Type I interferon blockade with anifrolumab in patients with systemic lupus erythematosus modulates key immunopathological pathways in a gene expression and proteomic analysis of two phase 3 trials.

INTRODUCTION: Anifrolumab is a type I interferon (IFN) receptor 1 (IFNAR1) blocking antibody approved for treating patients with systemic lupus erythematosus (SLE). Here, we investigated the immunomodulatory mechanisms of anifrolumab using longitudinal transcriptomic and proteomic analyses of the 52-week, randomised, phase 3 TULIP-1 and TULIP-2 trials. METHODS: Patients with moderate to severe SLE were enrolled in TULIP-1 and TULIP-2 and received intravenous anifrolumab or placebo alongside standard therapy. Whole-blood expression of 18 017 genes using genome-wide RNA sequencing (RNA-seq) (pooled TULIP; anifrolumab, n=244; placebo, n=258) and 184 plasma proteins using Olink and Simoa panels (TULIP-1; anifrolumab, n=124; placebo, n=132) were analysed. We compared treatment groups via gene set enrichment analysis using MetaBase pathway analysis, blood transcriptome modules, in silico deconvolution of RNA-seq and longitudinal linear mixed effect models for gene counts and protein levels. RESULTS: Compared with placebo, anifrolumab modulated >2000 genes by week 24, with overlapping results at week 52, and 41 proteins by week 52. IFNAR1 blockade with anifrolumab downregulated multiple type I and II IFN-induced gene modules/pathways and type III IFN-λ protein levels, and impacted apoptosis-associated and neutrophil extracellular traps-(NET)osis-associated transcriptional pathways, innate cell activating chemokines and receptors, proinflammatory cytokines and B-cell activating cytokines. In silico deconvolution of RNA-seq data indicated an increase from baseline of mucosal-associated invariant and γδT cells and a decrease of monocytes following anifrolumab treatment. DISCUSSION: Type I IFN blockade with anifrolumab modulated multiple inflammatory pathways downstream of type I IFN signalling, including apoptotic, innate and adaptive mechanisms that play key roles in SLE immunopathogenesis.

Resilience improvement through a multicomponent physical and cognitive intervention for older people: the DanzArTe emotional well-being technology project.

BACKGROUND: Resilience is a crucial component of successful aging. However, which interventions might increase resilience in older adults is yet unclear. AIMS: This study aims to assess the feasibility and the physical and psychological effects of a technology-based multicomponent dance movement intervention that includes physical, cognitive, and sensory activation in older people living in community-dwelling and nursing home. METHODS: DanzArTe program consists of four sessions on a weekly basis, using a technological platform that integrates visual and auditory contents in real time. 122 participants (mean age = 76.3 ± 8.8 years, 91 females = 74.6%) from seven nursing homes and community-dwelling subjects were assessed, before and after the intervention, with the Resilience Scale-14 items (RES-14), the Multidimensional Prognostic Index (MPI), the Psychological General Well-Being Index (PGWBI-S), and the Client Satisfaction Questionnaire-8 (CSQ-8). Mann-Whitney and Wilcoxon signed-ranks tests were used for statistical analyses. RESULTS: At baseline significant differences in MPI and RES-14 between community-dwelling and nursing home residents were observed (p < 0.001 for both analyses). After the intervention, resilience significantly increased in total sample (RES-14 mean T1 = 74.6 Vs. T2 = 75.7) and in the nursing home residents (RES-14 mean T1 = 68.1 Vs. T2 = 71.8). All participants showed high overall satisfaction for DanzArTe program (CSQ-8 mean = 23.9 ± 4.4). No differences in MPI and PGWBI-S were observed. DISCUSSION: DanzArTe was a feasible intervention and high appreciated by all older adults. Nursing home residents revealed improvements in resilience after DanzArTe program. CONCLUSION: The DanzArTe technology-based multi-component intervention may improve resilience in older people living in nursing homes.

Pairwise summation as a method for the additive combination of probabilities in qualitative risk assessments.

Qualitative frameworks are widely employed to tackle urgent animal or public health issues when data are scarce and/or urgent decisions need to be made. In qualitative models, the degree of belief regarding the probabilities of the events occurring along the risk pathway(s) and the outcomes is described in nonnumerical terms, typically using words such as Low, Medium, or High. The main methodological challenge, intrinsic in qualitative models, relates to performing mathematical operations and adherence to the rule of probabilities when probabilities are nonnumerical. Although methods to obtain the qualitative probability from the conditional realization of n events are well-established and consistent with the multiplication rule of probabilities, there is a lack of accepted methods for addressing situations where the probability of an event occurring can increase, and the rule of probability P(AUB) = P(A) + P(B) - P(A∩B) should apply. In this work, we propose a method based on the pairwise summation to fill this methodological gap. Our method was tested on two qualitative models and compared by means of scenario analysis to other approaches found in literature. The qualitative nature of the models prevented formal validation; however, when using the pairwise summation, results consistently appeared more coherent with probability rules. Even if the final qualitative estimate can only represent an approximation of the actual probability of the event occurring, qualitative models have proven to be effective in providing scientific-based evidence to support decision-making. The method proposed in this study contributes to reducing the subjectivity that characterizes qualitative models, improving transparency and reproducibility.

Seroprevalence and risk factors of Toxoplasma gondii infection in goats from South Punjab Province, Pakistan.

Layyah District in South Punjab Province of Pakistan offers the most intensive caprine economy in the country; its Indus riverine and desert environment makes the area peculiar and worthy of specific investigations. This study aimed to investigate the prevalence of anti-Toxoplasma gondii (T. gondii) IgG-antibody in goats in serum samples and the potential risk factors. The prevalence of T. gondii infection was estimated using a two-stage sample design. All caprine farms in the study area were stratified by size, and from these 110 were randomly selected. Twelve goats (>1-year-old) were selected from each farm and a total of 1320 serum samples were collected and tested by ELISA. A questionnaire on the conditions and management practices of each farm was administered to 110 farmers. Four hundred and sixteen out of 1320 sera samples (31.5%) were found positive and 89% of the flock had at least one seropositive goat. The proportion of seropositive goats tested within each flock ranged from 8.3% to 83.3%. with several factors contributing to this heterogeneity. Goat age played a significant role in the presence of cats. Significant interactions were related to goat farms having floor of dirt and kitten presence. Moreover, age class, abortion history and water source supply were modulated by owner education levels. This is the first study to determine the prevalence of anti-T. gondii antibodies in goats sera in Layyah district and the largest carried out so far in Pakistan. The remarkable presence of T. gondii among goats in areas where goat farming plays a significant economic role may pose a production threat to the small-stock industry, as well as to public health and food safety. Therefore, investigations to identify high-risk goat populations are highly recommended in order to facilitate the implementation of local control strategies.