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Martin Granath,1 Pär Hedlund,1 Christoph Spang,2 Håkan Alfredson3,4 1Orthopaedic Department, Hässleholm Hospital, Hässleholm, Sweden; 2Private Orthopaedic Spine Center, Würzburg, Germany; 3Institute of Sports Exercise and Health, University College Hospital London, London, UK; 4Department of Community Medicine and Rehabilitation, Sports Medicine, Umeå University, Umeå, 90187, SwedenCorrespondence: Håkan Alfredson, Department of Community Medicine and Rehabilitation, Sports Medicine, Umeå University, Umeå, 90187, Sweden, Tel +46 702288441, Email hakan.alfredson@umu.seBackground: Delayed Achilles tendon ruptures leaving large defects are difficult to treat, and the potential for tendon regeneration is thought to be limited. Furthermore, post-operative wound healing problems, sometimes including infections, can be challenging to treat and negatively affect rehabilitation.Case Presentation: This 74-year-old lady suffered from insertional Achilles tendinopathy. After treatment with a local cortisone injection, she sustained a total insertional Achilles tendon rupture. This rupture was treated conservatively, and after treatment the Achilles re-ruptured in the insertional area. The rupture was then treated with re-insertion into the calcaneal insertion. Early in the post-operative period the patient sustained a deep surgical wound infection and sepsis. Because of poor effect of treatment with antibiotics, and total tendon destruction, the whole Achilles was extirpated. After extirpation there was immobilization in a cast followed by mobilization and gradually increased loading. At a one-year follow-up, the patient was walking without a limp, could do heel-raise halfway up standing on one leg, there was a palpable Achilles tendon and ultrasound scanning showed a structure very similar to a slightly thickened and tendinopathic Achilles tendon. There was an obvious regeneration of the whole Achilles tendon, and the tendon function was surprisingly good.Conclusion: This case study clearly shows the regeneration potential in the Achilles tendon and provides significant knowledge of importance for clinicians dealing with Achilles tendon injuries.Keywords: Achilles tendon, tendinopathy, Achilles rupture, infection, regeneration

Abstract Few aerobic hyperthermophilic microorganisms degrade polysaccharides. Here, we describe the genome-enabled enrichment and optical tweezer-based isolation of an aerobic polysaccharide-degrading hyperthermophile, Fervidibacter sacchari, previously ascribed to candidate phylum Fervidibacteria. F. sacchari uses polysaccharides and monosaccharides for growth at 65–87.5 °C and expresses 191 carbohydrate-active enzymes (CAZymes) according to RNA-Seq and proteomics, including 31 with unusual glycoside hydrolase domains (GH109, GH177, GH179). Fluorescence in-situ hybridization and nanoscale secondary ion mass spectrometry confirmed rapid assimilation of 13C-starch in spring sediments. Purified GHs were optimally active at 80–100 °C on ten different polysaccharides. Finally, we propose reassigning Fervidibacteria as a class within phylum Armatimonadota, along with 18 other species, and show that a high number and diversity of CAZymes is a hallmark of the phylum, in both aerobic and anaerobic lineages. Our study establishes Fervidibacteria as hyperthermophilic polysaccharide degraders in terrestrial geothermal springs and suggests a broad role for Armatimonadota in polysaccharide catabolism.

Abstract Background and aim Common mental disorders are common reasons for long-term sick leave, especially among women. Return to work is often complex and unsuccessful, why more knowledge is needed regarding women’s health and psychological well-being in the return-to-work process. Therefore, the aim was to describe women’s health and psychological well-being in the return-to-work process, from women’s and first-line managers’ perspectives. Methods Individual interviews were conducted with 17 women and 16 first-line managers. Qualitative content analysis was performed based on the content areas “Women’s health (i.e. overall well-being, both physical and psychological) throughout the whole RTW process” and “Women’s psychological well-being (happiness, meaning and a sense of being significant) at work after work resumption” Themes and categories were created. Results Women and managers had similar descriptions, i.e. that women’s health and psychological well-being depend on the individual characteristics of women themselves, their private life, work and other stakeholders. However, women described relational work tasks (e.g. meeting patients) as beneficial for health, and highlighted small stressors in the work environment, which the managers did not. Having work that was compatible with private life, being in good health, having stimulating work tasks and strengthening relationships at work were important for the women’s psychological well-being. Conclusions Based on women’s and first-line managers experiences, promotion of women’s health and psychological well-being during the return-to-work process requires individually adapted assessments and actions involving women’s entire life situation. First-line managers should know that relational work tasks (e.g., meeting patients) can be beneficial for women’s health as well as that minor stressor in the work environment can put their health at risk.

Abstract Background Beyond being a pulmonary disease, chronic obstructive pulmonary disease (COPD) presents with extrapulmonary manifestations including reduced cognitive, cardiovascular, and muscle function. While exercise training is the cornerstone in the non-pharmacological treatment of COPD, there is a need for new exercise training methods due to suboptimal adaptations when following traditional exercise guidelines, often applying moderate-intensity continuous training (MICT). In people with COPD, short-duration high-intensity interval training (HIIT) holds the potential to induce a more optimal stimulus for training adaptations while circumventing the ventilatory burden often associated with MICT in people with COPD. We aim to determine the effects of supramaximal HIIT and MICT on extrapulmonary manifestations in people with COPD compared to matched healthy controls. Methods COPD-HIIT is a prospective, multi-centre, randomized, controlled trial with blinded assessors and data analysts, employing a parallel-group designed trial. In phase 1, we will investigate the effects and mechanisms of a 12-week intervention of supramaximal HIIT compared to MICT in people with COPD (n = 92) and matched healthy controls (n = 70). Participants will perform watt-based cycling two to three times weekly. In phase 2, we will determine how exercise training and inflammation impact the trajectories of neurodegeneration, in people with COPD, over 24 months. In addition to the 92 participants with COPD performing HIIT or MICT, a usual care group (n = 46) is included in phase 2. In both phases, the primary outcomes are a change from baseline in cognitive function, cardiorespiratory fitness, and muscle power. Key secondary outcomes include change from baseline exercise tolerance, brain structure, and function measured by MRI, neuroinflammation measured by PET/CT, systemic inflammation, and intramuscular adaptations. Feasibility of the interventions will be comprehensively investigated. Discussion The COPD-HIIT trial will determine the effects of supramaximal HIIT compared to MICT in people with COPD and healthy controls. We will provide evidence for a novel exercise modality that might overcome the barriers associated with MICT in people with COPD. We will also shed light on the impact of exercise at different intensities to reduce neurodegeneration. The goal of the COPD-HIIT trial is to improve the treatment of extrapulmonary manifestations of the disease. Trial registration Clinicaltrials.gov: NCT06068322. Prospectively registered on 2023-09-28.

Edeltraut Garbe,1 Fabian Hoti,2 Tania Schink,1 Kristian Svendsen,3 Haydar Al-Eid,4 Per Arkhammar,5 Marie Carlholm,6 Harald Fjällbrant,6 Stefan Franzén,7,8 Cecilia Hedlund,9 Bianca Kollhorst,10 Atul Kumar,11 Muriel Lobier,2 Vasili Mushnikov,2 Tore Persson,9 Xu Qiao,2 Aaro Salosensaari,12 Wiebke Schäfer,1 Nicholas M Sicignano,13 Gunnar Johansson,14 Eileen O Dareng15 1Department Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 2Biostatistics, Scientific Services, Real World Solutions, IQVIA, Espoo, Finland; 3Department of Pharmacy, UiT The Arctic University of Norway, Tromsø, Norway; 4United States Navy, Naval Medical Center, Portsmouth, Virginia, USA; 5Global Patient Safety Biopharma, AstraZeneca, Gothenburg, Sweden; 6Late-Stage Respiratory and Immunology, BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden; 7BPM Evidence Statistics, Medical Evidence, BioPharmaceuticals Medical, Gothenburg, Sweden; 8School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 9Biometrics, Late-stage Respiratory and Immunology, BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden; 10Department Biometry and Data Management, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 11Global Patient Safety Biopharma, AstraZeneca, Bangalore, India; 12Biostatistics, Scientific Services, Real World Solutions, IQVIA, Turku, Finland; 13Health ResearchTx LLC, Trevose, Pennsylvania, USA; 14Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; 15Safety Epidemiology and Risk Management, AstraZeneca, Cambridge, UKCorrespondence: Eileen O Dareng, AstraZeneca, City House, 126-130 Hills Road, Cambridge, CB2 1RY, United Kingdom, Tel +44 7789447801, Email eileen.dareng@astrazeneca.comPurpose: This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US).Patients and Methods: The study population consisted of patients aged ≥ 40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010– 2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI).Results: 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for “ever use” of roflumilast, compared to “never use”, were 1.12 (95% CI, 1.08– 1.17) in Germany, 1.00 (95% CI, 0.92– 1.08) in Norway, 0.98 (95% CI, 0.92– 1.04) in Sweden, and 1.16 (95% CI, 1.12– 1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among “current users” in Germany (HR: 0.93, 95% CI: 0.88– 0.98), Norway (HR: 0.77, 95% CI: 0.67– 0.87), and Sweden (HR: 0.80, 95% CI: 0.73– 0.88).Conclusion: There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.Keywords: roflumilast, 5-year all-cause mortality, COPD, electronic healthcare database, propensity score

Abstract Ovarian cancer is the 8th most common cancer among women and has a 5-year survival of only 30–50%. While the survival is close to 90% for stage I tumours it is only 20% for stage IV. Current biomarkers are not sensitive nor specific enough, and novel biomarkers are urgently needed. We used the Explore PEA technology for large-scale analysis of 2943 plasma proteins to search for new biomarkers using two independent clinical cohorts. The discovery analysis using the first cohort identified 296 proteins that had significantly different levels in malign tumours as compared to benign and for 269 (91%) of these, the association was replicated in the second cohort. Multivariate modelling, including all proteins independent of their association in the univariate analysis, identified a model for separating benign conditions from malign tumours (stage I–IV) consisting of three proteins; WFDC2, KRT19 and RBFOX3. This model achieved an AUC of 0.92 in the replication cohort and a sensitivity and specificity of 0.93 and 0.77 at a cut-off developed in the discovery cohort. There was no statistical difference of the performance in the replication cohort compared to the discovery cohort. WFDC2 and KRT19 have previously been associated with ovarian cancer but RBFOX3 has not previously been identified as a potential biomarker. Our results demonstrate the ability of using high-throughput precision proteomics for identification of novel plasma protein biomarker for ovarian cancer detection.

Abstract Background The Atribacterota are widely distributed in the subsurface biosphere. Recently, the first Atribacterota isolate was described and the number of Atribacterota genome sequences retrieved from environmental samples has increased significantly; however, their diversity, physiology, ecology, and evolution remain poorly understood. Results We report the isolation of the second member of Atribacterota, Thermatribacter velox gen. nov., sp. nov., within a new family Thermatribacteraceae fam. nov., and the short-term laboratory cultivation of a member of the JS1 lineage, Phoenicimicrobium oleiphilum HX-OS.bin.34TS, both from a terrestrial oil reservoir. Physiological and metatranscriptomics analyses showed that Thermatribacter velox B11T and Phoenicimicrobium oleiphilum HX-OS.bin.34TS ferment sugars and n-alkanes, respectively, producing H2, CO2, and acetate as common products. Comparative genomics showed that all members of the Atribacterota lack a complete Wood-Ljungdahl Pathway (WLP), but that the Reductive Glycine Pathway (RGP) is widespread, indicating that the RGP, rather than WLP, is a central hub in Atribacterota metabolism. Ancestral character state reconstructions and phylogenetic analyses showed that key genes encoding the RGP (fdhA, fhs, folD, glyA, gcvT, gcvPAB, pdhD) and other central functions were gained independently in the two classes, Atribacteria (OP9) and Phoenicimicrobiia (JS1), after which they were inherited vertically; these genes included fumarate-adding enzymes (faeA; Phoenicimicrobiia only), the CODH/ACS complex (acsABCDE), and diverse hydrogenases (NiFe group 3b, 4b and FeFe group A3, C). Finally, we present genome-resolved community metabolic models showing the central roles of Atribacteria (OP9) and Phoenicimicrobiia (JS1) in acetate- and hydrocarbon-rich environments. Conclusion Our findings expand the knowledge of the diversity, physiology, ecology, and evolution of the phylum Atribacterota. This study is a starting point for promoting more incisive studies of their syntrophic biology and may guide the rational design of strategies to cultivate them in the laboratory. Video Abstract

Background and objective: There is an unmet need to avoid long-term morbidity associated with standard cytotoxic treatment for low-volume metastatic seminoma. Our aim was to assess the oncological efficacy and surgical safety of retroperitoneal lymph node dissection (RPLND) as treatment in a population-based cohort of metastatic seminoma patients with limited retroperitoneal lymphadenopathy. Methods: Sixty-two seminoma patients in Norway and Sweden were included in the cohort from 2019 to 2022. Patients with lymphadenopathy ≤3 cm, having primary clinical stage (CS) IIA/B or CS I with a relapse, were operated with uni- or bilateral template RPLND, open or robot assisted. The outcome measures included surgical complications as per Clavien-Dindo, and Kaplan-Meier survival estimates for 24-mo progression-free survival (PFS) and overall survival (OS). Key findings and limitations: In the cohort, 33 (53%) had CS I with a relapse during surveillance, six (10%) CS I with a relapse following adjuvant chemotherapy, and 23 (37%) initial CS IIA/B. Metastatic seminoma was verified in 58 patients (94%) with a median largest diameter of 18 mm (interquartile range [IQR] 13–24). Robot-assisted RPLND was performed in 40 patients (65%). Clavien-Dindo III complications were observed in three patients (5%); no grade ≥IV complications occurred. Eighteen patients (29%) received adjuvant chemotherapy after surgery. The median follow-up was 23 mo (IQR 16–30), and recurrence occurred in six patients (10%) after a median of 8 mo (IQR 4–14). PFS was 90% (95% confidence interval: 0.86–1) and OS was 100% at 24 mo. Conclusions and clinical implications: RPLND as primary treatment is an option for selected low-stage seminomas with a limited burden of disease, showing low complications and low relapse rates, with the potential to reduce long-term morbidity. Patient summary: In seminoma patients with limited metastatic spread, surgery is a treatment option offering an alternative to chemotherapy or radiation. This paper covers the first 62 patients operated in Norway and Sweden.

Introduction Mental health concerns are prevalent among adult patients with long COVID (LC), but the current state of knowledge regarding mental health in the context of LC is not fully understood. The objective of this scoping review is to map and summarise the existing research on mental health conditions among LC patients and highlight the knowledge gaps. This review aims to provide a comprehensive overview of the evolving landscape of research in the area.Methods and analysis The concept of interest is mental health in adult LC patients. This scoping review will be guided by the Joanna Briggs Institute Manual for Evidence Synthesis and reported according to the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review guidelines. Using predefined search parameters, a comprehensive search of two electronic databases (Medline and APA PsycINFO) and grey literature sources identified 3104 potentially eligible articles published from 1 January 2020 to 4 April 2024. Following the removal of duplicates, 2767 articles were imported for screening in Covidence. The study selection process involves screening titles, abstracts and full text of potentially relevant articles, which will then be analysed using thematic analysis. Data will be extracted using a predefined extraction form.Ethics and dissemination Ethical approval is not required because this study does not involve human participants or primary data collection. The findings from this review will be disseminated through a peer-reviewed publication, conference presentations and professional networks. In addition, a summary of the results will be shared with patient partners and other relevant stakeholders.Public health implications The findings from this scoping review will contribute to a better understanding of mental health issues arising in LC patients and inform future research directions and public health interventions in this area.

Abstract Terrestrial geothermal springs are physicochemically diverse and host abundant populations of Archaea. However, the diversity, functionality, and geological influences of these Archaea are not well understood. Here we explore the genomic diversity of Archaea in 152 metagenomes from 48 geothermal springs in Tengchong, China, collected from 2016 to 2021. Our dataset is comprised of 2949 archaeal metagenome-assembled genomes spanning 12 phyla and 392 newly identified species, which increases the known species diversity of Archaea by ~48.6%. The structures and potential functions of the archaeal communities are strongly influenced by temperature and pH, with high-temperature acidic and alkaline springs favoring archaeal abundance over Bacteria. Genome-resolved metagenomics and metatranscriptomics provide insights into the potential ecological niches of these Archaea and their potential roles in carbon, sulfur, nitrogen, and hydrogen metabolism. Furthermore, our findings illustrate the interplay of competition and cooperation among Archaea in biogeochemical cycles, possibly arising from overlapping functional niches and metabolic handoffs. Taken together, our study expands the genomic diversity of Archaea inhabiting geothermal springs and provides a foundation for more incisive study of biogeochemical processes mediated by Archaea in geothermal ecosystems.

ABSTRACT: Individual differences in free-range chicken systems are important factors influencing how birds use the range (or not), even if individuals are reared in the same environmental conditions. Here, we investigated how various aspects of the birds' behavioral and cognitive tendencies, including their optimism/pessimism, cognitive flexibility, sociability, and exploration levels, are associated with range use and how they may change over time (before and after range access). To achieve this, 100 White Leghorn laying hen chicks underwent three distinct behavioral/cognitive tests—the cognitive bias test, the detour test, and the multivariate test—prior to gaining access to the range, between 9 and 39 days of age. After range access was allowed (from day 71), birds' range use was evaluated over 7 nonconsecutive days (from 74–91 days of age). Subsequently, a subset of birds, classified as high rangers (n = 15) and low rangers (n = 15) based on their range use, underwent retesting on the same three previous tests between 94 and 108 days of age. Our results unveiled a negative correlation trend between birds' evaluation of the ambiguous cue and their subsequent range use (rho = -0.19, p = 0.07). Furthermore, low rangers were faster to learn the detour task (χ2 = 7.34, df = 1, p = 0.006), coupled with increased sociability during the multivariate test (rho = -0.23, p = 0.02), contrasting with their high-ranging counterparts, who displayed more exploratory behaviors (F[1,27] = 3.64, p = 0.06). These behavioral patterns fluctuated over time (before and after range access); however, conclusively attributing these changes to birds' aging and development or the access to the range remains challenging. Overall, our results corroborate that behavioral and cognitive individual differences may be linked to range use and offer novel perspectives on the early behavioral and cognitive traits that may be linked to range use. These findings may serve as a foundation for adapting environments to meet individual needs and improve animal welfare in the future.

Abstract The SeqCode, formally called the Code of Nomenclature of Prokaryotes Described from Sequence Data, is a new code of nomenclature in which genome sequences are the nomenclatural types for the names of prokaryotic species. While similar to the International Code of Nomenclature of Prokaryotes (ICNP) in structure and rules of priority, it does not require the deposition of type strains in international culture collections. Thus, it allows for the formation of permanent names for uncultured prokaryotes whose nearly complete genome sequences have been obtained directly from environmental DNA as well as other prokaryotes that cannot be deposited in culture collections. Because the diversity of uncultured prokaryotes greatly exceeds that of readily culturable prokaryotes, the SeqCode is the only code suitable for naming the majority of prokaryotic species. The start date of the SeqCode was January 1, 2022, and the online Registry (https://seqco.de/) was created to ensure valid publication of names. The SeqCode recognizes all names validly published under the ICNP before 2022. After that date, names validly published under the SeqCode compete with ICNP names for priority. As a result, species can have only one name, either from the SeqCode or ICNP, enabling effective communication and the creation of unified taxonomies of uncultured and cultured prokaryotes. The SeqCode is administered by the SeqCode Committee, which is comprised of the SeqCode Community and elected administrative components. Anyone with an interest in the systematics of prokaryotes is encouraged to join the SeqCode Community and participate in the development of this resource.

Abstract Background The professional role of a nurse anaesthetist involves taking a pedagogical approach towards students, including supervision during clinical practice. Although supervisors are facilitators of student learning, they are offered little training in adult learning principles. The aim of this study was to describe supervisors’ experience of student nurse anaesthetist learning during clinical practice in the operating room. Method In this qualitative interview study, 12 semi-structured individual interviews were carried out with clinical supervising nurse anaesthetists. The data were analysed inductively using thematic analysis. Results The results are illustrated with one theme and five sub-themes. The clinical learning situation of student nurse anaesthetists is described as a reflection of different cultures coming together. The operating room environment is a new context to students, and students enter with different clinical background and experiences. There is tension in facilitating student learning due to demands for productivity; supervisors suggest the use of separate operating rooms with a special focus on learning in the future. Conclusion Clinical practice facilitates student learning and is a parallel process to routine care. Thus, it requires the cultures of higher education and healthcare organizations to co-exist. This is illustrated with the theme “Contributing to students’ future professional roles by bridging the hospital and university cultures”. In the operating room, student learning is challenged by a new context and time pressure as shown by subthemes. To overcome challenges and support student learning in the operating room from a supervisors’ perspective, interprofessional student teams are suggested as a future approach and need to be further investigated.

I denne artikkelen belyser vi samspill mellom barn med og uten funksjonsnedsettelse i barnehager og hva som kjennetegner samspill som dannet et fellesskap mellom barna. Vi bruker kvalitativ analyse fra observasjonsdata fra barna og intervjudata av ansatte i barnehagen for å belyse problemstillingen. Vår hensikt er å studere hvordan barn med og uten funksjonsnedsettelse kan danne et samspill for å omgås, leke og inngå i et vanlig fellesskap i barnehagen, og hva som blir utfordrende for å få til et slikt samspill. I artikkelen gir vi illustrasjoner på et slikt samspill og hvilke utfordringer som finnes i norske barnehager. Vi diskuterer funnene i lys av teori om barneperspektiv, stigma og norsk integreringspolitikk for barn med funksjonsnedsettelse. Resultatene viser tre hovedmønster i barnas samspill og fellesskap: (1) å leke på like premisser; (2) å være lekbar; (3) den støttende leken. I artikkelen diskuterer vi fordelene med denne typen samspill og gir eksempler på hvordan det kan bidra til å fremme sosial inkludering og forbedre kommunikasjonsferdighetene for alle involverte barn. Samtidig diskuterer vi utfordringer som finnes i samspillet mellom barna når det gjelder at barna med funksjonsnedsettelse som sliter med selvstigmatisering eller opplever problemer som skaper utenforskap i forhold til samspillet. I artikkelen belyser vi hva som kjennetegner disse utfordringene, og hvordan voksne i barnehagen kan gi gode forutsetninger for involvering og samarbeid mellom barna. English abstract The Importance of Interplay – Children With and Without Disabilities Interacting in ECEC institutions In this article, we illuminate the interactions between children with and without disabilities in ECEC institutions, focusing on the characteristics of interactions that form a sense of community among the children. To address this issue, we employ qualitative analysis using observational data from the children and interview data from the ECEC staff. We aim to examine how children with and without disabilities can engage, play, and participate in a shared community in ECEC institutions and the challenges involved in fostering such interactions. The article provides illustrations of such interactions and discusses the challenges present in Norwegian ECEC institutions. We analyze the findings in the context of child perspective theory, stigma, and Norwegian integration policies for children with disabilities. The results reveal three main patterns in the children’s interactions and community formation: (1) playing on equal terms, (2) being play-worthy, and (3) supportive play. We discuss the benefits of these interactions and provide examples of how they can promote social inclusion and enhance communication skills for all involved children. Simultaneously, we discuss challenges in the interactions among children, particularly for those with disabilities who may struggle with self-stigmatization or encounter issues that create a sense of exclusion concerning these interactions. The article sheds light on the characteristics of these challenges and explores how ECEC staff professionals can create favorable conditions for involvement and collaboration among children.

IntroductionSurgical glove use may be associated with a decrease in tactile sensitivity, with thicker gloves or double-gloving techniques further altering sensation. This study evaluates digital tactile sensitivity by use of a Grating Orientation Task (GOT) with multiple sterile gloving techniques (no gloves, single standard gloving, double standard gloving, orthopedic gloves, and micro-thickness gloves).MethodsEach participant performed the GOT at increasing grating widths until correctly noting orientation in ≥8 of 10 trials with multiple glove types or double-gloving technique. Glove order was randomly assigned and participants were blinded to the orientation and dome size.ResultsAll gloves except micro-thickness gloves showed increased threshold sensitivity values (i.e. worse fingertip sensitivity) when compared to control (micro:control, p = 0.105, others:control, p < 0.05). Single-layer gloves showed no significant difference in sensitivity when compared to orthopedic (p = 0.06) or double-layer latex gloves (p = 0.26).DiscussionStandard latex gloves decreased fingertip sensitivity when evaluated with the GOT. Double-layer and orthopedic latex gloves do not decrease sensitivity when compared with single-layer gloving. Micro-thickness gloves may provide similar tactile sensitivity to no surgical glove.

This article examines sport/discipline-specific market concentrations in the context of the eight Summer Olympic Games held between 1992 and 2020. Three market concentration-related debates underpin this study: (1) the number of competing firms; (2) market size; and (3) time. A normalized version of the Herfindahl-Hirschman Index (HHIN) is calculated for gold medal and medal concentrations for all 42 sports/disciplines. The analyses included panel data models and Pearson correlations. The main findings are that (1) market concentrations for (gold) medals within most sport/disciplines have not significantly declined over time; and (2) neither an increased number of competing National Olympic Committees (NOCs) nor increased market size is likely to have impacted market concentration within a sport/discipline. The findings advance the understanding of market concentration trends and have implications for elite sport practitioners including the International Olympic Committee (IOC) and International Federations (IFs) in terms of an evaluation of existing measures introduced to promote competitive balance, and NOCs in terms of resource distribution among sports/disciplines and prioritization strategies.

The aerobic hyperthermophile “Fervidibacter sacchari” catabolizes diverse polysaccharides and is the only cultivated member of the class “Fervidibacteria” within the phylum Armatimonadota. It encodes 117 putative glycoside hydrolases (GHs), including two from GH family 50 (GH50). In this study, we expressed, purified, and functionally characterized one of these GH50 enzymes, Fsa16295Glu. We show that Fsa16295Glu is a β-1,3-endoglucanase with optimal activity on carboxymethyl curdlan (CM-curdlan) and only weak agarase activity, despite most GH50 enzymes being described as β-agarases. The purified enzyme has a wide temperature range of 4–95°C (optimal 80°C), making it the first characterized hyperthermophilic representative of GH50. The enzyme is also active at a broad pH range of at least 5.5–11 (optimal 6.5–10). Fsa16295Glu possesses a relatively high kcat/KM of 1.82 × 107 s−1 M−1 with CM-curdlan and degrades CM-curdlan nearly completely to sugar monomers, indicating preferential hydrolysis of glucans containing β-1,3 linkages. Finally, a phylogenetic analysis of Fsa16295Glu and all other GH50 enzymes revealed that Fsa16295Glu is distant from other characterized enzymes but phylogenetically related to enzymes from thermophilic archaea that were likely acquired horizontally from “Fervidibacteria.” Given its functional and phylogenetic novelty, we propose that Fsa16295Glu represents a new enzyme subfamily, GH50_3.

Abstract Almost 25 years ago, sociologist Anthony Giddens wrote that ‘risk and responsibility are in fact closely linked’1. Extending this to climate risk, this perspective paper argues that climate risk assessment is not just a scientific endeavour but also deeply political. As climate risks become more complex and demand more science- and policy-driven integration across sectors and regions, assessments may involve significant political constraints that impede effective and just climate adaptation. Using a framework of integration challenges, this paper uncovers political constraints that may arise in developing integrated climate risk assessment. It argues that the framing and structuring of climate risk assessment may yield political constraints such as biases towards certain groups, sectoral incoherence, decisions not aiding the most exposed, distributional conflicts, and ambiguous responsibility in managing complex climate risks. Left unaddressed, such political constraints may hamper climate adaptation rather than enable progress.

Background: Concomitant type 2 diabetes (T2DM) and cardiovascular disease (CVD) is frequent with a poor prognosis with high risk of comorbidities. Strict risk factor control reduces the risk for complications – yet many people do not achieve treatment targets. The complexity and fragmentation of the healthcare system may, together with the vulnerability of these patients, be a reason. Objective: The purpose of this paper is to describe the protocol of a non-randomized interventional pilot study testing the feasibility and effect of a multidisciplinary, shared care clinic using personalized medicine and coordinated care in people living with concomitant T2D and CVD. Methods: Participants were included from the Holbaek area in Denmark. People suffered from T2DM and CVD and were dysregulated regarding to HbA1c, cholesterol, micro/macroalbuminuaria or blood pressure. Participants went through a thorough evaluation to identify their needs and resources and received consultations every three months for one year. Results: A total of 63 participants with T2DM and CVD were enrolled in the clinic. The participants had a mean age of 69 years and a BMI of 30.9 kg/m2. Almost 50 % had heart failure, 95 % dyslipidemia and 91 % hypertension. Around 54 % received GLP-1 agonists and 39 % received SGLT-2-inhibitors. Perspectives: To our knowledge, a similar study with a multidisciplinary, shared care, outpatient clinic treating people living with concomitant T2DM and CVD, has not been performed previously. This study will provide information about the feasibility and efficacy of a multidisciplinary clinic based on changes in cardiovascular risk factors and medication.

Summary: Early detection is key for increased survival in ovarian cancer, but no general screening program exists today due to lack of biomarkers and overall cost versus benefit over traditional clinical methods. Here, we used dried cervico-vaginal fluid (CVF) as sampling matrix coupled with mass spectrometry for detection of protein biomarkers. We find that self-collected CVF on paper cards yields robust results and is suitable for high-throughput proteomics. Artificial intelligence–based methods were used to identify an 11-protein panel that separates cases from controls. In validation data, the panel achieved a sensitivity of 0.97 (95% CI 0.91–1.00) at a specificity of 0.67 (0.40–0.87). Analyses of samples collected prior to development of symptoms indicate that the panel is informative also of future risk of disease. Dried CVF is used in cervical cancer screening, and our results opens the possibility for a screening program also for ovarian cancer, based on self-collected CVF samples.

Abstract Background Follow-ups more than 20 years after neck surgery are extremely rare. No previous randomized studies have investigated differences in pain and disability more than 20 years after ACDF surgery using different techniques. The purpose of this study was to describe pain and functioning more than 20 years after anterior cervical decompression and fusion surgery, and to compare outcomes between the Cloward Procedure and the carbon fiber fusion cage (CIFC). Methods This study is a 20 to 24-year follow-up of a randomized controlled trial. Questionnaires were sent to 64 individuals, at least 20 years after ACDF due to cervical radiculopathy. Fifty individuals (mean age 69, 60% women, 55% CIFC) completed questionnaires. Mean time since surgery was 22.4 years (range 20,5–24). Primary outcomes were neck pain and neck disability index (NDI). Secondary outcomes were frequency and intensity of neck and arm pain, headache, dizziness, self-efficacy, health related quality of life or global outcome. Clinically relevant improvements were defined as 30 mm decrease in pain and a decrease in disability of 20 percentage units. Between-group differences over time were analyzed with mixed design ANOVA and relationships between main outcomes and psychosocial factors were analyzed by Spearman´s rho. Results Neck pain and NDI score significantly improved over time (p

I denne studien undersøker vi hvordan studenter med usynlige funksjonsnedsettelser opplever digitale læringsformer under koronapandemien. Studien er en casestudie basert på intervjuer av studenter ved et stort norsk universitet samt observasjon. Resultatene viser at studentene kan oppleve at digitale læringsformer gir dårlige forutsetninger for læring. Andre opplever bedre tilpasset læring med digital undervisning sammenlignet med studiehverdagen på campus. Studien viser også at det sosiale aspektet er viktig for studentenes læring, og at digitale læringsformer kan virke hemmende på det sosiale. Konklusjonen er at studenter med funksjonsnedsettelser opplever både fordeler og ulemper ved digitale læringsformer, og at dette er avhengig av hver enkelt student samt type funksjonsnedsettelse. Dette kan påvirke disse studentenes oppfatning av digitale læringsformer som noe positivt eller negativt.

Poorly differentiated esophageal adenocarcinoma (PDEAC) has a dismal prognosis. Glypican-1(GPC-1) is known to be upregulated in several cancer types in contrast to healthy tissues, rendering it as a biomarker. Nevertheless, the potential therapeutic targeting of GPC-1 has not been explored in PDEAC. There is accumulating evidence that GPC-1, via upregulation of PI3K/Akt/ERK signaling, plays a crucial role in the progression and chemoresistance in cancer. Pictilisib, a class I pan PI3K inhibitor, has shown promising antitumor results in clinical trials, however, has not gained widespread success due to acquired drug resistance. This study investigated the role of GPC-1 in chemo-resistant PDEAC and appraises the impact of targeted silencing of GPC-1 on the antitumor effects of Pictilisib in PDEAC cell lines. Immunohistochemistry assays in PDEAC tissue specimens demonstrated a pronounced intensity of staining with GPC-1. Upregulation of GPC-1 was found to be correlated with advanced stage and poor prognosis. In-vitro studies examined the influence of GPC-1 knockdown and Pictilisib, both as individual agents and in combination, on cytotoxicity, cell cycle distribution, apoptosis, and gene expression profiles. Silencing GPC-1 alone showed significantly reduced cell viability, migration, colony formation, epithelial-mesenchymal transition, and stemness in PDEAC cells. Significantly, knockdown of GPC-1 combined with low-dose Pictilisib led to enhancement of cytotoxicity, cell cycle arrest, and apoptosis in ESO-26 and OE-33 cells. In the xenograft mouse model, the combination of Pictilisib and GPC-1 knockdown exhibited synergy. These findings suggest that GPC-1 represents a promising target to augment chemosensitivity in esophageal adenocarcinoma.

ABSTRACT Staphylococcus aureus (S. aureus) represents a major clinical challenge due to its explicit capacity to select mutations that increase antibiotic resistance and immune evasion. However, the molecular mechanisms are poorly defined, especially for adaptive immunity. Cancer immunotherapy targeting programmed cell death protein 1 (PD-1) enhances T-cell activity and is emerging for the treatment of certain viral infections, while its potential against bacterial infections remains elusive. We show that an S. aureus clpP mutant, selected during clinical antibiotic therapy, inhibits T-cell activity by directly interacting with PD-1 on human T cells. Specificity of the interaction was confirmed using recombinant PD-1, as well as PD-1 overexpressing and knock out cells. Moreover, the PD-1-binding S. aureus inhibited intracellular calcium mobilization, T-cell proliferation, CD25 expression, and IL-2 secretion, while the key effects were alleviated by antibody-mediated PD-1 blockade using an engineered IgG1-based anti-PD-1 antibody. Our results suggest that clpP mutant S. aureus directly targets PD-1 to evade immune activation and that therapeutic targeting of PD-1 may be used against certain staphylococcal infections. IMPORTANCE Therapies that target and aid the host immune defense to repel cancer cells or invading pathogens are rapidly emerging. Antibiotic resistance is among the largest threats to human health globally. Staphylococcus aureus (S. aureus) is the most common bacterial infection, and it poses a challenge to the healthcare system due to its significant ability to develop resistance toward current available therapies. In long-term infections, S. aureus further adapt to avoid clearance by the host immune defense. In this study, we discover a new interaction that allows S. aureus to avoid elimination by the immune system, which likely supports its persistence in the host. Moreover, we find that blocking the specific receptor (PD-1) using antibodies significantly relieves the S. aureus-imposed inhibition. Our findings suggest that therapeutically targeting PD-1 is a possible future strategy for treating certain antibiotic-resistant staphylococcal infections.

Abstract Background Despite remarkable progress, the immunotherapies currently used in the clinic, such as immune checkpoint blockade (ICB) therapy, still have limited efficacy against many types of solid tumors. One major barrier to effective treatment is the lack of a durable long-term response. Tumor-targeted superantigen (TTS) therapy may overcome this barrier to enhance therapeutic efficacy. TTS proteins, such as the clinical-stage molecule naptumomab estafenatox (NAP), increase tumor recognition and killing by both coating tumor cells with bacterial-derived superantigens (SAgs) and selectively expanding T-cell lineages that can recognize them. The present study investigated the efficacy and mechanism of action of repeated TTS (C215Fab-SEA) treatments leading to a long-term antitumor immune response as monotherapy or in combination with PD-1/PD-L1 inhibitors in murine tumor models. Methods We used syngeneic murine tumor models expressing the human EpCAM target (C215 antigen) to assess the efficacy and mechanism of action of repeated treatment with TTS C215Fab-SEA alone or with anti-PD-1/PD-L1 monoclonal antibodies. Tumor draining lymph nodes (TDLNs) and tumor tissues were processed and analyzed by immunophenotyping and immunohistochemistry. Isolated RNA from tumors was used to analyze gene expression and the TCR repertoire. Tumor rechallenge and T-cell transfer studies were conducted to test the long-term antitumor memory response. Results TTS therapy inhibited tumor growth and achieved complete tumor rejection, leading to a T-cell-dependent long-term memory response against the tumor. The antitumor effect was derived from inflammatory responses converting the immunosuppressive TME into a proinflammatory state with an increase in T-cell infiltration, activation and high T-cell diversity. The combination of TTS with ICB therapy was significantly more effective than the monotherapies and resulted in higher tumor-free rates. Conclusions These new results indicate that TTSs not only can turn a “cold” tumor into a “hot” tumor but also can enable epitope spreading and memory response, which makes TTSs ideal candidates for combination with ICB agents and other anticancer agents.

Endosomal escape and subsequent cytosolic delivery of siRNA therapeutics is inefficient, and quantification is difficult. Here the authors report a confocal microscopy-based method to quantify cytosolic delivery of fluorescently labelled siRNA during lipid-mediated delivery.