Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma : results from two phase 3, randomised, double-blind, placebo-controlled trials

BACKGROUND: Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). METHODS: Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count <400 cells/μL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per μL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). FINDINGS: Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. INTERPRETATION: Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. FUNDING: Teva Branded Pharmaceutical Products R&D

Effect of ACE1 polymorphism rs1799752 on protein levels of ACE2, the SARS-CoV-2 entry receptor, in alveolar lung epithelium

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Current Limitations in Cyberbullying Detection: on Evaluation Criteria, Reproducibility, and Data Scarcity

The detection of online cyberbullying has seen an increase in societal importance, popularity in research, and available open data. Nevertheless, while computational power and affordability of resources continue to increase, the access restrictions on high-quality data limit the applicability of state-of-the-art techniques. Consequently, much of the recent research uses small, heterogeneous datasets, without a thorough evaluation of applicability. In this paper, we further illustrate these issues, as we (i) evaluate many publicly available resources for this task and demonstrate difficulties with data collection. These predominantly yield small datasets that fail to capture the required complex social dynamics and impede direct comparison of progress. We (ii) conduct an extensive set of experiments that indicate a general lack of cross-domain generalization of classifiers trained on these sources, and openly provide this framework to replicate and extend our evaluation criteria. Finally, we (iii) present an effective crowdsourcing method: simulating real-life bullying scenarios in a lab setting generates plausible data that can be effectively used to enrich real data. This largely circumvents the restrictions on data that can be collected, and increases classifier performance. We believe these contributions can aid in improving the empirical practices of future research in the field

Sex-linked genetic diversity originates from persistent sociocultural processes at microgeographic scales.

Population genetics has been successful at identifying the relationships between human groups and their interconnected histories. However, the link between genetic demography inferred at large scales and the individual human behaviours that ultimately generate that demography is not always clear. While anthropological and historical context are routinely presented as adjuncts in population genetic studies to help describe the past, determining how underlying patterns of human sociocultural behaviour impact genetics still remains challenging. Here, we analyse patterns of genetic variation in village-scale samples from two islands in eastern Indonesia, patrilocal Sumba and a matrilocal region of Timor. Adopting a 'process modelling' approach, we iteratively explore combinations of structurally different models as a thinking tool. We find interconnected socio-genetic interactions involving sex-biased migration, lineage-focused founder effects, and on Sumba, heritable social dominance. Strikingly, founder ideology, a cultural model derived from anthropological and archaeological studies at larger regional scales, has both its origins and impact at the scale of villages. Process modelling lets us explore these complex interactions, first by circumventing the complexity of formal inference when studying large datasets with many interacting parts, and then by explicitly testing complex anthropological hypotheses about sociocultural behaviour from a more familiar population genetic standpoint

The buzz about bees and poverty alleviation: Identifying drivers and barriers of beekeeping in sub-Saharan Africa

The potential of beekeeping to mitigate the exposure of rural sub-Sahara African farmers to economic stochasticity has been widely promoted by an array of development agencies. Robust outcome indicators of the success of beekeeping to improve household well-being are unfortunately lacking. This study aimed to identify the key drivers and barriers of beekeeping adoption at the household level, and quantified the associated income contribution in three agro-ecological zones in Uganda. Beekeepers were generally the most economically disadvantaged people in the study areas and tended to adopt beekeeping following contact with non-government organisations and access to training. Whilst incomes were not statistically lower than their non-beekeeping counterparts; their mean household well-being scores were significantly lower than non-beekeeping households. The inability of beekeeping to significantly improve well-being status can in part be attributed to a lack of both training in bee husbandry and protective equipment provision such as suits, gloves and smokers. These are critical tools for beekeepers as they provide the necessary confidence to manage honey bees. Rather than focussing solely on the socio-economic conditions of farmers to effectively adopt beekeeping, future research should also attempt to evaluate the effectiveness of development agencies’ provision to the beekeeping sector