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OBJECTIVE: To provide a large-scale assessment of serum protein dysregulation in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features. METHODS: We investigated serum protein profiles of 66 participants with dcSSc at baseline who were enrolled in the Scleroderma: Cyclophosphamide or Transplant Trial and 66 age- and sex-matched healthy control subjects. A panel of 230 proteins, including several cytokines and chemokines, was investigated. Whole blood gene expression profiling in concomitantly collected samples was performed. RESULTS: Among the participants with dcSSc, the mean disease duration was 2.3 years. All had interstitial lung disease (ILD), and none were being treated with immunosuppressive agents at baseline. Ninety proteins were differentially expressed in participants with dcSSc compared to healthy control subjects. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion, and diapedesis were the top overrepresented pathways. Eighteen proteins correlated with the modified Rodnan skin thickness score (MRSS). Soluble epidermal growth factor receptor was significantly down-regulated in dcSSc and showed the strongest negative correlation with the MRSS, being predictive of the scores course over time, whereas α1 -antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with the MRSS. Furthermore, higher levels of cancer antigen 15-3 correlated with more severe ILD, based on findings of reduced forced vital capacity and higher scores of disease activity on high-resolution computed tomography. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses. CONCLUSION: Diffuse cutaneous SSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells.

Purpose: The purpose of this paper is to focus on a designed research methodology to distil existing research findings from an esrc/ahrc funded japan/uk network on location-based virtual reality experiences for children in order to generate new knowledge. Design/methodology/approach: The structured co-production methodology was undertaken in three stages. These were: (1) a collaborative workshop which produced a series of collage narratives, (2) collaborating with a non-human entity in the form of a digital coded tool to reconfigure the workshop responses and mediate the hierarchy of roles, (3) the co-production of a zine as a collaborative reflection method, which shared via postal service enabled a dialogue and exchange of round Robin interventions by the network members. Findings: The analysis of the data collected in this study highlighted five themes that could be used by other researchers on a wide range of projects. These were: (1) knowing through making, (2) the importance of process, (3) beyond linear representations, (4) agency of physical materials and (5) agency of digital code. Research limitations/implications: The context of the study being undertaken during the first phase of the global pandemic, revealed insight into a method of co-production that was undertaken under emergency remote working conditions. The knowledge generated from this can be applied to other research contexts such as working with researchers or participants across global borders without the need to travel. Originality/value: The research provides an innovative rethinking of co-production methods in order to generate new knowledge from multidisciplinary and multimodal research.

BackgroundDespite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.MethodsWe randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.ResultsIn the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.ConclusionsMyeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

ImportanceMost patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.ObjectiveTo evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT.Design, setting, and participantsHematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.InterventionsAutologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.Main outcomes and measuresThe primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.ResultsGrafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.Conclusions and relevanceAt 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.

Adult plaice in the Irish Sea have distinct traits that reflect the spawning locations that could suggest a number of different populations. However, do connectivity pathways support this concept? Different tools are directed at measuring exchange or connectivity between different life‐history stages, and the challenge is to integrate the signals to obtain full life‐cycle estimates. Collectively, the different methods reveal stable connectivity between known spawning and nursery grounds, with sufficient exchange to maintain a single population with weak genetic structure. [ABSTRACT FROM AUTHOR]

The 2023 Annual Symposium of the Fisheries Society of the British Isles hosted opportunities for researchers, scientists, and policy makers to reflect on the state of art of predicting fish distributions and consider the implications to the marine and aquatic environments of a changing climate. The outcome of one special interest group at the Symposium was a collection of questions, organized under five themes, which begin to capture the state of the field and identify priorities for research and management over the coming years. The five themes were Physiology, Mechanisms, Detect and Measure, Manage, and Wider Ecosystems. The questions, 25 of them, addressed concepts which remain poorly understood, are data deficient, and/or are likely to be impacted in measurable or profound ways by climate change. Moving from the first to the last theme, the questions expanded in the scope of their considerations, from specific processes within the individual to ecosystem‐wide impacts, but no one question is bigger than any other: each is important in detecting, understanding, and predicting fish distributions, and each will be impacted by an aspect of climate change. In this way, our questions, particularly those concerning unknown mechanisms and data deficiencies, aimed to offer a guide to other researchers, managers, and policy makers in the prioritization of future work as a changing climate is expected to have complex and disperse impacts on fish populations and distributions that will require a coordinated effort to address. [ABSTRACT FROM AUTHOR]

Methods to reliably identify jump discontinuities in biological time series and to assess the specific contribution of various covariates are rapidly progressing. Here, we took advantage of these statistical improvements as well as those seen in complementary, down‐scaled climate and biogeochemical models to investigate causes of the substantial interannual variability observed in recruitment strength in hindcast analyses. This systematic meta‐analysis included 23 data‐rich, commercially valuable, warm‐ and cold‐temperate stocks in the North, Norwegian and Barents Seas. Since this study focuses on recruitment strength variability, we have used the term "recruitment regime shift" to distinguish from the concept of ecosystem regime shift. The breakpoint analysis revealed that the former criterion applied to more than half of the time series, mainly with respect to North Sea stocks but also to those in the Norwegian Sea. The exploratory analysis using vcGAM indicated that 1–3 shifts per stock were real, when using five drivers spanning spawning stock biomass to large‐scale climatic processes. Thus, non‐stationary relationships were extensively prevalent, indicating that each stock is uniquely adapted to its locally varying conditions. Outputs from the stationary GAM resembled those from the vcGAM but not after the threshold year. In‐depth case studies showed that the proxy of a given driver for the process which was to be included should be critically considered in a spatiotemporal context. Furthermore, the stock‐specific uncertainty associated with the given recruitment figures as such should also be an in‐built component of the model construct and thereby in the evaluation of the output. [ABSTRACT FROM AUTHOR]

Previous studies have shown that four commercially important demersal species, namely Atlantic cod (Gadus morhua), haddock (Melanogrammus aeglefinus), whiting (Merlangius merlangus), and European plaice (Pleuronectes platessa), spawn in distinct areas across the North Sea. Based on two comprehensive ichthyoplankton surveys in 2004 and 2009, the present study uses generalized additive mixed models to delimit these spawning grounds using the distribution of recently spawned eggs, investigates their relationship to specific environmental conditions, and examines egg dispersal during their development. Results indicate that presence-absence of early stage eggs is more related to temporal and topographic variables, while egg densities are closely linked with hydrography. Egg distribution patterns were relatively consistent during development and only changed near hatching. Compared with historic observations, the location of the spawning grounds appeared stable on the broad scale but centres of egg abundance varied between the surveyed years. Potential effects of long-term climate change and anthropogenic short-term disturbances, such as seismic surveys, on fish reproduction are discussed, pointing out the demand for multispecies studies on these issues. Des etudes anterieures ont demontre que quatre especes demersales d'importance commerciale, soit la morue franche (Gadus morhua), l'aiglefin (Melanogrammus aeglefinus), le merlan (Merlangius merlangus) et la plie (Pleuronectes platessa), fraient dans des aires distinctes dans la mer du Nord. A la lumiere de deux inventaires exhaustifs de l'ichtyoplancton realises en 2004 et 2009, l'etude fait appel a des modeles additifs generalises mixtes pour delimiter ces lieux de frai sur la base de la repartition des oeufs recemment pondus, explore leur lieu avec differentes conditions ambiantes et examine la dispersion des oeufs durant leur developpement. Les resultats indiquent que la presence ou l'absence d'oeufs precoces est plus fortement reliee a des variables temporelles et topographiques, alors que les densites d'oeufs sont etroitement reliees a l'hydrographie. Les motifs de repartition des oeufs etaient assez constants durant le developpement et ne changeaient qu'a l'approche de l'eclosion. Comparativement aux observations passees, l'emplacement des lieux de frai semblait stable a grande echelle, mais l'emplacement de centres d'abondance d'oeufs etait different pour les deux annees d'inventaire. Les effets potentiels de changements climatiques a long terme et de perturbations d'origine humaine de courte duree, comme des leves sismiques, sur la reproduction des poissons sont abordes, soulignant la pertinence d'etudes plurispecifiques sur ces questions. [Traduit par la Redaction], Introduction Annually visited spawning grounds are a common feature in the life cycle of many fish populations (Daan et al. 1981; Heath et al. 1994) and have been demonstrated for [...]