (HR: 0.21; 95%CI: 0.08, 0.55; P = 0.001), and mycophenolate mofetil (HR: 0.27; 95%CI: 0.09, 0.77; P = 0.01) was associated with a decreased risk of relapsing disease course. A polyphasic first attack (HR:2.4; 95%CI:1.31, 4.4; P = 0.004) and high CSF protein (HR:2.06; 95%CI: 1.01, 4.16; P = 0.04) were associated with a relapsing course. CONCLUSIONS: In MOGAD patients, starting maintenance therapy following the index event reduces the risk of relapsing disease regardless of age, sex, and onset phenotype, while polyphasic first attack, and elevated CSF protein predict relapsing disease course.

Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders.

Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.

Short- and long-term outcomes of coronary stenting in women versus men: results from the National Cardiovascular Data Registry Centers for Medicare & Medicaid services cohort.

BACKGROUND: Conflicting evidence exists on sex-based outcomes after coronary stenting. METHODS AND RESULTS: Data on 426 996 patients ≥65 years old (42.3% women) from the National Cardiovascular Data Registry CathPCI Registry (2004-2008) were linked to Medicare inpatient claims to compare in-hospital outcomes by sex and long-term outcomes by sex and stent type. In-hospital complications were more frequent in women than in men: death (3869 [2.2%] versus 3737 [1.6%]; adjusted odds ratio, 1.41; 95% confidence interval [CI], 1.33-1.49), myocardial infarction (2365 [1.3%] versus 2858 [1.2%]; odds ratio, 1.19; 95% CI, 1.11-1.27), bleeding (7860 [4.4%] versus 5627 [2.3%]; odds ratio, 1.86; 95% CI, 1.79-1.93), and vascular complications (2381 [1.3%] versus 1648 [0.7%]; odds ratio, 1.85; 95% CI, 1.73-1.99). At 20.4 months, women had a lower adjusted risk of death (hazard ratio [HR], 0.92; 95% CI, 0.90-0.94) but similar rates of myocardial infarction, revascularization, and bleeding. Relative to bare metal stent use, drug-eluting stent use was associated with similar improved long-term outcomes in both sexes: death (women: adjusted HR, 0.78; 95% CI, 0.76-0.81; men: HR, 0.77; 95% CI, 0.74-0.79), myocardial infarction (women: HR, 0.79; 95% CI, 0.74-0.84; men: HR, 0.81; 95% CI, 0.77-0.85), and revascularization (women: HR, 0.93; 95% CI, 0.90-0.97; men: HR, 0.91; 95% CI, 0.88-0.94). There was no interaction between sex and stent type for long-term outcomes. CONCLUSIONS: In contemporary coronary stenting, women have a slightly higher procedural risk than men but have better long-term survival. In both sexes, use of a drug-eluting stent is associated with lower long-term likelihood for death, myocardial infarction, and revascularization.