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I. The arena of quantum mechanics and quantum field theory is the abstract, unobserved and unobservable, M-dimensional formal Hilbert space ≠ spacetime. II. The arena of observations—and, more generally, of all events (i.e., everything) in the real physical world—is the classical four-dimensional physical spacetime. III. The “Born rule” is the random process “magically” transforming I into II. Wavefunctions are superposed and entangled only in the abstract space I, never in spacetime II. Attempted formulations of quantum theory directly in real physical spacetime actually constitute examples of “locally real” theories, as defined by Clauser and Horne, and are therefore already empirically refuted by the numerous tests of Bell’s theorem in real, controlled experiments in laboratories here on Earth. Observed quantum entities (i.e., events) are never superposed or entangled as they: (1) exclusively “live” (manifest) in real physical spacetime and (2) are not described by entangled wavefunctions after “measurement” effectuated by III. When separated and treated correctly in this way, a number of fundamental problems and “paradoxes” of quantum theory vs. relativity (i.e., spacetime) simply vanish, such as the black hole information paradox, the infinite zero-point energy of quantum field theory and the quantization of general relativity.

Objective To assess the efficacy of inhaled ciclesonide in reducing the duration of oxygen therapy (an indicator of time to clinical improvement) among adults hospitalised with COVID-19.Design Multicentre, randomised, controlled, open-label trial.Setting 9 hospitals (3 academic hospitals and 6 non-academic hospitals) in Sweden between 1 June 2020 and 17 May 2021.Participants Adults hospitalised with COVID-19 and receiving oxygen therapy.Intervention Inhaled ciclesonide 320 µg two times a day for 14 days versus standard care.Main outcome measures Primary outcome was duration of oxygen therapy, an indicator of time to clinical improvement. Key secondary outcome was a composite of invasive mechanical ventilation/death.Results Data from 98 participants were analysed (48 receiving ciclesonide and 50 receiving standard care; median (IQR) age, 59.5 (49–67) years; 67 (68%) men). Median (IQR) duration of oxygen therapy was 5.5 (3–9) days in the ciclesonide group and 4 (2–7) days in the standard care group (HR for termination of oxygen therapy 0.73 (95% CI 0.47 to 1.11), with the upper 95% CI being compatible with a 10% relative reduction in oxygen therapy duration, corresponding to a

Abstract BRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.

Abstract Background Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. Methods Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. Results A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. Conclusions Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.

Abstract Background The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only. Methods The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/− whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group. Discussion This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM. Results The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden. Trial registration ClinicalTrials.gov , NCT 03116412 . Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412

Abstract Background There is increasing interest in and demands for partnerships between academia and healthcare practices. Few empirical studies have described the influence of such partnerships from a practice perspective. The purpose of this study was to evaluate the impact of a reform launched to increase integration between primary care and academia and to identify potential reasons for why the observed impact occurred in three areas targeted by the reform: research, student education, and continued professional development. Methods The study was conducted in Stockholm County, the largest healthcare region in Sweden, at the introduction of a partnership between primary care and academia, including eight coordinating centres and approximately 500 surrounding primary care units. A programme theory-based qualitative approach to evaluation was used, building on document analysis, and in-depth interviews with the centre managers (n = 6) and coordinators (n = 8) conducted 42–66 months after the initiation of the reform. Results The analysis showed that the reform had some impact on all three areas targeted by the reform: research, student education, and continued professional development. The input that contributed most extensively to the impact was the establishment of facilitating roles. Most changes occurred at the coordinating centres and primarily in the area of student education. The effect on student education was primarily due to having prior experience in this area and perceptions of timely benefits of students to care practice. Conclusions Partnerships between primary care and academia hold the potential of practice impact. To increase integration between primary care and academia, the components of the integration must be understandable and relevant for primary care practitioners, and importantly, compliant with delivery of primary care.

Abstract Background Comprehensive policies are becoming common for addressing wicked problems in health and social care. Success of these policies often varies between target organizations. This variation can often be attributed to contextual factors. However, there is a lack of knowledge about the conditions for successful policy implementation and how context influences this process. The aim of this study was to investigate county-level actors’ perspectives on the implementation of a comprehensive national policy in three Swedish counties. The policy focused on developing quality of care for elderly based on the use of national quality registries (NQRs) and to improve coordination of care. Methods A comparative case study approach was used. Data was collected longitudinally through documents and interviews. The Consolidated Framework for Implementation Research (CFIR) guided the analysis. Results All three counties shared the view that the policy addressed important issues. Still, there was variation regarding how it was perceived and managed. Adaptable features—i.e., NQRs and improvement coaches—were perceived as relevant and useful. However, the counties differed in their perceptions of another policy component—i.e., senior management program—as an opportunity or a disturbance. This program, while tackling complex issues of collaboration, fell short in recognizing the counties’ pre-existing conditions and needs and also offered few opportunities for adaptations. Performance bonuses and peer pressure were strong incentives for all counties to implement the policy, despite the poor fit of policy content and local context. Conclusions Comprehensive health policies aiming to address wicked problems have better chances of succeeding if the implementation includes assessments of the target organizations’ implementation capacity as well as the implicit quid pro quos involved in policy development. Special attention is warranted regarding the use of financial incentives when dealing with wicked problems since the complexity makes it difficult to align incentives with the goals and to assess potential consequences. Other important aspects in the implementation of such policies are the use of collaborative approaches to engage stakeholders with differing perspectives, and the tailoring of policy communication to facilitate shared understanding and commitment.

Background While programmed cell death receptor 1 (PD-1) blockade treatment has revolutionized treatment of patients with melanoma, clinical outcomes are highly variable, and only a fraction of patients show durable responses. Therefore, there is a clear need for predictive biomarkers to select patients who will benefit from the treatment.Method To identify potential predictive markers for response to PD-1 checkpoint blockade immunotherapy, we conducted single-cell RNA sequencing analyses of peripheral blood mononuclear cells (PBMC) (n=8), as well as an in-depth immune monitoring study (n=20) by flow cytometry in patients with advanced melanoma undergoing treatment with nivolumab at Karolinska University Hospital. Blood samples were collected before the start of treatment and at the time of the second dose.Results Unbiased single-cell RNA sequencing of PBMC in patients with melanoma uncovered that a higher frequency of monocytes and a lower ratio of CD4+ T cells to monocyte were inversely associated with overall survival. Similarly, S100A9 expression in the monocytic subset was correlated inversely with overall survival. These results were confirmed by a flow cytometry-based analysis in an independent patient cohort.Conclusion Our results suggest that monocytic cell populations can critically determine the outcome of PD-1 blockade, particularly the subset expressing S100A9, which should be further explored as a possible predictive biomarker. Detailed knowledge of the biological role of S100A9+ monocytes is of high translational relevance.

Dysregulation of the kynurenine pathway has been regarded as a mechanism of tumor immune escape by the enzymatic activity of indoleamine 2, 3 dioxygenase and kynurenine production. However, the immune-modulatory properties of other kynurenine metabolites such as kynurenic acid, 3-hydroxykynurenine, and anthranilic acid are poorly understood. In this study, plasma from patients diagnosed with metastatic cutaneous malignant melanoma (CMM) was obtained before (PRE) and during treatment (TRM) with inhibitors of mitogen-activated protein kinase pathway (MAPKIs). Immuno-oncology related protein profile and kynurenine metabolites were analyzed by proximity extension assay (PEA) and LC/MS-MS, respectively. Correlation network analyses of the data derived from PEA and LC/MS-MS identified a set of proteins that modulate the differentiation of Th1 cells, which is linked to 3-hydroxykynurenine levels. Moreover, MAPKIs treatments are associated with alteration of 3-hydroxykynurenine and 3hydroxyanthranilic acid (3HAA) concentrations and led to higher “CXCL11,” and “KLRD1” expression that are involved in T and NK cells activation. These findings imply that the kynurenine pathway is pathologically relevant in patients with CMM.

Development of T cell-directed immune checkpoint inhibitors (ICI) has revolutionized metastatic melanoma (MM) therapy, but 36 and >18 months, respectively). In addition, two patients had partial responses (PR), one still ongoing (>42 months) with only a small bone-lesion remaining, and one of short duration (

Blockade of the PD-1 receptor has revolutionized the treatment of metastatic melanoma, with significant increases in overall survival (OS) and a dramatic improvement in patient quality of life. Despite the success of this approach, the number of benefitting patients is limited and there is a need for predictive biomarkers as well as a deeper mechanistic analysis of the cellular populations involved in clinical responses. With the aim to find predictive biomarkers for PD-1 checkpoint blockade, an in-depth immune monitoring study was conducted in 36 advanced melanoma patients receiving pembrolizumab or nivolumab treatment at Karolinska University Hospital. Blood samples were collected before treatment and before administration of the second and fourth doses. Peripheral blood mononuclear cells were isolated and stained for flow cytometric analysis within 2 h of sample collection. Overall survival and progression-free survival (PFS) were inversely correlated with CD69 expression NK cells. In the myeloid compartment, high frequencies of non-classical monocytes and low frequencies of monocytic myeloid derived suppressor cells (MoMDSCs) correlated with response rates and OS. A deeper characterization of monocytic subsets showed that PD-L1 expression in MDSCs, non-classical and intermediate monocytes was significantly increased in patients with shorter PFS in addition to correlating inversely with OS. Our results suggest that cellular populations other than T cells can be critical in the outcome of PD-1 blockade treatment. Specifically, the frequencies of activated NK cells and monocytic subsets are inversely correlated with survival and clinical benefit, suggesting that their role as predictive biomarkers should be further evaluated.

Tumor-infiltrating lymphocytes (TIL) are considered enriched for T cells recognizing shared tumor antigens or mutation-derived neoepitopes. We performed exome sequencing and HLA-A*02:01 epitope prediction from tumor cell lines from two HLA-A2-positive melanoma patients whose TIL displayed strong tumor reactivity. The potential neoepitopes were screened for recognition using autologous TIL by immunological assays and presentation on tumor major histocompatibility complex class I (MHC-I) molecules by Poisson detection mass spectrometry (MS). TIL from the patients recognized 5/181 and 3/49 of the predicted neoepitopes, respectively. MS screening detected 3/181 neoepitopes on tumor MHC-I from the first patient but only one was also among those recognized by TIL. Consequently, TIL enriched for neoepitope specificity failed to recognize tumor cells, despite being activated by peptides. For the second patient, only after IFN-γ treatment of the tumor cells was one of 49 predicted neoepitopes detected by MS, and this coincided with recognition by TIL sorted for the same specificity. Importantly, specific T cells could be expanded from patient and donor peripheral blood mononuclear cells (PBMC) for all neoepitopes recognized by TIL and/or detected on tumor MHC-I. In summary, stimulating the appropriate inflammatory environment within tumors may promote neoepitope MHC presentation while expanding T cells in blood may circumvent lack of specific TIL. The discordance in detection between physical and functional methods revealed here can be rationalized and used to improve neoantigen-targeted T cell immunotherapy.

Abstract Background Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4+ T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4+ T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy. Results Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4+ lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4+ lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4+ T cells for all four investigated loci, most prominently in IFNG p

Abstract Background Leadership has been identified as an influential factor in implementation processes in healthcare organizations. However, the processes through which leaders affect implementation outcomes are largely unknown. The purpose of this study is to analyse how managers interpret and make sense of a large scale top-down implementation initiative and what implications this has for the implementation process. This was studied at the implementation of an academic primary healthcare initiative covering 210 primary healthcare centres in central Sweden. The aim of the initiative was to integrate research and education into regular primary healthcare services. Methods The study builds on 16 in-depth individual semi-structured interviews with all managers (n = 8) who had operative responsibility for the implementation. Each manager was interviewed twice during the initial phase of the implementation. Data were analysed using a thematic approach guided by theory on managerial role taking based on the Transforming Experience Framework. Results How the managers interpreted and made sense of the implementation task built on three factors: how they perceived the different parts of the initiative, how they perceived themselves in relation to these parts, and the resources available for the initiative. Based on how they combined these three factors the managers chose to integrate or separate the different parts of the initiative in their management of the implementation process. Conclusions This research emphasizes that managers in healthcare seem to have a substantial impact on how and to what extent different tasks are addressed and prioritized in top-down implementation processes. This has policy implications. To achieve intended implementation outcomes, the authors recognize the necessity of an early and on-going dialogue about how the implementation is perceived by the managers responsible for the implementation.

Abstract Background Change initiatives face many challenges, and only a few lead to long-term sustainability. One area in which the challenge of achieving long-term sustainability is particularly noticeable is integrated health and social care. Service integration is crucial for a wide range of patients including people with complex mental health and social care needs. However, previous research has focused on the initiation, resistance and implementation of change, while longitudinal studies remain sparse. The objective of this study was therefore to gain insight into the dynamics of sustainable changes in integrated health and social care through an analysis of local actions that were triggered by a national policy. Methods A retrospective and qualitative case-study research design was used, and data from the model organisation’s steering-committee minutes covering 1995-2015 were gathered and analysed. The analysis generated a narrative case description, which was mirrored to the key elements of the Dynamic Sustainability Framework (DSF). Results The development of inter-sectoral cooperation was characterized by a participatory approach in which a shared structure was created to support cooperation and on-going quality improvement and learning based on the needs of the service user. A key management principle was cooperation, not only on all organisational levels, but also with service users, stakeholder associations and other partner organisations. It was shown that all these parts were interrelated and collectively contributed to the creation of a structure and a culture which supported the development of a dynamic sustainable health and social care. Conclusion This study provides valuable insights into the dynamics of organizational sustainability and understanding of key managerial actions taken to establish, develop and support integration of health and social care for people with complex mental health needs. The service user involvement and regular reviews of service users’ needs were essential in order to tailor services to the needs. Another major finding was the importance of continuously adapting the content of the change to suit its context. Hence, continuous refinement of the change content was found to be more important than designing the change at the pre-implementation stage.

Abstract Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy‐resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX‐derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF‐MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression.

Abstract Background The variable prognosis in stage III cutaneous melanoma is partially due to unknown prognostic factors. Improved prognostic tools are required to define patients with an increased risk of developing metastatic disease who might benefit from adjuvant therapies. The aim was to examine if cellular immune markers in association with tumor proliferation rate and BRAF mutation status have an impact on prognosis in stage III melanoma. Methods We have used two sets of case series with stage III disease: 23 patients with short survival (≤ 13 months) and 19 patients with long survival (≥ 60 months). Lymph node metastases were analyzed for Ki67, CD8 and FOXP3 protein expression using immunohistochemistry. BRAF mutation status was analyzed in a previous study on the same samples. Results Low tumor proliferation rate was significantly associated with a better prognosis (p = 0.013). Presence of FOXP3+ T cells was not correlated to adverse clinical outcome. A highly significant trend for a longer survival was found in the presence of an increasing number of markers; CD8+ and FOXP3+ T cells, low tumor proliferation and BRAF wildtype status (p = 0.003). Presence of at least three of these four markers was found to be an independent favorable prognostic factor (OR 19.4, 95% CI 1.9-197, p = 0.012), when adjusting for ulceration and number of lymph node metastases. Proliferation alone remained significant in multivariate analyses (OR 26.1, 95% CI 2.0-344, p = 0.013) but with a wider confidence interval. This panel still remained independent when also adjusting for a previously identified prognostic glycolytic-pigment panel. Conclusions We have demonstrated that presence of immune cells in association with tumor proliferation and BRAF mutation status may further contribute to identify stage III melanoma patients with high risk of relapse.

Purpose - The purpose of this paper is to address the concept of participatory research (PR) in terms of its values and challenges in project work. Design/methodology/approach - A participative research approach was used in which researchers worked collaboratively with key stakeholders involved in the development of a digital network model for expert diagnostics. The approach involved research and data gathering in six work packages: first, participation at workshops, including the presentation of a preliminary research agenda; second, presentation of a revised research agenda; third, interviews with project managers and steering committee members; fourth, feedback sessions; fifth, participation at a project conference, including additional feedback sessions; and sixth, concluding interviews with project managers. Findings - The findings suggest that PR might strengthen project work through challenging interview questions and clear feedback. PR might empower the project manager by illuminating challenges and possibilities in the project process. Practical implications - Project managers may use PR as one strategy to empower project work. Originality/value - Despite the vast research on projects and project management, researchers and practitioners are still looking for ways to advance project work. This paper contributes with knowledge on how PR may advance project work.

Background: Knowledge and understanding remains poor regarding what optimally integrated mental-health and social care services entail from the service users’ perspective, but this knowledge is important in the development of services. Aim: To identify key components of integrated mental-health and social care services that contribute to value for service users in Sweden. Method: An explorative research study design was used, based on data from four group interviews with service-user representatives. Results: The analysis resulted in eight subcategories reflecting components that were reported to contribute to value for service users. These subcategories were grouped into three main categories: 1) professionals who see and support the whole person, 2) organizational commitment to holistic care and 3) support for equal opportunities and active participation in society. Conclusion: The complexity of integrated mental-health and social care services requires coordination across the individual and organizational levels as well as ongoing dialogue and partnerships between service users, service-user associations, and health and social care organizations. In this integration, it is important that service users and service-user associations not only are invited but actively participate in the design of care and support efforts.

From its establishment in 1942, the Sami folk high school included crafts as an important part of its education program. The Swedish Mission Society, who founded the school, not only wanted to educate Sami youth to better their chances on the labour market but also to give them the opportunity to get acquainted with their Sami culture. Thus Sami crafts had a crucial role in educational activities at the folk high school. With the help of Gert Biesta’s concepts, the article shows that crafts had a socializing function. The teaching strengthened the students’ collective identity and provided them with traditional skills and knowledge. However, Lennart Wallmark, the school principal (1942-1972), stressed the importance of learning crafts for other purposes. Influenced by religious thinkers, he stated that the students would also be strengthened as individuals: a process of subjectification. Moreover, the crafts lessons had a third function: qualification. Though the studies were not vocational as such, they could simplify the process of procuring the quality label bestowed by the Sami organization Same Ätnam to crafts of especially high quality. Wallmark and the teachers in crafts were important for the development of craft education at the folk high school. However, Same Ätnam’s ideas of Sami handicraft and government regulations were also influential. These inner and outer forces contributed to the teaching so that it, on one hand, did not change much but, on the other hand, was congruous with the rest of the society.

BACKGROUND:Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers. MATERIALS AND METHODS:EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome. RESULTS:Increased levels of EV let-7g-5p during treatment compared to before treatment (EV let-7g-5p_delta) were associated with better disease control with MAPKis (odds ratio 8568.4, 95% CI = 4.8-1.5e+07, P = 0.000036). Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS) (hazard ratio = 0.27, 95% CI = 0.13-0.52, P

Introduction: Co-leadership has been identified as one approach to meet the managerial challenges of integrated services, but research on the topic is limited. In the present study, co-leadership, practised by pairs of managers – each manager representing one of the two principal organizations in integrated health and social care services – was explored. Aim: To investigate co-leadership in integrated health and social care, identify essential preconditions in fulfilling the management assignment, its operationalization and impact on provision of sustainable integration of health and social care. Method: Interviews with eight managers exercising co-leadership were analysed using directed content analysis. Respondent validation was conducted through additional interviews with the same managers. Results: Key contextual preconditions were an organization-wide model supporting co-leadership and co-location of services. Perception of the management role as a collective activity, continuous communication and lack of prestige were essential personal and interpersonal preconditions. In daily practice, office sharing, being able to give and take and support each other contributed to provision of sustainable integration of health and social care. Conclusion and discussion: Co-leadership promoted robust management by providing broader competence, continuous learning and joint responsibility for services. Integrated health and social care services should consider employing co-leadership as a managerial solution to achieve sustainability.

The Sami folk high school and the Sami languages 1942–1990 The Swedish Mission Society – SMS (Svenska missionssällskapet – SMS), wanted to improve the opportunities’ for Sami youth in Sweden and therefore they started a folk high school (folkhögskola) for the Sami in 1942. One of the aims of SMS was to help the Sámi to preserve and develop the Sami culture and languages. Over time Sami themes, the languages being one, became more prominent at the school. However some of the problems regarding the language teaching remained: the students wanted to learn different Sami languages, their linguistic skills varied a lot, and there was not that many students who wanted to learn Sami. Despite these problems, the teaching improved over the years and the Sami folk high school remained important for the Sami people during the researched period.

Background: Well-organised clinical cooperation between health and social services has been difficult to achieve in Sweden as in other countries. Purpose: This paper presents an empirical study of a mental health coordination network in one area in Stockholm. The aim was to describe the development and nature of coordination within a mental health and social care consortium and to assess the impact on care processes and client outcomes. Method: Data was gathered through interviews with coordina­tors from three rehabilitation units. The interviews focused on coordination activities aimed at supporting the clients’ needs and investigated how the coordinators acted according to the consortium's holistic approach. Data on The Camberwell Assess­ment of Need (CAN-S) showing clients’ satisfaction was used to assess on set of outcomes. Findings: The findings revealed different coordination activities and factors both helping and hindering the network coordination activities. One factor helping was the history of local and personal informal cooperation and shared responsibilities evident. Unclear roles and routines hindered cooperation Practical value: The contribution is an empirical example and a model for organisations establishing structures for network coordination. One lesson for current policy about integrated health care is to adapt and implement ”pair coordinators” where full structural integration is not possible. Another lesson, based on the idea of patient quality by coordinated care, is specific to adapt the work of the local psychiatric addictive team – an independent special team in the psychiatric outpatient care serving psychotic clients with complex addictive problems.