Astrocytic stress response is induced by exposure to astrocyte-binding antibodies expressed by plasmablasts from pediatric patients with acute transverse myelitis.

BACKGROUND: Pediatric acute transverse myelitis (ATM) accounts for 20-30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical presentation of a relapsing ADS such as multiple sclerosis (MS). B cells have been strongly implicated in the pathogenesis of adult MS. However, little is known about B cells in pediatric MS, and even less so in pediatric ATM. Our lab previously showed that plasmablasts (PB), the earliest B cell subtype producing antibody, are expanded in adult ATM, and that these PBs produce self-reactive antibodies that target neurons. The goal of this study was to examine PB frequency and phenotype, immunoglobulin selection, and B cell receptor reactivity in pediatric patients presenting with ATM to gain insight to B cell involvement in disease. METHODS: We compared the PB frequency and phenotype of 5 pediatric ATM patients and 10 pediatric healthy controls (HC) and compared them to previously reported adult ATM patients using cytometric data. We purified bulk IgG from the plasma samples and cloned 20 recombinant human antibodies (rhAbs) from individual PBs isolated from the blood. Plasma-derived IgG and rhAb autoreactivity was measured by mean fluorescence intensity (MFI) in neurons and astrocytes of murine brain or spinal cord and primary human astrocytes. We determined the potential impact of these rhAbs on astrocyte health by measuring stress and apoptotic response. RESULTS: We found that pediatric ATM patients had a reduced frequency of peripheral blood PB. Serum IgG autoreactivity to neurons in EAE spinal cord was similar in the pediatric ATM patients and HC. However, serum IgG autoreactivity to astrocytes in EAE spinal cord was reduced in pediatric ATM patients compared to pediatric HC. Astrocyte-binding strength of rhAbs cloned from PBs was dependent on somatic hypermutation accumulation in the pediatric ATM cohort, but not HC. A similar observation in predilection for astrocyte binding over neuron binding of individual antibodies cloned from PBs was made in EAE brain tissue. Finally, exposure of human primary astrocytes to these astrocyte-binding antibodies increased astrocytic stress but did not lead to apoptosis. CONCLUSIONS: Discordance in humoral immune responses to astrocytes may distinguish pediatric ATM from HC.

Impact of the COVID-19 pandemic from the perspective of patients with cardiovascular disease in Australia: mixed-methods study.

OBJECTIVES: The study explored the perceived impacts of COVID-19 and its associated policies and social restrictions on health, self-management and access to healthcare. DESIGN: Cross-sectional observational (online survey) and qualitative study (semi-structured interviews and thematic analysis). SETTING: Australia. PARTICIPANTS: People with self-reported cardiovascular disease (CVD) and/or risk factors. RESULTS: Survey responses were collected from 690 participants (43.8% women, 40.1% over 65 years). Participants reported that their heart health had been affected by the pandemic (26.3%), were less likely to exercise (47.1%), have a healthy diet (25.9%) and take medications (9.4%). A large proportion were admitted to hospital (46.2%) and presented to the emergency department (40.6%). Difficulties in accessing healthcare providers (53.2%) and use of telemedicine (63.6%) were reported. We conducted 16 semi-structured interviews and identified five key themes: adding burden in seeking medical care, impediments in accessing a readjusted health system, exacerbating vulnerability and distress, coping with self-management and adapting to telehealth. CONCLUSIONS: Patients with CVD expressed an additional burden in seeking medical care and difficulties navigating a readjusted health system during the COVID-19 pandemic. Associated policies and access issues heightened vulnerabilities and distress, making self-management of health difficult for patients with CVD.

Prevalence of anti-myelin oligodendrocyte glycoprotein antibodies across neuroinflammatory and neurodegenerative diseases.

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.

Alendronate-functionalized porous nano-crystalsomes mitigate osteolysis and consequent inhibition of tumor growth in a tibia-induced metastasis model.

Bone is one of the most prevalent sites of metastases in various epithelial malignancies, including breast cancer and this metastasis to bone often leads to severe skeletal complications in women due to its osteolytic nature. To address this, we devised a novel drug delivery approach using an Alendronate (ALN) functionalized self-assembled porous crystalsomes for concurrent targeting of Oleanolic acid (OA) and ALN (ALN + OA@NCs) to bone metastasis. Initially, the conjugation of both PEG-OA and OA-PEG-ALN with ALN and OA was achieved, and this conjugation was then self-assembled into porous crystalsomes (ALN + OA@NCs) by nanoemulsion crystallization. The reconstruction of a 3D single particle using transmission electron microscopy ensured the crystalline porous structure of ALN + OA@NCs, was well aligned with characteristic nanoparticle attributes including size distribution, polydispersity, and zeta potential. Further, ALN + OA@NCs showed enhanced efficacy in comparison to OA@NCs suggesting the cytotoxic roles of ALN towards cancer cells, followed by augmentation ROS generation (40.81%), mitochondrial membrane depolarization (57.20%), and induction of apoptosis (40.43%). We found that ALN + OA@NCs facilitated inhibiting osteoclastogenesis and bone resorption followed by inhibited osteolysis. In vivo activity of ALN + OA@NCs in the 4 T1 cell-induced tibia model rendered a reduced bone loss in the treated mice followed by restoring bone morphometric markers which were further corroborated bone-targeting effects of ALN + OA@NCs to reduce RANKL-stimulated osteoclastogenesis. Further, In vivo intravenous pharmacokinetics showed the improved therapeutic profile of the ALN + OA@NCs in comparison to the free drug, prolonging the levels of the drug in the systemic compartment by reducing the clearance culminating the higher accumulation at the tumor site. Our finding proposed that ALN + OA@NCs can effectively target and treat breast cancer metastasis to bone and its associated complications.

Use of digital patient decision-support tools for atrial fibrillation treatments: a systematic review and meta-analysis.

OBJECTIVES: To assess the effects of digital patient decision-support tools for atrial fibrillation (AF) treatment decisions in adults with AF. STUDY DESIGN: Systematic review and meta-analysis. ELIGIBILITY CRITERIA: Eligible randomised controlled trials (RCTs) evaluated digital patient decision-support tools for AF treatment decisions in adults with AF. INFORMATION SOURCES: We searched MEDLINE, EMBASE and Scopus from 2005 to 2023.Risk-of-bias (RoB) assessment: We assessed RoB using the Cochrane Risk of Bias Tool 2 for RCTs and cluster RCT and the ROBINS-I tool for quasi-experimental studies. SYNTHESIS OF RESULTS: We used random effects meta-analysis to synthesise decisional conflict and patient knowledge outcomes reported in RCTs. We performed narrative synthesis for all outcomes. The main outcomes of interest were decisional conflict and patient knowledge. RESULTS: 13 articles, reporting on 11 studies (4 RCTs, 1 cluster RCT and 6 quasi-experimental) met the inclusion criteria. There were 2714 participants across all studies (2372 in RCTs), of which 26% were women and the mean age was 71 years. Socioeconomically disadvantaged groups were poorly represented in the included studies. Seven studies (n=2508) focused on non-valvular AF and the mean CHAD2DS2-VASc across studies was 3.2 and for HAS-BLED 1.9. All tools focused on decisions regarding thromboembolic stroke prevention and most enabled calculation of individualised stroke risk. Tools were heterogeneous in features and functions; four tools were patient decision aids. The readability of content was reported in one study. Meta-analyses showed a reduction in decisional conflict (4 RCTs (n=2167); standardised mean difference -0.19; 95% CI -0.30 to -0.08; p=0.001; I2=26.5%; moderate certainty evidence) corresponding to a decrease in 12.4 units on a scale of 0 to 100 (95% CI -19.5 to -5.2) and improvement in patient knowledge (2 RCTs (n=1057); risk difference 0.72, 95% CI 0.68, 0.76, p<0.001; I2=0%; low certainty evidence) favouring digital patient decision-support tools compared with usual care. Four of the 11 tools were publicly available and 3 had been implemented in healthcare delivery. CONCLUSIONS: In the context of stroke prevention in AF, digital patient decision-support tools likely reduce decisional conflict and may result in little to no change in patient knowledge, compared with usual care. Future studies should leverage digital capabilities for increased personalisation and interactivity of the tools, with better consideration of health literacy and equity aspects. Additional robust trials and implementation studies are warranted. PROSPERO REGISTRATION NUMBER: CRD42020218025.