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Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.

INTRODUCTION: Upadacitinib (UPA) is a Janus kinase inhibitor that has demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA) with an acceptable safety profile. We investigated laboratory parameter changes in UPA RA clinical trials. METHODS: Pooled data from six randomized trials in the SELECT phase 3 program were included. Key laboratory parameters and safety data were measured for UPA 15 and 30 mg once daily (QD), adalimumab (ADA) 40 mg every other week + methotrexate (MTX), and MTX monotherapy. Exposure-adjusted event rates (EAERs) of adverse events were calculated. RESULTS: A total of 3209 patients receiving UPA 15 mg QD (10 782.7 patient-years [PY]), 1204 patients receiving UPA 30 mg QD (3162.5 PY), 579 patients receiving ADA + MTX (1573.2 PY), and 314 patients receiving MTX monotherapy (865.1 PY) were included, representing up to 6.5 years of total exposure. Decreases in mean levels of hemoglobin, neutrophils, and lymphocytes, and increases in mean levels of liver enzymes and creatinine phosphokinase were observed with UPA, with grade 3 or 4 changes observed in some patients. Mean low- and high-density lipoprotein cholesterol ratios remained stable for patients receiving UPA 15 mg QD. EAERs of anemia and neutropenia occurred at generally consistent rates between UPA and active comparators (3.1-4.3 and 1.7-5.0 events [E]/100 PY across treatment groups, respectively). Rates of hepatic disorder were higher with MTX monotherapy, UPA 15 mg and UPA 30 mg (10.8, 9.7, and 11.0 E/100 PY, respectively) versus ADA + MTX (6.4 E/100 PY). Rates of lymphopenia were highest with MTX monotherapy (3.2 E/100 PY). Treatment discontinuations due to laboratory-related events were rare, occurring in 1.1% and 2.2% of patients treated with UPA 15 and 30 mg QD, respectively. CONCLUSIONS: The results of this integrated long-term analysis of laboratory parameters continue to support an acceptable safety profile of UPA 15 mg QD for moderate-to-severe RA.

Dehydration and tomato spotted wilt virus (TSWV) infection substantially impact the feeding of western flower thrips, Frankliniella occidentalis. Until now, the dynamics between these biotic and abiotic stresses have not been examined for thrips. Here, we report water balance characteristics and changes in other biological parameters during infection with TSWV for the western flower thrips. There were no apparent differences in water balance parameters during TSWV infection of male or female thrips. Our results show that, although water balance characteristics of western flower thrips are minimally impacted by TSWV infection, the increase in feeding and activity when dehydration and TSWV are combined suggests that virus transmission could be increased under periods of drought. Importantly, survival and progeny generation were impaired during TSWV infection and dehydration bouts. The negative impact on survival and reproduction suggests that the interactions between TSWV infection and dehydration will likely reduce thrips populations. The opposite effects of dehydration on feeding/activity and survival/reproduction for virus infected thrips suggest the impact of vectorial capacity will likely be minor for TSWV transmission. As water stress significantly impacts insect-plant-virus dynamics, these studies highlight that all interactions and effects need to be measured to understand thrips-TSWV interactions in their role as viral vector to plants.

Computational and data-enabled science and engineering are revolutionizing advances throughout science and society, at all scales of computing. For example, teams in the U.S. Department of Energy's Exascale Computing Project have been tackling new frontiers in modeling, simulation, and analysis by exploiting unprecedented exascale computing capabilities-building an advanced software ecosystem that supports next-generation applications and addresses disruptive changes in computer architectures. However, concerns are growing about the productivity of the developers of scientific software. Members of the Interoperable Design of Extreme-scale Application Software project serve as catalysts to address these challenges through fostering software communities, incubating and curating methodologies and resources, and disseminating knowledge to advance developer productivity and software sustainability. This article discusses how these synergistic activities are advancing scientific discovery-mitigating technical risks by building a firmer foundation for reproducible, sustainable science at all scales of computing, from laptops to clusters to exascale and beyond.

BACKGROUND: 1.8 million Veterans are estimated to need legal services, such as for housing eviction prevention, discharge upgrades, and state and federal Veterans benefits. While having ones legal needs met is known to improve ones health and its social determinants, many Veterans legal needs remain unmet. Public Law 116-315 enacted in 2021 authorizes VA to fund legal services for Veterans (LSV) by awarding grants to legal service providers including nonprofit organizations and law schools legal assistance programs. This congressionally mandated LSV initiative will award grants to about 75 competitively selected entities providing legal services. This paper describes the protocol for evaluating the initiative. The evaluation will fulfill congressional reporting requirements, and inform continued implementation and sustainment of LSV over time. METHODS: Our protocol calls for a prospective, mixed-methods observational study with a repeated measures design, aligning to the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) and Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) frameworks. In 2023, competitively selected legal services-providing organizations will be awarded grants to implement LSV. The primary outcome will be the number of Veterans served by LSV in the 12 months after the awarding of the grant. The evaluation has three Aims. Aim 1 will focus on measuring primary and secondary LSV implementation outcomes aligned to RE-AIM. Aim 2 will apply the mixed quantitative-qualitative Matrixed Multiple Case Study method to identify patterns in implementation barriers, enablers, and other i-PARIHS-aligned factors that relate to observed outcomes. Aim 3 involves a mixed-methods economic evaluation to understand the costs and benefits of LSV implementation. DISCUSSION: The LSV initiative is a new program that VA is implementing to help Veterans who need legal assistance. To optimize ongoing and future implementation of this program, it is important to rigorously evaluate LSVs outcomes, barriers and enablers, and costs and benefits. We have outlined the protocol for such an evaluation, which will lead to recommending strategies and resource allocation for VAs LSV implementation.

Objective The objective of this study was to assess 52‐week efficacy and safety of bimekizumab in patients with active psoriatic arthritis (PsA) with or without concomitant methotrexate (+/−MTX) treatment at baseline. Methods We conducted a post hoc analysis of patients in BE OPTIMAL (NCT03895203; biologic disease‐modifying antirheumatic drug [bDMARD]‐naïve), BE COMPLETE (NCT03896581; prior inadequate response or intolerance to tumor necrosis factor inhibitors [TNFi‐IR]), and the BE VITAL open‐label extension (NCT04009499) study. Patients were randomized to one of the following treatment groups: bimekizumab 160 mg every four weeks, placebo, or a reference drug (adalimumab 40 mg every two weeks; BE OPTIMAL only). From Week 16, placebo‐randomized patients received bimekizumab. Missing data were imputed using non‐responder imputation, multiple imputation, or worst‐category imputation. Results Through Week 52, similar proportions of bimekizumab‐treated patients achieved American College of Rheumatology 50% (ACR50) response criteria for both +MTX and −MTX (BE OPTIMAL: 54.4% +MTX, 54.7% −MTX; BE COMPLETE: 56.3% +MTX, 48.0% −MTX). Similar proportions of bimekizumab‐treated patients achieved complete skin clearance (Psoriasis Area and Severity Index 100% [PASI100] response) and minimal disease activity in both +MTX and −MTX groups. Similar trends were seen in placebo/bimekizumab‐treated patients. Through Week 52, the proportion of bimekizumab‐treated patients with ≥1 treatment‐emergent adverse event were similar between the +MTX and −MTX groups (BE OPTIMAL 325 of 410 [79.3%] vs 230 of 292 [78.8%], BE COMPLETE 105 of 168 [62.5%] vs 138 of 220 [62.7%]). The safety profile was comparable between subgroups and consistent with the prior safety profile of bimekizumab. Conclusion Treatment with bimekizumab demonstrated consistent, sustained efficacy to 52 weeks in bDMARD‐naïve and TNFi‐IR patients with PsA and was well tolerated, irrespective of concomitant MTX.

Abstract Background Nurse-initiated supported implementation of protocols to manage fever, hyperglycaemia (sugar) and swallowing (FeSS) following acute stroke reduced 90-day death and disability in the landmark Australian Quality in Acute Stroke Care (QASC)-Trial. An international interprofessional collaboration sought to evaluate the effects of nurse-led FeSS implementation on FeSS Protocol adherence in German stroke units. Methods This pre-test/post-test study was conducted in eight German stroke units between 2020 and 2022. Stroke nurses as clinical champions, supported by the project team, conducted multidisciplinary workshops discussing pre-implementation medical record audit results, barriers and facilitators to FeSS Protocol implementation, developed action plans and provided education, with ongoing support from Australia. Medical record audit data were collected by nurses, pre-implementation and three months post-implementation. Results In 771 (pre-implementation) and 679 (post-implementation) patients there were improvements in overall FeSS adherence (pre 20%, post 28%; adjusted difference in proportions (95% CI) 11%, (5.1%, 16%); p

As a species highly reliant on stable fast ice as a breeding platform, emperor penguins are increasingly challenged in their breeding attempts due to changes in fast ice conditions. We collated habitat information of 27 emperor penguin colonies in East Antarctica (43°-167°E) from 2018 to 2023 using European Space Agency Sentinel-2 satellite images. Our objective was to examine the variability in habitat and ice conditions and associated repercussions for colony location and breeding success. Variables, such as location, colony movement and inter-annual variability in these parameters, were used to assess the adaptability of emperor penguins when local conditions change markedly. The major challenge emperor penguins currently face throughout Antarctica is untimely loss of breeding habitat resulting in increased or complete breeding failure, as observed in 8 colonies at least once during the study. One small colony at the West Ice Shelf lost its breeding area and has not been seen since 2021. The inter-annual movement of some colonies demonstrates the species’ adaptability and the need for ongoing monitoring of the global emperor penguin population using satellite imagery. We highlight caveats, such as availability of suitable satellite images and movement of colonies, that need to be accounted for to ensure sound interpretation of the monitoring findings. Ongoing Antarctic-wide monitoring is essential to quantify the impact of changing fast ice conditions on emperor penguins and also the cumulative impacts of other threats such as disease. The information presented is to provide background and empirical data for researchers, policy makers and managers.

Abstract Background Small extracellular vesicles (sEV) derived from synovial fibroblasts (SF) represent a novel molecular mechanism regulating cartilage erosion in osteoarthritis (OA). However, a comprehensive evaluation using disease relevant cells has not been undertaken. The aim of this study was to isolate and characterise sEV from OA SF and to look at their ability to regulate OA chondrocyte effector responses relevant to disease. Profiling of micro (mi) RNA signatures in sEV and parental OA SF cells was performed. Methods SF and chondrocytes were isolated from OA synovial membrane and cartilage respectively (n = 9). sEV were isolated from OA SF (± IL-1β) conditioned media by ultracentrifugation and characterised using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Particle size was confirmed by nanoparticle tracking analysis (NTA). sEV regulation of OA chondrocyte and cartilage effector response was evaluated using qPCR, ELISA and sulphated glycosaminoglycan assay (sGAG). RNA-sequencing was used to establish miRNA signatures in isolated sEV from OA SF. Results OA SF derived sEV were readily taken up by OA chondrocytes, with increased expression of the catabolic gene MMP 13 (p

This paper uses insider research within a Cultural Historical Activity Theory (CHAT) framework to examine the lived induction-to-teaching experiences of twelve new academics at a case-study Northern UK university. A CHAT lens foregrounds contradictions as a source for change in the induction-to-teaching process. Data generated through semi-structured interviews with these academics were analysed and, informed by CHAT, allowed us to discern contradictions in sociocultural and structural aspects of the induction activity systems which significantly impact new academics' experiences. Examining these contradictions enabled us to identify interventions for enhancing academic induction policy and practice within the case-study University, but also more widely.

The Asian rodent tick (Ixodes granulatus) occurs throughout much of Asia, it frequently bites humans, and zoonotic pathogens, such as Borrelia burgdorferi (sensu lato) and Rickettsia honei, have been detected within it. Unfortunately, the ecology of I. granulatus remains poorly known, including drivers of its abundance and the interaction ecology with its sylvatic hosts. To elucidate the ecology of this medically important species, the habitat preferences of I. granulatus were assessed in Singapore and Malaysia. Ixodes granulatus showed strong associations with old forest habitats, though across different age classes of old forest there was limited variation in abundance. Ixodes granulatus was absent from other habitats including young forest, scrubland, and parks/gardens. Within its sylvatic rodent hosts, a range of factors were found to be statistically significant predictors of I. granulatus load and/or infestation risk, including sex and body condition index. Male rodents were significantly more likely to be infested and to have higher loads than females, similarly, animals with a lower body condition index were significantly more likely to be infested. Proactive public health efforts targeted at preventing bites by this tick should carefully consider its ecology to minimise ecological overlap between humans and I. granulatus.