Outcome selection for tissue-agnostic drug trials for immune-mediated inflammatory diseases: a systematic review of core outcome sets and regulatory guidance

Background Tissue-agnostic drug development provides a paradigm shift in precision medicine and requires innovative trial designs. However, outcome selection for such trials can prove challenging. The objectives of this review were to: Identify and map core outcome sets (COS), across 11 immune-mediated inflammatory diseases (IMIDs) in order to facilitate the selection of relevant outcomes across the conditions for innovative trials of tissue-agnostic drug therapies. Compare outcomes or endpoints recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to identify and highlight similarities and differences. Methods The Core Outcome Measures in Effectiveness Trials (COMET), International Consortium for Health Outcomes Measurement (ICHOM), FDA and EMA databases were searched from inception to 28th December 2019. Two reviewers independently screened titles and abstracts of retrieved entries and conducted the subsequent full text screening. Hand searching of the reference lists and citation searching of the selected publications was conducted. The methodological quality of the included peer-reviewed articles was independently assessed by the reviewers based on the items of the COS–Standards for Development recommendations (COS–STAD) checklist. Core outcomes from the included publications were extracted and mapped across studies and conditions. Regulatory guidance from FDA and EMA, where available for clinical trials for the IMIDs, were obtained from their databases and recommendations on outcomes to measure directly compared. Results Forty-four COS publications were included in the final analysis. Outcomes such as disease activity, pain, fatigue, quality of life, physical function, work limitation/productivity, steroid use and biomarkers were recommended across majority of the conditions. There were significant similarities and differences in FDA and EMA recommendations. The only instance where either regulatory body directly referenced a COS was for jSLE—both referenced the Paediatric Rheumatology International Trials Organization (PRINTO) COS. Conclusions The findings from this systematic review provide valuable information to inform outcome selection in tissue-agnostic trials for IMIDs. There is a need for increased collaboration between regulators and COS developers and inclusion of regulators as key stakeholders in COS development to enhance the quality of COS. Trial registration Not registered.

Working with Wolt

In this paper, we present the results of an ethnographic study focusing on food deliveries for the digital platform Wolt. The platform manages food transport ordered by customers to be delivered at home from restaurants, and subcontracts the transport to workers called 'couriers', who act as independent firms or entrepreneurs. The paper is based on six months of participant observation, during which time the first author worked as a courier, as well as on ad-hoc conversations and semi-structured interviews with other couriers. We describe couriers' work for the platform and discuss our findings using Möhlmann and Zalmanson's definition of algorithmic management. We found both similarities and differences. It was noticeable that the couriers were positive about their work that no penalties or wage reductions were enforced, and that human support complemented the platform's algorithmic management. Thus, the algorithmic management we observed is neither harsh (as it has been described on other platforms including Uber), nor like the algorithmic despotism present on Instacart, for example. Hence, we refer to it as 'lenient algorithmic management' and underline the importance of adding new perspectives to our understanding of what algorithmic management can be, as well as looking at the context in which it is practised. To complement this finding of lenient algorithmic management, we present a set of strategies couriers must engage in to be effective on the platform: Thus, couriers must 1) schedule their work for peak hours to limit the amount of time they waste, 2) bundle orders to increase their payment per tour, 3) make use of support to handle customers and cancel orders involving delays, and 4) make use of the ecology of local support structures. The contribution of this paper is to add new perspectives to the way we perceive algorithmic management by presenting a lenient form of algorithmic management and indicating the importance of looking at the context in which it is practised, while describing what it takes to be an effective worker on the Wolt platform.

Cognitive Digital Twins for Resilience in Production: A Conceptual Framework

Digital Twins (DTs) are a core enabler of Industry 4.0 in manufacturing. Cognitive Digital Twins (CDTs), as an evolution, utilize services and tools towards enabling human-like cognitive capabilities in DTs. This paper proposes a conceptual framework for implementing CDTs to support resilience in production, i.e., to enable manufacturing systems to identify and handle anomalies and disruptive events in production processes and to support decisions to alleviate their consequences. Through analyzing five real-life production cases in different industries, similarities and differences in their corresponding needs are identified. Moreover, a connection between resilience and cognition is established. Further, a conceptual architecture is proposed that maps the tools materializing cognition within the DT core together with a cognitive process that enables resilience in production by utilizing CDTs.

Similarities and differences between bone quality parameters, trabecular bone score and femur geometry

Bone quality is a critical factor that, along with bone quantity, determines bone strength. Image-based parameters are used for assessing bone quality non-invasively. The trabecular bone score (TBS) is used to assess quality of trabecular bone and femur geometry for cortical bone. Little is known about the associations between these two bone quality parameters and whether they show differences in the relationships with age and body mass index (BMI). We investigated the associations between the trabecular bone score (TBS) and femur cortical geometry. Areal bone mineral density (BMD) was assessed using dual energy X-ray absorptiometry (DXA) and the TBS was assessed using iNsight software and, femur geometry using APEX (Hologic). A total of 452 men and 517 women aged 50 years and older with no medical history of a condition affecting bone metabolism were included. Z-scores for TBS and cortical thickness were calculated using the age-specific mean and SD for each parameter. A ‘discrepancy group’ was defined as patients whose absolute Z-score difference between TBS and cortical thickness was > 1 point. TBS and cortical thickness correlated negatively with age both in men and women, but the associations were stronger in women. Regarding the associations with BMI, TBS provided significant negative correlation with BMI in the range of BMI > 25 kg/m2. By contrast, cortical thickness correlated positively with BMI for all BMI ranges. These bone quality-related parameters, TBS and cortical thickness, significantly correlated, but discordance between these two parameters was observed in about one-third of the men and women (32.7% and 33.4%, respectively). Conclusively, image-based bone quality parameters for trabecular and cortical bone exhibit both similarities and differences in terms of their associations with age and BMI. These different profiles in TBS and FN cortical thickness might results in different risk profiles for the vertebral fractures or hip fractures in a certain percentage of people.

A single-cell atlas reveals shared and distinct immune responses and metabolism during SARS-CoV-2 and HIV-1 infections

SARS-CoV-2 and HIV-1 are RNA viruses that have killed millions of people worldwide. Understanding the similarities and differences between these two infections is critical for understanding disease progression and for developing effective vaccines and therapies, particularly for 38 million HIV-1+ individuals who are vulnerable to SARS-CoV-2 co-infection. Here, we utilized single-cell transcriptomics to perform a systematic comparison of 94,442 PBMCs from 7 COVID-19 and 9 HIV-1+ patients in an integrated immune atlas, in which 27 different cell types were identified using an accurate consensus single-cell annotation method. While immune cells in both cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activities, and downregulated mitophagy. Our results elucidate transcriptional signatures associated with COVID-19 and HIV-1 that may reveal insights into fundamental disease biology and potential therapeutic targets to treat these viral infections.

A quantitative analysis of the similarities and differences of the HIV/FIV gag genome

Among viruses, human immunodeficiency virus (HIV) presents the greatest challenge to humans. Here, we retrieved genome sequences from NCBI and were then run through LALIGN bioinformatics software to compute the E value, bit score, Waterman eggert score, and percent identity, which are four important indicators of how similar the sequences are. The E value was 3.1 x 10^-9, the percent identity was 54.4 percent, and the bit score was 51.9. It was also sensed that bases 1600 to 1990 in HIV and bases 800 to 910 in FIV have a higher than normal similarity. This reflects that while the DNA sequences of the gag region of both the HIV and FIV genomes are rather similar, it is unlikely that this similarity is due to random chance; therefore, there are a noticeable number of differences. A better understanding of the level of similarity and differences in the gag region of the genome sequence would facilitate our understanding of structural and cellular behavioral differences between FIV and HIV, and in the long term, it will provide new insights into the differences observed in previous studies or even facilitate the development of an effective HIV treatment.

Systematic Genetic Interaction Analysis Identifies a Transcription Factor Circuit Required for Oropharyngeal Candidiasis

The pathology of oral candidiasis has features of biofilm formation, a well-studied process in vitro . Based on that analogy, we hypothesized that the network of transcription factors that regulates in vitro biofilm formation has similarities and differences during oral infection.