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Research ethics is increasingly formally regulated, but little is known about how ethical considerations are reported in dissertations. The aim of this literature study was to describe the status and trends of ethical considerations in Swedish doctoral dissertations written by registered nurses. A total of 77 dissertations from 1987, 1997, and 2007 met the inclusion criteria and were analyzed by descriptive statistics. Ethical considerations were mostly overlooked in 1987, but almost ubiquitous by 2007. All dissertations in 2007, except one, had a section on ethical considerations; however, these were short, lacking in references, and short on content. The most common topic was informed consent and approval from research ethics review boards, followed by confidentiality and ethical aspects of methodological issues. Our results imply that the quantity and quality of ethical considerations must be improved in order to assure ethical soundness for participants, patients, researchers, and society. [ABSTRACT FROM AUTHOR]

Objectives: Analyse reported processes of co-design and co-production in the context of health and social care to explore the underlying mechanisms that enable inclusive and reciprocal engagement., Search Strategy: Peer review research was obtained from a prior scoping review searching eight databases consisting of all methodologies relevant to co-design or co-production in the context of health and social care services and involving service-users., Methods of Selection: Articles were included for synthesis if they reported a process of dialogue, with mutuality, insight and clarification in their engagement process. Ninety-three peer-review articles informed our programme theory development., Analysis: Data relating to co-design and co-production processes were extracted and analysed through inductive, abductive, and deductive analysis leading to the development of an initial programme theory., Main Results: This realist synthesis finds that co-design and co-production can occur at different times, in part or all of the research and participatory process. There is an over reliance on the term 'co-design' or 'co-production' to convey complex engagement or participatory processes. We identified six mechanisms (intention, assets, dialogue, documentation, interpretation and understanding). Interaction between these six identified mechanisms in context, even if only brief, is important for supporting meaningful engagement, alignment and agreement within a co-design or co-production process., Implications for Practice: The initial programme theory presented in this article provides clarity by identifying essential mechanisms which can guide the design and implementation of a range of participatory approaches. Rather than relying on a single label to convey complex participatory methods or processes, the values and principles of co-design or co-production, in combination with this programme theory, could be applied to guide implementation and reporting of specific activities within a range of research or participatory methods., Patient and Public Contribution: The initial programme theory was presented and piloted in a series of collaborative workshops between May 2023 and March 2024 with patient and public contributors, health professionals and researchers. This engagement process is currently underway to refine the programme theory and it is anticipated that this next phase will be completed in September 2024., (© 2024. The Author(s).)

Recent years have seen a dramatic growth in interest in the nature and extent of co-production in the health and social care sectors. Due to the proliferation of work on co-production, there is variation in practice in how co-production is defined, understood, and used in practice. We conducted a narrative review to explore, and provide an overview of, which models of health and social care co-production have been developed, applied, and critiqued over recent decades. Seventy-three peer-reviewed articles met our inclusion criteria. In this set of articles, we identified three broad types of models: conceptual/theoretical, practice-oriented, and presenting a typology. We found that practice-oriented models, predominantly from the Health Services Research and Quality Improvement literature, had largely not drawn on conceptual/theoretical models from the disciplinary fields of Public Administration & Management and Sociology. In particular, they have largely neglected theoretical perspectives on relationships and power and agency in co-production work. The concepts of Service-Dominant Logic and Public Service-Dominant Logic as ways to think about the joint, collaborative process of producing new value, particularly in the context of the use of a service, have also been neglected. Our review has identified distinct literatures which have contributed a variety of models of health and social care co-production. Our findings highlight under-explored dimensions of co-production that merit greater attention in the health and social care contexts. The overview of models of co-production we provide aims to offer a useful platform for the integration of different perspectives on co-production in future research and practice in health and social care., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Quality in Health Care.)

Recent advances in mass spectrometry-based peptidomics have catalyzed the identification and quantification of thousands of endogenous peptides across diverse biological systems. However, the vast peptidomic landscape generated by proteolytic processing poses several challenges for downstream analyses and limits the comparability of clinical samples. Here, we present an algorithm that aggregates peptides into peptide clusters, reducing the dimensionality of peptidomics data, improving the definition of protease cut sites, enhancing inter-sample comparability, and enabling the implementation of large-scale data analysis methods akin to those employed in other omics fields. We showcase the algorithm by performing large-scale quantitative analysis of wound fluid peptidomes of highly defined porcine wound infections and human clinical non-healing wounds. This revealed signature phenotype-specific peptide regions and proteolytic activity at the earliest stages of bacterial colonization. We validated the method on the urinary peptidome of type 1 diabetics which revealed potential subgroups and improved classification accuracy., (© 2024. The Author(s).)

Primary graft dysfunction (PGD) remains a challenge for lung transplantation (LTx) recipients as a leading cause of poor early outcomes. New methods are needed for more detailed monitoring and understanding of the pathophysiology of PGD. The measurement of particle flow rate (PFR) in exhaled breath is a novel tool to monitor and understand the disease at the proteomic level. In total, 22 recipient pigs underwent orthotopic left LTx and were evaluated for PGD on postoperative day 3. Exhaled breath particles (EBPs) were evaluated by mass spectrometry and the proteome was compared to tissue biopsies and bronchoalveolar lavage fluid (BALF). Findings were confirmed in EBPs from 11 human transplant recipients. Recipients with PGD had significantly higher PFR [686.4 (449.7-8,824.0) particles per minute (ppm)] compared to recipients without PGD [116.6 (79.7-307.4) ppm, p = 0.0005]. Porcine and human EBP proteins recapitulated proteins found in the BAL, demonstrating its utility instead of more invasive techniques. Furthermore, adherens and tight junction proteins were underexpressed in PGD tissue. Histological and proteomic analysis found significant changes to the alveolar-capillary barrier explaining the high PFR in PGD. Exhaled breath measurement is proposed as a rapid and non-invasive bedside measurement of PGD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Niroomand, Hirdman, Bèchet, Ghaidan, Stenlo, Kjellström, Isaksson, Broberg, Pierre, Hyllén, Olm and Lindstedt.)

Background: Innovations in coproduction are shaping public service reform in diverse contexts around the world. Although many innovations are local, others have expanded and evolved over time. We know very little, however, about the process of implementation and evolution of coproduction. The purpose of this study was to explore the adoption, implementation and assimilation of three approaches to the coproduction of public services with structurally vulnerable groups., Methods: We conducted a 4 year longitudinal multiple case study (2019-2023) of three coproduced public service innovations involving vulnerable populations: ESTHER in Jönköping Region, Sweden involving people with multiple complex needs (Case 1); Making Recovery Real in Dundee, Scotland with people who have serious mental illness (Case 2); and Learning Centres in Manitoba, Canada (Case 3), also involving people with serious mental illness. Data sources included 14 interviews with strategic decision-makers and a document analysis to understand the history and contextual factors relating to each case. Three frameworks informed the case study protocol, semi-structured interview guides, data extraction, deductive coding and analysis: the Consolidated Framework for Implementation Research, the Diffusion of Innovation model and Lozeau's Compatibility Gaps to understand assimilation., Results: The adoption of coproduction involving structurally vulnerable populations was a notable evolution of existing improvement efforts in Cases 1 and 3, while impetus by an external change agency, existing collaborative efforts among community organizations, and the opportunity to inform a new municipal mental health policy sparked adoption in Case 2. In all cases, coproduced innovation centred around a central philosophy that valued lived experience on an equal basis with professional knowledge in coproduction processes. This philosophical orientation offered flexibility and adaptability to local contexts, thereby facilitating implementation when compared with more defined programming. According to the informants, efforts to avoid co-optation risks were successful, resulting in the assimilation of new mindsets and coproduction processes, with examples of how this had led to transformative change., Conclusions: In exploring innovations in coproduction with structurally vulnerable groups, our findings suggest several additional considerations when applying existing theoretical frameworks. These include the philosophical nature of the innovation, the need to study the evolution of the innovation itself as it emerges over time, greater attention to partnered processes as disruptors to existing power structures and an emphasis on driving transformational change in organizational cultures., (© 2024. The Author(s).)

Three quarters of all breast cancers express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancer, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and without direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and mTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells. Our study is the first proteome-centric characterization of ESR1 mutant models, out of which we confirm estrogen independence of ER mutants and reveal the enrichment of immune signaling pathways at the proteomic level., (© 2024. The Author(s).)

Background: As coproduction in public services increases, understanding the role of leadership in this context is essential to the tasks of establishing relational partnerships and addressing power differentials among groups. The aims of this review are to explore models of coproduction leadership and the processes involved in leading coproduction as well as, based on that exploration, to develop a guiding framework for coproduction practices., Methods: A systematic review that synthesizes the evidence reported by 73 papers related to coproduction of health and welfare., Results: Despite the fact that models of coleadership and collective leadership exhibit a better fit with the relational character of coproduction, the majority of the articles included in this review employed a leader-centric underlying theory. The practice of coproduction leadership is a complex activity pertaining to interactions among people, encompassing nine essential practices: initiating, power-sharing, training, supporting, establishing trust, communicating, networking, orchestration, and implementation., Conclusions: This paper proposes a novel framework for coproduction leadership practices based on a systematic review of the literature and a set of reflective questions. This framework aims to help coproduction leaders and participants understand the complexity, diversity, and flexibility of coproduction leadership and to challenge and enhance their capacity to collaborate effectively., (© 2024. The Author(s).)

Surgical site infections (SSI) are a clinical and economic burden. Suture-associated SSI may develop when bacteria colonize the suture surface and form biofilms that are resistant to antibiotics. Thrombin-derived C-terminal peptide (TCP)-25 is a host defense peptide with a unique dual mode of action that can target both bacteria and the excessive inflammation induced by bacterial products. The peptide demonstrates therapeutic potential in preclinical in vivo wound infection models. In this study, the authors set out to explore whether TCP-25 can provide a new bioactive innate immune feature to hydrophilic polyglactin sutures (Vicryl). Using a combination of biochemical, biophysical, antibacterial, biofilm, and anti-inflammatory assays in vitro, in silico molecular modeling studies, along with experimental infection and inflammation models in mice, a proof-of-concept that TCP-25 can provide Vicryl sutures with a previously undisclosed host defense capacity, that enables targeting of bacteria, biofilms, and the accompanying inflammatory response, is shown., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Background: Immune checkpoint inhibitors (ICIs) have been established as a routine treatment in patients with metastatic urothelial cancer (mUC). However, there has been no standard of care after progression on ICIs. We investigated real-world treatment patterns and efficacy of chemotherapy (CHT) after pembrolizumab, in the era before introduction of maintenance avelumab and antibody-drug conjugates (ADC)., Patients and Methods: An observational, retrospective study was conducted at twelve Nordic centers. Patients with mUC were treated according to investigator´s choice of CHT after pembrolizumab. Primary endpoint was overall response (ORR) and disease control rate (DCR); secondary endpoints were progression-free (PFS) and overall survival (OS)., Results: In total, 102 patients were included whereof 23 patients received CHT after pembrolizumab as second line treatment (subcohort A) and 79 patients in third line (subcohort B). Platinum-gemcitabine combinations were the most common regimens in subcohort A, and vinflunine in subcohort B. The ORR and DCR were 36% and 47%, respectively. Presence of liver metastases was independently associated with lower ORR and DCR. The PFS and OS were 3.3 months and 7.7 months, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS) and number of previous cycles of pembrolizumab were found to be independent prognostic factors associated with OS., Conclusion: In a real-world setting, CHT showed clinically meaningful response rates and survival in mUC patients after progression with pembrolizumab. Clinical benefit may primarily be achieved in patients with favorable ECOG PS, in patients treated with > 6 cycles pembrolizumab as well as in patients without presence of liver metastases., Competing Interests: Disclosure Anders Ullén: Research Funding: Bayer, the healthcare business of Merck KGaA, Darmstadt, Germany, Pierre Fabre. Consulting or Advisory Role: Astellas Pharma, Janssen-Cilag, Merck & Co, Kenilworth, NJ, Pierre Fabre, Pfizer, Roche, and the healthcare business of Merck KGaA, Darmstadt, Germany. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: In recent years, the field of graft preservation has made considerable strides in improving outcomes related to solid organ restoration and regeneration. Ex vivo lung perfusion (EVLP) in line with the related devices and treatments has yielded promising results within preclinical and clinical studies, with the potential to improve graft quality. Its main benefit is to render marginal and declined donor lungs suitable for transplantation, ultimately increasing the donor pool available for transplantation. In addition, using such therapies in machine perfusion could also increase preservation time, facilitating logistical planning. Cytokine adsorption has been demonstrated as a potentially safe and effective therapy when applied to the EVLP circuit and post-transplantation. However, the mechanism by which this therapy improves the donor lung on a molecular basis is not yet fully understood., Methods: We hypothesized that there were characteristic inflammatory and immunomodulatory differences between the lungs treated with and without cytokine adsorption, reflecting proteomic changes in the gene ontology pathways and across inflammation-related proteins. In this study, we investigate the molecular mechanisms and signaling pathways of how cytokine adsorption impacts lung function when used during EVLP and post-transplantation as hemoperfusion in a porcine model. Lung tissues during EVLP and post-lung transplantation were analyzed for their proteomic profiles using mass spectrometry., Results: We found through gene set enrichment analysis that the inflammatory and immune processes and coagulation pathways were significantly affected by the cytokine treatment after EVLP and transplantation., Conclusion: In conclusion, we showed that the molecular mechanisms are using a proteomic approach behind the previously reported effects of cytokine adsorption when compared to the non-treated transplant recipients undergoing EVLP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Niroomand, Hirdman, Pierre, Ghaidan, Kjellström, Stenlo, Hyllén, Olm and Lindstedt.)

There is a clinical need for conceptually new treatments that target the excessive activation of inflammatory pathways during systemic infection. Thrombin-derived C-terminal peptides (TCPs) are endogenous anti-infective immunomodulators interfering with CD14-mediated TLR-dependent immune responses. Here we describe the development of a peptide-based compound for systemic use, sHVF18, expressing the evolutionarily conserved innate structural fold of natural TCPs. Using a combination of structure- and in silico-based design, nuclear magnetic resonance spectroscopy, biophysics, mass spectrometry, cellular, and in vivo studies, we here elucidate the structure, CD14 interactions, protease stability, transcriptome profiling, and therapeutic efficacy of sHVF18. The designed peptide displays a conformationally stabilized, protease resistant active innate fold and targets the LPS-binding groove of CD14. In vivo, it shows therapeutic efficacy in experimental models of endotoxin shock in mice and pigs and increases survival in mouse models of systemic polymicrobial infection. The results provide a drug class based on Nature´s own anti-infective principles., (© 2023. Springer Nature Limited.)

Bacterial lipopolysaccharide (LPS) induces rapid protein aggregation in human wound fluid. We aimed to characterize these LPS-induced aggregates and their functional implications using a combination of mass spectrometry analyses, biochemical assays, biological imaging, cell experiments, and animal models. The wound-fluid aggregates encompass diverse protein classes, including sequences from coagulation factors, annexins, histones, antimicrobial proteins/peptides, and apolipoproteins. We identified proteins and peptides with a high aggregation propensity and verified selected components through Western blot analysis. Thioflavin T and Amytracker staining revealed amyloid-like aggregates formed after exposure to LPS in vitro in human wound fluid and in vivo in porcine wound models. Using NF-κB-reporter mice and IVIS bioimaging, we demonstrate that such wound-fluid LPS aggregates induce a significant reduction in local inflammation compared with LPS in plasma. The results show that protein/peptide aggregation is a mechanism for confining LPS and reducing inflammation, further emphasizing the connection between host defense and amyloidogenesis., Competing Interests: A.S. is a founder of in2cure AB, a parent company of Xinnate AB, companies that are developing therapies based on thrombin-derived peptides and variants. G.P. is employed part-time (20%) by Xinnate AB. TCP-25 and variants are patent protected., (© 2023 The Author(s).)

Policy Points The concept of value complexity (complexity arising from differences in people's worldviews, interests, and values, leading to mistrust, misunderstanding, and conflict among stakeholders) is introduced and explained. Relevant literature from multiple disciplines is reviewed. Key theoretical themes, including power, conflict, language and framing, meaning-making, and collective deliberation, are identified. Simple rules derived from these theoretical themes are proposed., (© 2023 The Authors. The Milbank Quarterly published by Wiley Periodicals LLC on behalf of The Milbank Memorial Fund.)

Background: Definition of temporal serum proteome profiles after out-of-hospital cardiac arrest may identify biological processes associated with severe hypoxia-ischaemia and reperfusion. It may further explore intervention effects for new mechanistic insights, identify candidate prognostic protein biomarkers and potential therapeutic targets. This pilot study aimed to investigate serum proteome profiles from unconscious patients admitted to hospital after out-of-hospital cardiac arrest according to temperature treatment and neurological outcome., Methods: Serum samples at 24, 48, and 72 h after cardiac arrest at three centres included in the Target Temperature Management after out-of-hospital cardiac arrest trial underwent data-independent acquisition mass spectrometry analysis (DIA-MS) to find changes in serum protein concentrations associated with neurological outcome at 6-month follow-up and targeted temperature management (TTM) at 33 °C as compared to 36 °C. Neurological outcome was defined according to Cerebral Performance Category (CPC) scale as "good" (CPC 1-2, good cerebral performance or moderate disability) or "poor" (CPC 3-5, severe disability, unresponsive wakefulness syndrome, or death)., Results: Of 78 included patients [mean age 66 ± 12 years, 62 (80.0%) male], 37 (47.4%) were randomised to TTM at 36 °C. Six-month outcome was poor in 47 (60.3%) patients. The DIA-MS analysis identified and quantified 403 unique human proteins. Differential protein abundance testing comparing poor to good outcome showed 19 elevated proteins in patients with poor outcome (log 2 -fold change (FC) range 0.28-1.17) and 16 reduced proteins (log 2 (FC) between - 0.22 and - 0.68), involved in inflammatory/immune responses and apoptotic signalling pathways for poor outcome and proteolysis for good outcome. Analysis according to level of TTM showed a significant protein abundance difference for six proteins [five elevated proteins in TTM 36 °C (log 2 (FC) between 0.33 and 0.88), one reduced protein (log 2 (FC) - 0.6)] mainly involved in inflammatory/immune responses only at 48 h after cardiac arrest., Conclusions: Serum proteome profiling revealed an increase in inflammatory/immune responses and apoptosis in patients with poor outcome. In patients with good outcome, an increase in proteolysis was observed, whereas TTM-level only had a modest effect on the proteome profiles. Further validation of the differentially abundant proteins in response to neurological outcome is necessary to validate novel biomarker candidates that may predict prognosis after cardiac arrest., (© 2023. The Author(s).)

In the present era of evolving gene-based therapies for inherited retinal dystrophies (IRDs), it has become increasingly important to verify the genotype in every case, to identify all subjects eligible for treatment. Moreover, combined insight concerning phenotypes and genotypes is crucial for improved understanding of thevisual impairment, prognosis, and inheritance. The objective of this study was to investigate to what extent renewed comprehensive genetic testing of patients diagnosed with IRD but with previously inconclusive DNA test results can verify the genotype, if confirmation of the genotype has an impact on the understanding of the clinical picture, and, to describe the genetic spectrum encountered in a Swedish IRD cohort. The study included 279 patients from the retinitis pigmentosa research registry (comprising diagnosis within the whole IRD spectrum), hosted at the Department of Ophthalmology, Skåne University hospital, Sweden. The phenotypes had already been evaluated with electrophysiology and other clinical tests, e.g., visual acuity, Goldmann perimetry, and fundus imaging at the first visit, sometime between 1988-2015 and the previous-in many cases, multiple-genetic testing, performed between 1995 and 2020 had been inconclusive. All patients were aged 0-25 years at the time of their first visit. Renewed genetic testing was performed using a next generation sequencing (NGS) IRD panel including 322 genes (Blueprint Genetics). Class 5 and 4 variants, according to ACMG guidelines, were considered pathogenic. Of the 279 samples tested, a confirmed genotype was determined in 182 (65%). The cohort was genetically heterogenous, including 65 different genes. The most prevailing were ABCA4 (16.5%) , RPGR (6%), CEP290 (6%), and RS1 (5.5%). Other prevalent genes were CACNA1F (3%), PROM1 (3%) , CHM (3%) , and NYX (3%). In 7% of the patients there was a discrepancy between the diagnosis made based on phenotypical or genotypical findings alone. To conclude, repeated DNA-analysis was beneficial also in previously tested patients and improved our ability to verify the genotype-phenotype association increasing the understanding of how visual impairment manifests, prognosis, and the inheritance pattern. Moreover, repeated testing using a widely available method could identify additional patients eligible for future gene-based therapies.

First-line managers (FLMs) have a vital role in developing stable output and organizational competitiveness through their ability to manage front-line operations in daily work. It is also well known that FLMs are strong determinants of good ergonomics and well-being for front-line staff. However, research focusing on how FLMs deal with their important role is lacking particularly regarding empirical studies. The focus here is how they deal with uncertainties and disruptive interruptions and develop more resilient performance in daily work - introduced in this article as resilient action strategies. This research uses two conceptual frameworks on resilient engineering for analysis of FLM's actions in daily work in two manufacturing companies, to explore how resilient action strategies can be organizationally supported. The study combines analysis of front-line activities with multilevel organizational support based on 30 semi-structured in-depth interviews with FLMs and support functions, 21 workshops as well as policy documents of the two companies. The analysis exemplifies how resilience engineering was enabled in practice in the organizations. The study contributes to the empirical understanding of how resilience can be organizationally supported in daily front-line work. Our results show that a developed and consistent infrastructure in companies promotes the emergence of resilient action strategies in front-line work. We propose an extended model for resilient front-line performance enhancement by including coordination as a linking aspect between the earlier suggested resilient potentials - anticipate, monitor, respond and learn. This highlights the importance of both organizational support and coordination between system levels to enable the development of resilient action strategies by FLMs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: SARS-CoV-2 has been shown to predominantly infect the airways and the respiratory tract and too often have an unpredictable and different pathologic pattern compared to other respiratory diseases. Current clinical diagnostical tools in pulmonary medicine expose patients to harmful radiation, are too unspecific or even invasive. Proteomic analysis of exhaled breath particles (EBPs) in contrast, are non-invasive, sample directly from the pathological source and presents as a novel explorative and diagnostical tool., Methods: Patients with PCR-verified COVID-19 infection (COV-POS, n = 20), and patients with respiratory symptoms but with > 2 negative polymerase chain reaction (PCR) tests (COV-NEG, n = 16) and healthy controls (HCO, n = 12) were prospectively recruited. EBPs were collected using a "particles in exhaled air" (PExA 2.0) device. Particle per exhaled volume (PEV) and size distribution profiles were compared. Proteins were analyzed using liquid chromatography-mass spectrometry. A random forest machine learning classification model was then trained and validated on EBP data achieving an accuracy of 0.92., Results: Significant increases in PEV and changes in size distribution profiles of EBPs was seen in COV-POS and COV-NEG compared to healthy controls. We achieved a deep proteome profiling of EBP across the three groups with proteins involved in immune activation, acute phase response, cell adhesion, blood coagulation, and known components of the respiratory tract lining fluid, among others. We demonstrated promising results for the use of an integrated EBP biomarker panel together with particle concentration for diagnosis of COVID-19 as well as a robust method for protein identification in EBPs., Conclusion: Our results demonstrate the promising potential for the use of EBP fingerprints in biomarker discovery and for diagnosing pulmonary diseases, rapidly and non-invasively with minimal patient discomfort., (© 2023. The Author(s).)

Objectives: This study aimed to explore how the concepts of co-production and co-design have been defined and applied in the context of health and social care and to identify the temporal adoption of the terms., Methods: A systematic scoping review of CINAHL with Full Text, Cochrane Central Register of Controlled Trials, MEDLINE, PsycINFO, PubMed and Scopus was conducted to identify studies exploring co-production or co-design in health and social care. Data regarding date and conceptual definitions were extracted. From the 2933 studies retrieved, 979 articles were included in this review., Results: A network map of the sixty most common definitions and-through exploration of citations-eight definition clusters and a visual representation of how they interconnect and have informed each other over time are presented. Additional findings were as follows: (i) an increase in research exploring co-production and co-design in health and social care contexts; (ii) an increase in the number of new definitions during the last decade, despite just over a third of included articles providing no definition or explanation for their chosen concept; and (iii) an increase in the number of publications using the terms co-production or co-design while not involving citizens/patients/service users., Conclusions: Co-production and co-design are conceptualized in a wide range of ways. Rather than seeking universal definitions of these terms, future applied research should focus on articulating the underlying principles and values that need to be translated and explored in practice., Patient and Public Contribution: The search strategy and pilot results were presented at a workshop in May 2019 with patient and public contributors and researchers. Discussion here informed our next steps. During the analysis phase of the review, informal discussions were held once a month with a patient who has experience in patient and public involvement. As this involvement was conducted towards the end of the review, we agreed together that inclusion as an author would risk being tokenistic. Instead, acknowledgements were preferred. The next phase involves working as equal contributors to explore the values and principles of co-production reported within the most common definitions., (© 2022 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Objective: To overview the updated Swedish National Guidelines on Urothelial Carcinoma 2021, with emphasis on non-muscle-invasive bladder cancer (NMIBC) and upper tract urothelial carcinoma (UTUC)., Methods: A narrative review of the updated version of the Swedish National Guidelines on Urothelial Carcinoma 2021 and highlighting new treatment recommendations, with comparison to the European Association of Urology (EAU) guidelines and current literature., Results: For NMIBC the new EAU 2021 risk group stratification has been introduced for non-muscle invasive bladder cancer to predict risk of progression and the web-based application has been translated to Swedish (https://nmibc.net.). For patients with non-BCG -responsive disease treatment recommendations have been pinpointed, to guide patient counselling in this clinical situation. A new recommendation in the current version of the guidelines is the introduction of four courses of adjuvant platinum-based chemotherapy to patients with advanced disease in the nephroureterectomy specimen (pT2 or higher and/or N+). Patients with papillary urothelial neoplasms with low malignant potential (PUNLMP) can be discharged from follow-up already after 3 years based on a very low subsequent risk of further recurrences., Conclusions: The current version of the Swedish national guidelines introduces a new risk-stratification model and follow-up recommendation for NMIBC and adjuvant chemotherapy after radical surgery for UTUC.

Introduction: Clinical guidelines promote recognising persons with heart failure (referred to as PWHF) as coproducers of their own care. Coproduction of healthcare-involving PWHF, families and professionals in care processes-aims to promote the best possible health. Still, it is unclear how to coproduce heart failure (HF) care. This study explores whether and how Experience-Based Co-Design (EBCD) involving PWHF, family members and professionals can be undertaken online, in a Swedish cardiac care setting, to codesign improved experiences of HF care., Methods and Analysis: In EBCD, stakeholders' experiences are solicited to redesign healthcare services. First, we will undertake a thematic analysis of field notes from consultations and filmed/audio-recorded interviews with PWHF (n=10-12). This analysis will identify 'touchpoints' (emotionally positive/negative events that shape overall service experiences), edited into a 'trigger film'. Next, a thematic analysis of family members' (n=10-12) and professionals' (n=10-12) interviews will identify key themes mirroring their experiences. Separate feedback events with each stakeholder group will confirm identified touchpoints and key themes and identify areas for HF care improvement. At a joint event, prompted by the 'trigger film', stakeholders will agree on one area for HF care improvement. A team including PWHF, family members and professionals, led by an improvement adviser, will then plan, design, implement and evaluate an improvement activity addressing the identified problem area. A deductive thematic analysis of field notes, project documentation and stakeholder focus group interviews, underpinned by MUSIQ , will identify how organisational conditions influence the process. Quantitative measurements, describing the results of the improvement activity, will be integrated with qualitative data to strengthen the case. To reduce resource intensity, we will use online tools during the process., Ethics and Dissemination: The Swedish Ethical Review Authority approved the study in May 2021. The results will be disseminated through seminars, conference presentations and publications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Finding new sustainable means of diagnosing and treating diseases is one of the most pressing issues of our time. In recent years, several endogenous peptides have been found to be both excellent biomarkers for many diseases and to possess important physiological roles which may be utilized in treatments. The detection of peptides has been facilitated by the rapid development of biological mass spectrometry and now the combination of fast and sensitive high resolution MS instruments and stable nano HP-LC equipment sequences thousands of peptides in one single experiment. In most research conducted with these advanced systems, proteolytically cleaved proteins are analyzed and the specific peptides are identified by software dedicated for protein quantification using different proteomics workflows. Analysis of endogenous peptides with peptidomics workflows also benefit from the novel sensitive and advanced instrumentation, however, the generated peptidomic data is vast and subsequently laborious to visualize and examine, creating a bottleneck in the analysis. Therefore, we have created Peptimetric, an application designed to allow researchers to investigate and discover differences between peptidomic samples. Peptimetric allows the user to dynamically and interactively investigate the proteins, peptides, and some general characteristics of multiple samples, and is available as a web application at https://peptimetric.herokuapp.com. To illustrate the utility of Peptimetric, we've applied it to a peptidomic dataset of 15 urine samples from diabetic patients and corresponding data from healthy subjects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hartman, Mahdavi, Kjellström and Schmidtchen.)

The normal wound healing process is characterised by proteolytic events, whereas infection results in dysfunctional activations by endogenous and bacterial proteases. Peptides, downstream reporters of these proteolytic actions, could therefore serve as a promising tool for diagnosis of wounds. Using mass-spectrometry analyses, we here for the first time characterise the peptidome of human wound fluids. Sterile post-surgical wound fluids were found to contain a high degree of peptides in comparison to human plasma. Analyses of the peptidome from uninfected healing wounds and Staphylococcus aureus -infected wounds identify unique peptide patterns of various proteins, including coagulation and complement factors, proteases, and antiproteinases. Together, the work defines a workflow for analysis of peptides derived from wound fluids and demonstrates a proof-of-concept that such fluids can be used for analysis of qualitative differences of peptide patterns from larger patient cohorts, providing potential biomarkers for wound healing and infection., Competing Interests: Mv, JC, JP, KS, SK, AS No competing interests declared, (© 2021, van der Plas et al.)

Objective: The study aimed to explore users' experiences and care patterns concerning telemedicine consultations with physicians in Swedish primary care from 2017 to 2019. Design and participants : A mixed methods study involving 26 qualitative interviews with users of telemedicine consultations from a national sample, complemented by a quantitative registry study of data from 10,400 users in a Swedish region., Results: Users mainly described telemedicine consultations as a positive experience and perceived that the service met their current health care needs. Users also valued high accessibility, timesaving, and the contribution to ecological sustainability. Users felt competent about choosing when to use telemedicine consultations, most commonly for less severe health care concerns. This was confirmed by the quantitative results; only a few users had other care contacts within physical primary care before, or after, the telemedicine consultation, attended acute care or phoned 1177 Health Care Guidance., Conclusions: This study provides a rare account of users' experiences of telemedicine consultations. Users expressed satisfaction with this up-to-date use of health care resources for them as individuals, the health care system, and the environment. Telemedicine consultations were perceived as efficient and safe according to users. In addition, the study shows a low degree of further physical contacts in primary care or in acute care related to the telemedicine consultations.Key pointsUsers have positive experiences of telemedicine consultations with physicians and experienced that the service had meet their actual needs for health care.Users were mainly satisfied with the service and highlighted the value of high accessibility.Users experienced that telemedicine consultants provided an alternative care service for mostly minor health problems, perceiving them to save time and resources for themselves, the health care system, and the environment.Most telemedicine consultations did not result in additional contacts with 1177 Health Care Guidance, physical visits to primary care, or acute health care.Telemedicine consultations with physicians were mainly used by persons aged 0-30 years and need to be further developed to suit other age groups.

Is the oncogene MYC upregulated or hyperactive? In the majority of human cancers, finding agents that target c-MYC has proved difficult. Here we report specific bacterial effector molecules that inhibit cellular MYC (c-MYC) in human cells. We show that uropathogenic Escherichia coli (UPEC) degrade the c-MYC protein and attenuate MYC expression in both human cells and animal tissues. c-MYC protein was rapidly degraded by both cell-free bacterial lysates and the purified bacterial protease Lon. In mice, intravesical or peroral delivery of Lon protease delayed tumor progression and increased survival in MYC-dependent bladder and colon cancer models, respectively. These results suggest that bacteria have evolved strategies to control c-MYC tissue levels in the host and that the Lon protease shows promise for therapeutic targeting of c-MYC in cancer.

Background: Co-production of health and care involving patients, families of patients, and professionals in care processes can create joint learning about how to meet patients' needs. Although barriers and facilitators to co-production have been examined previously in various health care contexts, the preconditions in Swedish chronic cardiac care contexts are yet to be explored. This study is set in the health system of the Swedish region of Jönköping County and is part of system-wide efforts to promote better health for persons with heart failure (HF)., Objective: The objective of this study was to test the usefulness of the Capability, Opportunity, and Motivation Behavior (COM-B) model when assessing the barriers to and facilitators of co-production of health and care perceived by patients with HF, family members of patients with HF, and professionals in a Swedish chronic cardiac care context as a guide for subsequent initiatives., Methods: Data collection involved 1 focus group interview (FGI) with patients with HF (n=5), 1 FGI with family members of patients with HF (n=5), 1 FGI with professionals in primary care (n=7), and 1 FGI with professionals in cardiac care (n=4). In addition, patients with HF kept diaries of their thoughts regarding co-production. Using a deductive approach to content analysis, underpinned by the COM-B model, barriers and facilitators were categorized into capabilities, opportunities, and motivations to co-produce health and care., Results: The participants showed limited understanding of co-production as a practice. They appeared to view it as a privilege to be offered to patients on top of traditional care and rarely as an approach for improving health care processes. The interviews revealed the limited health literacy among patients and the struggle of professionals to convey health information to these patients. Co-production was considered to be more resource-intensive than traditional care. Different expectations of stakeholders' roles were revealed: professionals expected older patients not to want to co-produce health and care, and all participants expected professionals to be in charge of health care services. The family members' position involved trying to balance their desire to support their relatives with understanding when, how, and with whom to co-produce. Presumed benefits motivated stakeholders: co-production was recognized to motivate patients to improve self-care. However, the participants recognized that motivation to get involved in health and care decisions varies over time among stakeholders., Conclusions: Co-production can be facilitated by the stakeholders' motivation. However, varying levels of understanding of co-production, patients' limited health literacy, unease with power sharing between patients and professionals, and resource constraints are barriers that need to be managed to promote co-produced care and better health for persons living with HF. Further research is warranted to explore how to co-produce health care services with patients with HF and how leaders can facilitate the inevitable cultural change it requires and represents., (©Anne-Marie Suutari, Johan Thor, Annika M M Nordin, Sofia Kjellström, Kristina Areskoug Josefsson. Originally published in Journal of Participatory Medicine (https://jopm.jmir.org), 11.05.2021.)

Wound infection is a common and serious medical condition with an unmet need for improved diagnostic tools. A peptidomic approach, aided by mass spectrometry and bioinformatics, could provide novel means of identifying new peptide biomarkers for wound healing and infection assessment. Wound fluid is suitable for peptidomic analysis since it is both intimately tied to the wound environment and is readily available. In this study we investigate the peptidomes of wound fluids derived from surgical drainages following mastectomy and from wound dressings following facial skin grafting. By applying sorting algorithms and open source third party software to peptidomic label free tandem mass spectrometry data we provide an unbiased general methodology for analyzing and differentiating between peptidomes. We show that the wound fluid peptidomes of patients are highly individualized. However, differences emerge when grouping the patients depending on wound type. Furthermore, the abundance of peptides originating from documented antimicrobial regions of hemoglobin in infected wounds may contribute to an antimicrobial wound environment, as determined by in silico analysis. We validate our findings by compiling literature on peptide biomarkers and peptides of physiological significance and cross checking the results against our dataset, demonstrating that well-documented peptides of immunological significance are abundant in infected wounds, and originate from certain distinct regions in proteins such as hemoglobin and fibrinogen. Ultimately, we have demonstrated the power using sorting algorithms and open source software to help yield insights and visualize peptidomic data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hartman, Wallblom, van der Plas, Petrlova, Cai, Saleh, Kjellström and Schmidtchen.)

There is a link between high lipopolysaccharide (LPS) levels in the blood and the metabolic syndrome, and metabolic syndrome predisposes patients to severe COVID-19. Here, we define an interaction between SARS-CoV-2 spike (S) protein and LPS, leading to aggravated inflammation in vitro and in vivo. Native gel electrophoresis demonstrated that SARS-CoV-2 S protein binds to LPS. Microscale thermophoresis yielded a KD of ∼47 nM for the interaction. Computational modeling and all-atom molecular dynamics simulations further substantiated the experimental results, identifying a main LPS-binding site in SARS-CoV-2 S protein. S protein, when combined with low levels of LPS, boosted nuclear factor-kappa B (NF-κB) activation in monocytic THP-1 cells and cytokine responses in human blood and peripheral blood mononuclear cells, respectively. The in vitro inflammatory response was further validated by employing NF-κB reporter mice and in vivo bioimaging. Dynamic light scattering, transmission electron microscopy, and LPS-FITC analyses demonstrated that S protein modulated the aggregation state of LPS, providing a molecular explanation for the observed boosting effect. Taken together, our results provide an interesting molecular link between excessive inflammation during infection with SARS-CoV-2 and comorbidities involving increased levels of bacterial endotoxins., (© The Author(s) (2020). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)

The human Transient Receptor Potential A1 (hTRPA1) ion channel, also known as the wasabi receptor, acts as a biosensor of various potentially harmful stimuli. It is activated by a wide range of chemicals, including the electrophilic compound N-methylmaleimide (NMM), but the mechanism of activation is not fully understood. Here, we used mass spectrometry to map and quantify the covalent labeling in hTRPA1 at three different concentrations of NMM. A functional truncated version of hTRPA1 (Δ1-688 hTRPA1), lacking the large N-terminal ankyrin repeat domain (ARD), was also assessed in the same way. In the full length hTRPA1, the labeling of different cysteines ranged from nil up to 95% already at the lowest concentration of NMM, suggesting large differences in reactivity of the thiols. Most important, the labeling of some cysteine residues increased while others decreased with the concentration of NMM, both in the full length and the truncated protein. These findings indicate a conformational switch of the proteins, possibly associated with activation or desensitization of the ion channel. In addition, several lysines in the transmembrane domain and the proximal N-terminal region were labeled by NMM, raising the possibility that lysines are also key targets for electrophilic activation of hTRPA1.

Background: Improvement work can be used in preschools to enrich outdoor environment for children's better health. Effective improvement work can facilitate the necessary changes, but little is known about professionals' experiences of participation in improvement interventions. The aim was to evaluate how preschool staff experience quality improvement work, using the Breakthrough Series Collaborative improvement programme, to enhance outdoor environments., Methods: An improvement intervention using a breakthrough collaborative was performed at 9 preschools in Sweden and examined with a longitudinal mixed method design. Staff completed questionnaires on 4 occasions (n=45 participants) and interviews took place after the intervention (n=16 participants)., Results: The intervention was successful in the sense that the staff were content with the learning seminars, and they had triggered physical changes in the outdoor environment. They integrated the quality improvement work with their ordinary work and increasingly involved the children. The staff tested improvement tools but did not find them entirely appropriate for their work, because they preferred existing methods for reflection., Conclusions: The challenges in quality improvement work seem to be similar across contexts. Using the Breakthrough Series Collaborative in a public health intervention is promising but needs to be integrated with preunderstandings, current reflections and quality tools and models., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There is a clinical need for improved wound treatments that prevent both infection and excessive inflammation. TCP-25, a thrombin-derived peptide, is antibacterial and scavenges pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, thereby preventing CD14 interaction and Toll-like receptor dimerization, leading to reduced downstream immune activation. Here, we describe the development of a hydrogel formulation that was functionalized with TCP-25 to target bacteria and associated PAMP-induced inflammation. In vitro studies determined the polymer prerequisites for such TCP-25-mediated dual action, favoring the use of noncharged hydrophilic hydrogels, which enabled peptide conformational changes and LPS binding. The TCP-25-functionalized hydrogels killed Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa bacteria in vitro, as well as in experimental mouse models of subcutaneous infection. The TCP-25 hydrogel also mediated reduction of LPS-induced local inflammatory responses, as demonstrated by analysis of local cytokine production and in vivo bioimaging using nuclear factor κB (NF-κB) reporter mice. In porcine partial thickness wound models, TCP-25 prevented infection with S. aureus and reduced concentrations of proinflammatory cytokines. Proteolytic fragmentation of TCP-25 in vitro yielded a series of bioactive TCP fragments that were identical or similar to those present in wounds in vivo. Together, the results demonstrate the therapeutic potential of TCP-25 hydrogel, a wound treatment based on the body's peptide defense, for prevention of both bacterial infection and the accompanying inflammation., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Intracellular aggregates of superoxide dismutase 1 (SOD1) are associated with amyotrophic lateral sclerosis. In vivo, aggregation occurs in a complex and dense molecular environment with chemically heterogeneous surfaces. To investigate how SOD1 fibril formation is affected by surfaces, we used an in vitro model system enabling us to vary the molecular features of both SOD1 and the surfaces, as well as the surface area. We compared fibril formation in hydrophilic and hydrophobic sample wells, as a function of denaturant concentration and extraneous hydrophobic surface area. In the presence of hydrophobic surfaces, SOD1 unfolding promotes fibril nucleation. By contrast, in the presence of hydrophilic surfaces, increasing denaturant concentration retards the onset of fibril formation. We conclude that the mechanism of fibril formation depends on the surrounding surfaces and that the nucleating species might correspond to different conformational states of SOD1 depending on the nature of these surfaces., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)