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.

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.

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.

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.

Low mortality rate in a large cohort of myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

The mortality rates of individuals with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are currently unknown. This study aimed to assess the mortality rate in a large cohort of patients with MOGAD. Since none of the patients in our cohort died, we estimated the upper limit of a 95% confidence interval of the crude mortality rate in the cohort to be 2.1%. These data suggest that mortality in MOGAD is lower than that reported in other neuroinflammatory diseases and comparable to the age-adjusted mortality rates of the general population in the United States. Additional studies are warranted to confirm this observation.

Neurosarcoidosis in children: A systematic review and summary of cases, imaging and management.

Neurosarcoidosis is a rare disorder in children. We identified 30 pediatric NS cases through a systematic review. Twenty-one (70%) had systemic sarcoidosis with 30% having primary neurosarcoidosis. Eyes (37%), lymph nodes (37%) and lungs (30%) were most commonly involved. Isolated neurosarcoidosis were more likely in children (30%) than in adults (6%, p = 0.0005). Seizures and optic neuritis were also more common in children than adults (33% vs 14%, p = 0.002; and 30% versus 6%, p = 0.008, respectively). Evaluation, imaging, laboratory findings, and treatments are discussed. Additional research, including multi-center studies, is needed.

Neurological Complications in Children Hospitalized With Seizures and Respiratory Infections: A Comparison Between SARS-CoV-2 and Other Respiratory Infections.

BACKGROUND: Children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can experience neurological symptoms, but limited data are available on neurological symptoms associated with other respiratory infections. We compared proportions of neurological symptoms in children hospitalized with seizures and respiratory infections, including SARS-CoV-2, influenza, and endemic coronaviruses. METHODS: A retrospective cohort study was performed on children admitted for seizures who had positive respiratory polymerase chain reactions for SARS-CoV-2, coronavirus NL63, coronavirus OC34, influenza (A and B), adenovirus, Mycoplasma pneumoniae, or parainfluenza 3 or 4. Primary outcomes were rates of new neurological diagnoses and mortality. RESULTS: A total of 883 children were included. Mortality rates ranged from 0% with M. pneumoniae to 4.9% with parainfluenza 4. Strokes were observed with all infections except for coronavirus OC43 and M. pneumoniae, with the highest rates in parainfluenza 4 (4.9%) and SARS-CoV-2 (5.9%). Compared with other infections, children with SARS-CoV-2 were older, had higher rates of stroke, and lower rates of intubation. The most common brain magnetic resonance imaging (MRI) abnormality was diffusion restriction. Abnormal MRI rates were lower in SARS-CoV-2, compared with patients with other coronavirus (OC). However, rates of stroke, encephalopathy, hypoxic-ischemic encephalopathy, and meningoencephalitis were similar between SARS-CoV-2 and influenza cohorts. CONCLUSIONS: In children hospitalized with seizures, higher rates of stroke were observed in SARS-CoV-2 versus OC. Similar rates of neurological symptoms were observed in patients with SARS-CoV-2 and those with influenza. Strokes can occur in children with these viral infections, particularly SARS-CoV-2.

The First North American Experience Using Glycosorb Immunoadsorption Columns for Blood Group-Incompatible Kidney Transplantation.

BACKGROUND: Blood group incompatibility (ABOi) is the most common barrier to living donor kidney transplantation. Options for such recipients include kidney paired donation (KPD) or desensitization methodology to reduce blood antibody response. OBJECTIVE: The objective of this study is to report on the first North America experience in ABOi living donor kidney transplantation using Glycosorb ABO immunoadsorption columns. DESIGN: Retrospective observational cohort study. SETTING: Renal transplant program at St. Michael's Hospital, Unity Health Toronto, University of Toronto. PATIENTS: Twenty-six ABOi living donor transplants from August 2011 through February 2020 were undertaken at our center. MEASUREMENTS: Renal allograft and patient survival postdesensitization for ABOi living donor transplants and isohemagglutinin titer reduction. METHODS: Preoperative immunosuppressive regimen consisted of a single dose of Rituximab 375 mg/m2 IV on day -28; tacrolimus, mycophenolic acid, and prednisone to start on day -7. Immunoadsorption treatments with Glycosorb A or B columns were performed on day -7 through day -1 based on anti-A or anti-B titers on Spectra Optia Apheresis System. Immunosuppression included basiliximab, solumedrol followed by oral prednisone, once-daily tacrolimus, and mycophenolic acid. The mean follow-up was 53 months (3-96 months). RESULTS: A total of 26 individuals underwent an attempt at desensitization of whom 24 patients underwent immediate transplant. One patient had a rebound in titers and subsequently was transplanted from a blood group compatible living donor. A second patient had an unrelated medical issue and desensitization was discontinued. Five-year patient survival was 96% and death censored allograft survival was 92%. Posttransplant anti-A or anti-B titers were monitored daily for the first 7 days posttransplant and every 2 days from days 7 to 14. There were no acute rejections seen in this cohort of transplant recipients. LIMITATIONS: As our protocol was first initiated as proof of concept, a few recipients had low initial isohemagglutinin titers. This may have contributed to improved clinical outcomes. CONCLUSIONS: ABO column immunoadsorption with specific columns is a safe and effective method for ABOi living donor kidney transplantation, and an option when KPD is less than ideal.Trial not registered as this was a retrospective cohort review.

CONTEXTE: L'incompatibilité du système ABO (ABOi) est l'obstacle le plus fréquent à la transplantation d'un rein provenant d'un donneur vivant. Un don croisé ou une désensibilisation visant à atténuer la réponse immunitaire constituent les seules options pour les receveurs de ce type de greffe. OBJECTIF: Faire état de la première expérience nord-américaine d'utilisation des colonnes d'immunoadsorption Glycosorb ABO pour la transplantation d'un rein ABOi provenant d'un donneur vivant. TYPE D'ÉTUDE: Étude de cohorte observationnelle rétrospective. CADRE: Le programme de transplantation rénale du centre hospitalier universitaire St Michael's de l'Unity Health Toronto. SUJETS: L'étude porte sur les 26 transplantations de reins ABOi provenant de donneurs vivants pratiquées à notre centre entre août 2011 et février 2020. MESURES: La survie du patient et de l'allogreffe après une désensibilisation en vue de la transplantation d'un rein ABOi provenant d'un donneur vivant, ainsi que la réduction du titre d'isohémagglutinine. MÉTHODOLOGIE: Le traitement préopératoire immunosuppressif consistait en une dose unique de 375 mg/m2 de Rituximab par voie intraveineuse (IV) au jour -28; et l'administration de tacrolimus, d'acide mycophénolique et de prednisone à partir du jour -7. Les traitements d'immunoadsorption avec les colonnes Glycosorb A ou B ont été effectués du jour -7 au jour -1 en fonction des titres anti-A ou anti-B obtenus avec le système d'apharèse Spectra Optia. Le traitement immunosuppressif était constitué de basiliximab, de solumédrol suivi de prednisone par voie orale, et d'une dose quotidienne de tacrolimus et d'acide mycophénolique. Le suivi s'est étalé sur une moyenne de 53 mois (3 à 96 mois). RÉSULTATS: En tout, 26 patients avaient tenté une désensibilisation, desquels 24 ont immédiatement subi une transplantation. Un rebond des titres a été observé chez un patient, lequel a par la suite été transplanté avec un organe provenant d'un donneur de groupe sanguin compatible. La désensibilisation a dû être interrompue chez un autre patient en raison d'un problème médical non relié. Cinq ans après la greffe, 96% des patients et 92% des allogreffes avaient survécu. Les titres d'anti-A et d'anti-B post-transplantation avaient été mesurés quotidiennement pour les sept premiers jours suivant l'intervention, puis tous les deux jours entre le jour 7 et le jour 14. Aucun rejet aigu n'est survenu dans la cohorte étudiée. LIMITES: Notre protocole ayant d'abord été utilisé comme preuve de concept, certains patients présentaient de faibles titres initiaux d'isohémagglutinine, ce qui pourrait avoir contribué à l'amélioration des résultats cliniques. CONCLUSIONS: L'immunoadsorption sur colonne ABO avec colonnes spécifiques s'avère une méthode sûre et efficace pour la transplantation d'un rein ABOi provenant d'un donneur vivant, et constitue une option valable lorsque le don croisé n'est pas idéal.Essai non enregistré puisqu'il s'agit d'une étude de cohorte rétrospective.

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.

Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes.

BACKGROUND: HTLV-1 infects over 20 million people worldwide and causes a progressive neuroinflammatory disorder in a subset of infected individuals called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The detection of HTLV-1 specific T cells in the cerebrospinal fluid (CSF) suggests this disease is immunopathologically mediated and that it may be driven by viral antigens. Exosomes are microvesicles originating from the endosomal compartment that are shed into the extracellular space by various cell types. It is now understood that several viruses take advantage of this mode of intercellular communication for packaging of viral components as well. We sought to understand if this is the case in HTLV-1 infection, and specifically if HTLV-1 proteins can be found in the CSF of HAM/TSP patients where we know free virus is absent, and furthermore, if exosomes containing HTLV-1 Tax have functional consequences. RESULTS: Exosomes that were positive for HTLV-1 Tax by Western blot were isolated from HAM/TSP patient PBMCs (25/36) in ex vivo cultures by trapping exosomes from culture supernatants. HTLV-1 seronegative PBMCs did not have exosomes with Tax (0/12), (Fisher exact test, p = 0.0001). We were able to observe HAM/TSP patient CSF (12/20) containing Tax+ exosomes but not in HTLV-1 seronegative MS donors (0/5), despite the absence of viral detection in the CSF supernatant (Fisher exact test p = 0.0391). Furthermore, exosomes cultivated from HAM/TSP PBMCs were capable of sensitizing target cells for HTLV-1 specific CTL lysis. CONCLUSION: Cumulatively, these results show that there are HTLV-1 proteins present in exosomes found in virus-free CSF. HAM/TSP PBMCs, particularly CD4+CD25+ T cells, can excrete these exosomes containing HTLV-1 Tax and may be a source of the exosomes found in patient CSF. Importantly, these exosomes are capable of sensitizing an HTLV-1 specific immune response, suggesting that they may play a role in the immunopathology observed in HAM/TSP. Given the infiltration of HTLV-1 Tax-specific CTLs into the CNS of HAM/TSP patients, it is likely that exosomes may also contribute to the continuous activation and inflammation observed in HAM/TSP, and may suggest future targeted therapies in this disorder.

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.

Role of Exosomes in Human Retroviral Mediated Disorders.

Retroviruses comprise an ancient and varied group of viruses with the unique ability to integrate DNA from an RNA transcript into the genome, a subset of which are able to integrate in humans. The timing of these integrations during human history has dictated whether these viruses have remained exogenous and given rise to various human diseases or have become inseparable from the host genome (endogenous retroviruses). Given the ability of retroviruses to integrate into the host and subsequently co-opt host cellular process for viral propagation, retroviruses have been shown to be closely associated with several cellular processes including exosome formation. Exosomes are 30-150 nm unilamellar extracellular vesicles that originate from intraluminal vesicles (ILVs) that form in the endosomal compartment. Exosomes have been shown to be important in intercellular communication and immune cell function. Almost every cell type studied has been shown to produce these types of vesicles, with the cell type dictating the contents, which include proteins, mRNA, and miRNAs. Importantly, recent evidence has shown that infection by viruses, including retroviruses, alter the contents and subsequent function of produced exosomes. In this review, we will discuss the important retroviruses associated with human health and disease. Furthermore, we will delve into the impact of exosome formation and manipulation by integrated retroviruses on human health, survival, and human retroviral disease pathogenesis.

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.

Association of Public Health Initiatives With Outcomes for Out-of-Hospital Cardiac Arrest at Home and in Public Locations.

Importance: Little is known about the influence of comprehensive public health initiatives according to out-of-hospital cardiac arrest (OHCA) location, particularly at home, where resuscitation efforts and outcomes have historically been poor. Objective: To describe temporal trends in bystander cardiopulmonary resuscitation (CPR) and first-responder defibrillation for OHCAs stratified by home vs public location and their association with survival and neurological outcomes. Design, Setting, and Participants: This observational study reviewed 8269 patients with OHCAs (5602 [67.7%] at home and 2667 [32.3%] in public) for whom resuscitation was attempted using data from the Cardiac Arrest Registry to Enhance Survival (CARES) from January 1, 2010, through December 31, 2014. The setting was 16 counties in North Carolina. Exposures: Patients were stratified by home vs public OHCA. Public health initiatives to improve bystander and first-responder interventions included training members of the general population in CPR and in the use of automated external defibrillators, teaching first responders about team-based CPR (eg, automated external defibrillator use and high-performance CPR), and instructing dispatch centers on recognition of cardiac arrest. Main Outcomes and Measures: Association of resuscitation efforts with survival and neurological outcomes from 2010 through 2014. Results: Among home OHCA patients (n = 5602), the median age was 64 years, and 62.2% were male; among public OHCA patients (n = 2667), the median age was 68 years, and 61.5% were male. After comprehensive public health initiatives, the proportion of patients receiving bystander CPR increased at home (from 28.3% [275 of 973] to 41.3% [498 of 1206], P < .001) and in public (from 61.0% [275 of 451] to 70.5% [424 of 601], P = .01), while first-responder defibrillation increased at home (from 42.2% [132 of 313] to 50.8% [212 of 417], P = .02) but not significantly in public (from 33.1% [58 of 175] to 37.8% [93 of 246], P = .17). Survival to discharge improved for arrests at home (from 5.7% [60 of 1057] to 8.1% [100 of 1238], P = .047) and in public (from 10.8% [50 of 464] to 16.2% [98 of 604], P = .04). Compared with emergency medical services-initiated CPR and resuscitation, patients with home OHCA were significantly more likely to survive to hospital discharge if they received bystander-initiated CPR and first-responder defibrillation (odds ratio, 1.55; 95% CI, 1.01-2.38). Patients with arrests in public were most likely to survive if they received both bystander-initiated CPR and defibrillation (odds ratio, 4.33; 95% CI, 2.11-8.87). Conclusions and Relevance: After coordinated and comprehensive public health initiatives, more patients received bystander CPR and first-responder defibrillation at home and in public, which was associated with improved survival.

Cardiopulmonary Resuscitation Training Disparities in the United States.

BACKGROUND: Bystander cardiopulmonary resuscitation (CPR) is associated with increased survival from cardiac arrest, yet bystander CPR rates are low in many communities. The overall prevalence of CPR training in the United States and associated individual-level disparities are unknown. We sought to measure the national prevalence of CPR training and hypothesized that older age and lower socioeconomic status would be independently associated with a lower likelihood of CPR training. METHODS AND RESULTS: We administered a cross-sectional telephone survey to a nationally representative adult sample. We assessed the demographics of individuals trained in CPR within 2 years (currently trained) and those who had been trained in CPR at some point in time (ever trained). The association of CPR training and demographic variables were tested using survey weighted logistic regression. Between September 2015 and November 2015, 9022 individuals completed the survey; 18% reported being currently trained in CPR, and 65% reported training at some point previously. For each year of increased age, the likelihood of being currently CPR trained or ever trained decreased (currently trained: odds ratio, 0.98; 95% CI, 0.97-0.99; P<0.01; ever trained: OR, 0.99; 95% CI, 0.98-0.99; P=0.04). Furthermore, there was a greater then 4-fold difference in odds of being currently CPR trained from the 30-39 to 70-79 year old age groups (95% CI, 0.10-0.23). Factors associated with a lower likelihood of CPR training were lesser educational attainment and lower household income (P<0.01 for each of these variables). CONCLUSIONS: A minority of respondents reported current training in CPR. Older age, lesser education, and lower income were associated with reduced likelihood of CPR training. These findings illustrate important gaps in US CPR education and suggest the need to develop tailored CPR training efforts to address this variability.

Outcomes of a multi-community hypertension implementation study: the American Heart Association's Check. Change. Control. program.

Single-site, intensive, community-based blood pressure (BP) intervention programs have led to BP improvements. The authors examined the American Heart Association's Check. Change. CONTROL: (CCC) program (4069 patients/18 cities) to determine whether BP interventions can effectively be scaled to multiple communities, using a simplified template and local customization. Effectiveness was evaluated at each site via site percent enrollment goals, participant engagement, and BP change from first to last measurement. High-enrolling sites frequently recruited at senior residential institutions and service organizations held hypertension management classes and utilized established and new community partners. High-engagement sites regularly held hypertension education classes and followed up with participants. Top-performing sites commonly distributed BP cuffs, checked BP at engagement activities, and trained volunteers. CCC demonstrated that simplified community-based hypertension intervention programs may lead to BP improvements, but there was high outcomes variability among programs. Several factors were associated with BP improvement that may guide future program development.

Association Between Hospital Process Composite Performance and Patient Outcomes After In-Hospital Cardiac Arrest Care.

IMPORTANCE: Survival rates after in-hospital cardiac arrest (IHCA) vary significantly among US centers; whether this variation is owing to differences in IHCA care quality is unknown. OBJECTIVE: To evaluate hospital-level variation to determine whether hospital process composite performance measures of IHCA care quality are associated with patient outcomes. DESIGN, SETTING, AND PARTICIPANTS: Using data from the American Heart Association's Get With the Guidelines-Resuscitation (GWTG-R) program, we analyzed 35 283 patients 18 years or older with IHCA treated at 261 US hospitals from January 1, 2010, through December 31, 2012. We calculated the hospital process composite performance score for IHCA using 5 guideline-recommended process measures. Opportunity-based scores were calculated for all patients, aggregated at the hospital level, divided into quartiles, and then associated with risk-standardized survival and neurologic status by a test for trend. The scores were then evaluated through hierarchical logistic regression and reported as odds ratios per 10% increment in hospital process composite performance. INTERVENTIONS: Acute care treatments for IHCA. MAIN OUTCOMES AND MEASURES: The primary outcome was survival to discharge measured as risk standard survival rates, and the secondary outcome was favorable neurologic status at hospital discharge. RESULTS: Of the 35 283 adults included in this study, the median age was 67 years (interquartile range [IQR] 56-78 years), and 57.9% were male. The median IHCA hospital process composite performance was 89.7% (interquartile range, 85.4%-93.1%) and varied among hospital quartiles from 82.6% (lowest) to 94.8% (highest). The IHCA hospital process composite performance was linearly associated with risk-standardized hospital survival to discharge rates: 21.1%, 21.4%, 22.8%, and 23.4% from lowest to highest performance quartiles, respectively (P < .001). After adjustment, each 10% increase in a hospital's process composite performance was associated with a 22% higher odds of survival (adjusted odds ratio, 1.22; 95% CI, 1.08-1.37; P = .01). Hospital process composite quality performance was also associated with favorable neurologic status at discharge (P = .004). CONCLUSIONS AND RELEVANCE: The quality of guideline-based care for IHCA varies significantly among US hospitals and is associated with patient survival and neurologic outcomes.