Oestrogen receptor β ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis.

Oestrogen treatments are neuroprotective in a variety of neurodegenerative disease models. Selective oestrogen receptor modifiers are needed to optimize beneficial effects while minimizing adverse effects to achieve neuroprotection in chronic diseases. Oestrogen receptor beta (ERβ) ligands are potential candidates. In the multiple sclerosis model chronic experimental autoimmune encephalomyelitis, ERβ-ligand treatment is neuroprotective, but mechanisms underlying this neuroprotection remain unclear. Specifically, whether there are direct effects of ERβ-ligand on CD11c+ microglia, myeloid dendritic cells or macrophages in vivo during disease is unknown. Here, we generated mice with ERβ deleted from CD11c+ cells to show direct effects of ERβ-ligand treatment in vivo on these cells to mediate neuroprotection during experimental autoimmune encephalomyelitis. Further, we use bone marrow chimeras to show that ERβ in peripherally derived myeloid cells, not resident microglia, are the CD11c+ cells mediating this protection. CD11c+ dendritic cell and macrophages isolated from the central nervous system of wild-type experimental autoimmune encephalomyelitis mice treated with ERβ-ligand expressed less iNOS and T-bet, but more IL-10, and this treatment effect was lost in mice with specific deletion of ERβ in CD11c+ cells. Also, we extend previous reports of ERβ-ligand’s ability to enhance remyelination through a direct effect on oligodendrocytes by showing that the immunomodulatory effect of ERβ-ligand acting on CD11c+ cells is necessary to permit the maturation of oligodendrocytes. Together these results demonstrate that targeting ERβ signalling pathways in CD11c+ myeloid cells is a novel strategy for regulation of the innate immune system in neurodegenerative diseases. To our knowledge, this is the first report showing how direct effects of a candidate neuroprotective treatment on two distinct cell lineages (bone marrow derived myeloid cells and oligodendrocytes) can have complementary neuroprotective effects in vivo.awx315media15688130498001.

A new technique for generating disordered point-light animations for the study of biological motion perception.

Studies of biological motion perception often use stimuli depicting human actions portrayed via point-light (PL) displays. Typically, counterpart, or control, stimuli for PL biological motion are created by spatially scrambling motion trajectories of individual PL dots. Depending on the purpose of the study, however, this procedure may be inappropriate as a foil for genuine PL animations, because spatial scrambling not only disrupts coherent motion activity but also eliminates pair-wise motion relationships among dots and, unless corrected, alters the spatial spread of PL dot motions. We introduce a new technique for producing perturbed PL animations, called pair-wise shuffled motion, that preserves the elementary features of biological motion in spatial and motion energy domains and only disrupts the specific sense of global, coherent perception of biological motion. First we describe the procedure for creating pair-wise shuffled motion sequences. Next we compare unperturbed PL animations to pair-wise shuffled motion, to spatially scrambled motion, and to spatially constrained scrambled motion in terms of spatial distributions of the dots, spatiotemporal amplitude spectra derived from Fourier analysis of those sequences, and space-time motion energy associated with those perturbed animations. We then show that the results from those analyses generalize to a large family of PL animations, including the widely used PL walker. Finally we present results from a two-interval forced-choice biological-motion discrimination experiment comparing the robustness of scrambled and pair-wise shuffled motions as foil stimuli. Results from these comparisons suggest that pair-wise shuffled motion offers advantages as a foil stimulus compared to foils using the conventional scrambling technique. Pair-wise shuffled motion provides an additional, effective control display for evaluating PL biological motion perception in future psychophysical, computational, and imaging studies that focus on mechanisms of processing spatiotemporal information signifying biological motion within PL displays.

COVID-19 in Patients with Multiple Sclerosis: Associations with Disease-Modifying Therapies.

BACKGROUND: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and alter its clinical course. We assessed these risks in patients with MS (PwMS). OBJECTIVE: The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE). In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated. Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies. METHODS: The IBM® Explorys electronic health record database of > 72,000,000 patients from US healthcare networks identified patients with MS or SLE, with and without polymerase chain reaction-confirmed COVID-19. COVID-19 cumulative incidence, hospitalization, and deaths among DMT classes were compared using logistic regression (adjusted for age, sex, body mass index, comorbidities, and race/ethnicity). As a secondary data source to assess safety data, COVID-19 reports for Biogen MS therapies were extracted and described from Biogen's Global Safety Database. RESULTS: 30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive. The most significant risk factors for acquiring COVID-19 were comorbidity score ≥ 1, body mass index ≥ 30, and Black/African ancestry. Similar risk factors were also identified for patients with SLE. Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both p < 0.001); anti-CD20 therapy was associated with the highest risk (3.45%; p < 0.0001). In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine. CONCLUSIONS: Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS. Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort. COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach.

Association of Delirium With Long-term Cognitive Decline: A Meta-analysis.

Importance: Delirium is associated with increased hospital costs, health care complications, and increased mortality. Long-term consequences of delirium on cognition have not been synthesized and quantified via meta-analysis. Objective: To determine if an episode of delirium was an independent risk factor for long-term cognitive decline, and if it was, whether it was causative or an epiphenomenon in already compromised individuals. Data Sources: A systematic search in PubMed, Cochrane, and Embase was conducted from January 1, 1965, to December 31, 2018. A systematic review guided by Preferred Reporting Items for Systematic Reviews and Meta-analyses was conducted. Search terms included delirium AND postoperative cognitive dysfunction; delirium and cognitive decline; delirium AND dementia; and delirium AND memory. Study Selection: Inclusion criteria for studies included contrast between groups with delirium and without delirium; an objective continuous or binary measure of cognitive outcome; a final time point of 3 or more months after the delirium episode. The electronic search was conducted according to established methodologies and was executed on October 17, 2018. Data Extraction and Synthesis: Three authors extracted data on individual characteristics, study design, and outcome, followed by a second independent check on outcome measures. Effect sizes were calculated as Hedges g. If necessary, binary outcomes were also converted to g. Only a single effect size was calculated for each study. Main Outcomes and Measures: The planned main outcome was magnitude of cognitive decline in Hedges g effect size in delirium groups when contrasted with groups that did not experience delirium. Results: Of 1583 articles, data subjected from the 24 studies (including 3562 patients who experienced delirium and 6987 controls who did not) were included in a random-effects meta-analysis for pooled effect estimates and random-effects meta-regressions to identify sources of study variance. One study was excluded as an outlier. There was a significant association between delirium and long-term cognitive decline, as the estimated effect size (Hedges g) for 23 studies was 0.45 (95% CI, 0.34-0.57; P < .001). In all studies, the group that experienced delirium had worse cognition at the final time point. The I2 measure of between-study variability in g was 0.81. A multivariable meta-regression suggested that duration of follow-up (longer with larger gs), number of covariates controlled (greater numbers were associated with smaller gs), and baseline cognitive matching (matching was associated with larger gs) were significant sources of variance. More specialized subgroup and meta-regressions were consistent with predictions that suggested that delirium may be a causative factor in cognitive decline. Conclusions and Relevance: In this meta-analysis, delirium was significantly associated with long-term cognitive decline in both surgical and nonsurgical patients.

Individual differences in the perception of biological motion and fragmented figures are not correlated.

WE LIVE IN A CLUTTERED, DYNAMIC VISUAL ENVIRONMENT THAT POSES A CHALLENGE FOR THE VISUAL SYSTEM: for objects, including those that move about, to be perceived, information specifying those objects must be integrated over space and over time. Does a single, omnibus mechanism perform this grouping operation, or does grouping depend on separate processes specialized for different feature aspects of the object? To address this question, we tested a large group of healthy young adults on their abilities to perceive static fragmented figures embedded in noise and to perceive dynamic point-light biological motion figures embedded in dynamic noise. There were indeed substantial individual differences in performance on both tasks, but none of the statistical tests we applied to this data set uncovered a significant correlation between those performance measures. These results suggest that the two tasks, despite their superficial similarity, require different segmentation and grouping processes that are largely unrelated to one another. Whether those processes are embodied in distinct neural mechanisms remains an open question.

Hybrid representation of hierarchical structures in point-of-care coded data capture platform.

Capturing structured clinical documentation remains a central challenge in clinical informatics. A solution which represented highly hierarchical data in a relational structure exhibited degradation in performance as complexity of hierarchies grew. To ameliorate the problem, we devised a hybrid approach whereby we commit a precompiled XML representation of hierarchical data as well as individual records to a relational database.

The Acute Respiratory Infection Quality Dashboard: a performance measurement reporting tool in an electronic health record.

Quality reporting tools, integrated with electronic health records, can help clinicians understand performance, manage populations, and improve quality. The Acute Respiratory Infection Quality Dashboard (ARI QD) for LMR users is a secure web report for performance measurement of an acute condition delivered through a central data warehouse and custom-built reporting tool. Pilot evaluation of the ARI QD indicates that clinicians prefer a quality report that combines not only structured data regarding diagnosis and antibiotic prescribing rates entered into EHRs but one that also shows billing data. The ARI QD has the potential to reduce inappropriate antibiotic prescribing for ARIs.

The coronary artery disease quality dashboard: a chronic care disease management tool in an electronic health record.

Quality reporting tools, integrated with ambulatory electronic health records (EHRs), may help clinicians understand performance, manage populations, and improve quality. The Coronary Artery Disease Quality Dash board (CAD QD) is a secure web report for performance measurement of a chronic care condition delivered through a central data warehouse and custom-built reporting tool. Pilot evaluation of the CAD Quality Dash board indicates that clinicians prefer a quality report that combines not only structured data from EHRs but one that facilitates actions to be taken on individual patients or on a population, i.e., for case management.

Quality Dashboards: technical and architectural considerations of an actionable reporting tool for population management.

Quality Dashboards (QD) is a condition-specific, actionable web-based application for quality reporting and population management that is integrated into the Electronic Health Record (EHR). Using server-based graphic web controls in a .Net environment to construct Quality Dashboards allows customization of the reporting tool without the need to rely on commercial business intelligence tool. Quality Dashboards will improve patient care and quality outcomes as clinicians utilize the reporting tool for population management.

Report Central: quality reporting tool in an electronic health record.

Quality reporting tools, integrated with ambulatory electronic health records, can help clinicians and administrators understand performance, manage populations, and improve quality. Report Central is a secure web report delivery tool built on Crystal Reports XItrade mark and ASP.NET technologies. Pilot evaluation of Report Central indicates that clinicians prefer a quality reporting tool that is integrated with our home-grown EHR to support clinical workflow.