Immunological, molecular and therapeutic mechanisms in endometrial cancer

Improving outcome for patients with endometrial cancer (EC) has fueled research into immunological, molecular and therapeutic mechanisms in EC. The research in this thesis aims to further increase our understanding of the interplay between these mechanisms. In chapter 2, we questioned if selection of patients for adjuvant treatment can be improved using immunological variables. We found that a combination of disease stage, presence of lymphovascular space invasion and tumor infiltrating cytotoxic T-cells best predicts recurrence. This implies that intratumoral cytotoxic T-cells can contribute to improved patient selection. Next we examined new immunological mechanisms contributing to disease course. We found that presence of tumor infiltrating natural killer cells relates to patient survival dependent expression of human leucocyte antigen E (chapter 3). In chapter 4 we describe how mutations of Janus Kinase 1 can contribute to immune escape, an acquired trait of tumors to avoid immune destruction. Chapter 5 and 6 focus on uterine carcinosarcoma, a rare but lethal subtype of EC. We examined expression of L1CAM adhesion molecule and epithelial-mesenchymal transition, an important mechanism in cancer progression and metastasis (Chapter 5). Surprisingly, expression was not related to tumor cells with a mesenchymal phenotype but limited to cells with an epithelial phenotype. Chapter 6 describes a large retrospective cohort study on treatment in uterine carcinosarcoma and shows a survival benefit for surgery extended with a lymphadenectomy. Chapter 7 discusses the findings in this thesis in relation to the current understanding and future developments

Assessment of core teaching competency of health professional educators in Ethiopia:an institution-based cross-sectional study

OBJECTIVES: Understanding the competency of educators is key to informing faculty development, recruitment and performance monitoring. This study aimed to assess the core teaching competency of nursing, midwifery and biomedical educators, and associated factors in Ethiopia. DESIGN: An institution-based cross-sectional study was conducted in January 2020 using structured tools adapted from the WHO’s nurse and midwifery educator competency frameworks. SETTING: Two health science colleges and nine student practice sites in Ethiopia. PARTICIPANTS: All classroom instructors and clinical preceptors of nursing, midwifery and biomedical technician training programmes, and all the graduating class students. MEASURES: Overall teaching competency scores, teaching domain competency scores, competency gaps and performance gaps of educators were outcome measures. Past training on teaching skills courses, teaching experiences and sociodemographic characteristics of educators are associated factors. RESULTS: Most educators were not trained in teaching methods (82%). The teaching competency scores of classroom instructors and clinical preceptors were 61.1% and 52.5%, respectively. Competency gaps were found in using active learning methods, performance assessment, feedback and digital learning. Professional background of classroom instructors had a significant and strong association with their competency score (p=0.004; V=0.507). Age and teaching experience of clinical preceptors had significant associations with their competency score (p=0.023 and p=0.007, respectively) and had strong associations (V=0.280 and 0.323, respectively). Sex of students and their perceptions of how well the educators give education resources had a significant and strong association (p<0.001; V=0.429). CONCLUSIONS: Nursing, midwifery and biomedical educators lacked the competency to undertake important teaching roles, which could contribute to the low quality of education. More attention should be given to strengthening faculty development

Junior doctors' experiences with interprofessional collaboration:Wandering the landscape

Context The transition from medical student to junior doctor is challenging. Junior doctors need to become part of the physician community of practice (CoP), while dealing with new responsibilities, tasks and expectations. At the same time, they need to learn how to navigate the frontiers and intersections with the other communities of practice that form the Landscape of Practice (LoP). This study aims to understand how junior doctors experience interprofessional collaboration (IPC) and what elements shape these experiences considering their transition to clinical practice. Methods In this multicentre qualitative study, 13 junior doctors individually drew two rich pictures of IPC experiences, one positive and one negative. A rich picture is a visual representation, a drawing of a particular situation intended to capture the complex and non-verbal elements of an experience. We used semi-structured interviews to deepen the understanding of junior doctors' depicted IPC experiences. We analysed both visual materials and interview transcripts iteratively, for which we adopted an inductive constructivist thematic analysis. Results While transitioning into a doctor, junior doctors become foremost members of the physician CoP and shape their professional identity based on perceived values in their physician community. Interprofessional learning occurs implicitly, without input from the interprofessional team. As a result, junior doctors struggle to bridge the gap between themselves and the interprofessional team, preventing IPC learning from developing into an integrative process. This professional isolation leaves junior doctors wandering the landscape of practice without understanding roles, attitudes and expectations of others. Conclusions Learning IPC needs to become a collective endeavour and an explicit learning goal, based on multisource feedback to take advantage of the expertise already present in the LoP. Furthermore, junior doctors need a safe environment to embrace and reflect on the emotions aroused by interprofessional interactions, under the guidance of experienced facilitators

The response of dual-species bacterial biofilm to 2% and 5% NaOCl mixed with etidronic acid:A laboratory real-time evaluation using optical coherence tomography

Aim: The addition of etidronic acid (HEDP) to sodium hypochlorite (NaOCl) could increase the antibiofilm potency of the irrigant, whilst maintaining the benefits of continuous chelation. Studies conducted so far have shown that mixing HEDP with NaOCl solutions of relatively low concentration does not compromise the antibiofilm efficacy of the irrigant. However, the working lifespan of NaOCl may decrease resulting in a reduction of its antibiofilm efficacy over time (efficiency). In this regard, continuous irrigant replenishment needs to be examined. This study investigated the response of a dual-species biofilm when challenged with 2% and 5% NaOCl mixed with HEDP for a prolonged timespan and under steady laminar flow. Methodology: Dual-species biofilms comprised of Streptococcus oralis J22 and Actinomyces naeslundii T14V-J1 were grown on human dentine discs in a constant depth film fermenter (CDFF) for 96 h. Biofilms were treated with 2% and 5% NaOCl, alone or mixed with HEDP. Irrigants were applied under steady laminar flow for 8 min. Biofilm response was evaluated by means of optical coherence tomography (OCT). Biofilm removal, biofilm disruption, rate of biofilm loss and disruption as well as bubble formation were assessed. One-way anova, Wilcoxon's signed-rank test and Kruskal–Wallis H test were performed for statistical analysis of the data. The level of significance was set at a ≤.05. Results: Increasing NaOCl concentration resulted in increased biofilm removal and disruption, higher rate of biofilm loss and disruption and increased bubble formation. Mixing HEDP with NaOCl caused a delay in the antibiofilm action of the latter, without compromising its antibiofilm efficacy. Conclusions: NaOCl concentration dictates the biofilm response irrespective of the presence of HEDP. The addition of HEDP resulted in a delay in the antibiofilm action of NaOCl. This delay affects the efficiency, but not the efficacy of the irrigant over time

Lymphadenectomy and Adjuvant Therapy Improve Survival with Uterine Carcinosarcoma:A Large Retrospective Cohort Study

OBJECTIVE: Uterine carcinosarcoma is a rare, aggressive subtype of endometrial cancer. Treatment consists of hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy (LND). The survival benefit of LND in relation to adjuvant radio- and/or chemotherapy is unclear. We evaluated the impact of LND on survival in relation to adjuvant therapy in uterine carcinosarcoma. METHODS: Retrospective data on 1,140 cases were combined from the Netherlands Cancer Registry (NCR) and the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA). LND was defined as the removal of any nodes. Additionally, cases where 10 nodes or less (LND ≤10) or more than 10 nodes (LND > 10) were removed were analyzed separately. Adjuvant therapy was evaluated as radiotherapy, chemotherapy, or radiochemotherapy. Associations were analyzed by χ2 test, log-rank test, and Cox regression analysis. RESULTS: Overall survival (OS) had improved after total abdominal hysterectomy with bilateral salpingo-oophorectomy with LND > 10 (HR 0.62, 95% CI 0.47-0.83). Adjuvant therapy was related to OS with an HR of 0.64 (95% CI 0.54-0.75) for radiotherapy, an HR of 0.65 (95% CI 0.48-0.88) for chemotherapy, and an HR of 0.25 (95% CI 0.13-0.46) for radiochemotherapy. Additionally, adjuvant treatment was related to OS when lymph nodes were positive (HR 0.22, 95% CI 0.11-0.42), but not when they were negative. CONCLUSION: LND is related to improved survival when more than 10 nodes are removed. Adjuvant therapy improves survival when LND is omitted, or when nodes are positive

Investigating feasibility of 2021 WHO protocol for cervical cancer screening in underscreened populations:PREvention and SCReening Innovation Project Toward Elimination of Cervical Cancer (PRESCRIP-TEC)

Abstract Background High-risk human papillomavirus (hrHPV) testing has been recommended by the World Health Organization as the primary screening test in cervical screening programs. The option of self-sampling for this screening method can potentially increase women’s participation. Designing screening programs to implement this method among underscreened populations will require contextualized evidence. Methods PREvention and SCReening Innovation Project Toward Elimination of Cervical Cancer (PRESCRIP-TEC) will use a multi-method approach to investigate the feasibility of implementing a cervical cancer screening strategy with hrHPV self-testing as the primary screening test in Bangladesh, India, Slovak Republic and Uganda. The primary outcomes of study include uptake and coverage of the screening program and adherence to follow-up. These outcomes will be evaluated through a pre-post quasi-experimental study design. Secondary objectives of the study include the analysis of client-related factors and health system factors related to cervical cancer screening, a validation study of an artificial intelligence decision support system and an economic evaluation of the screening strategy. Discussion PRESCRIP-TEC aims to provide evidence regarding hrHPV self-testing and the World Health Organization’s recommendations for cervical cancer screening in a variety of settings, targeting vulnerable groups. The main quantitative findings of the project related to the impact on uptake and coverage of screening will be complemented by qualitative analyses of various determinants of successful implementation of screening. The study will also provide decision-makers with insights into economic aspects of implementing hrHPV self-testing, as well as evaluate the feasibility of using artificial intelligence for task-shifting in visual inspection with acetic acid. Trial registration ClinicalTrials.gov, NCT05234112 . Registered 10 February 202

Mining microbial metatranscriptomes for expression of antibiotic resistance genes under natural conditions

Antibiotic resistance genes are found in a broad range of ecological niches associated with complex microbiota. Here we investigated if resistance genes are not only present, but also transcribed under natural conditions. Furthermore, we examined the potential for antibiotic production by assessing the expression of associated secondary metabolite biosynthesis gene clusters. Metatranscriptome datasets from intestinal microbiota of four human adults, one human infant, 15 mice and six pigs, of which only the latter have received antibiotics prior to the study, as well as from sea bacterioplankton, a marine sponge, forest soil and sub-seafloor sediment, were investigated. We found that resistance genes are expressed in all studied ecological niches, albeit with niche-specific differences in relative expression levels and diversity of transcripts. For example, in mice and human infant microbiota predominantly tetracycline resistance genes were expressed while in human adult microbiota the spectrum of expressed genes was more diverse, and also included beta-lactam, aminoglycoside and macrolide resistance genes. Resistance gene expression could result from the presence of natural antibiotics in the environment, although we could not link it to expression of corresponding secondary metabolites biosynthesis clusters. Alternatively, resistance gene expression could be constitutive, or these genes serve alternative roles besides antibiotic resistance.Peer reviewe