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Abstract Background Neuroblastoma (NB) is a heterogeneous embryonal malignancy and the deadliest tumor of infancy. It is a complex disease that can result in diverse clinical outcomes. In some children, tumors regress spontaneously. Others respond well to existing treatments. But for the high-risk group, which constitutes approximately 40% of all patients, the prognosis remains dire despite collaborative efforts in basic and clinical research. While its exact cellular origin is still under debate, NB is assumed to arise from the neural crest cell lineage including multipotent Schwann cell precursors (SCPs), which differentiate into sympatho-adrenal cell states eventually producing chromaffin cells and sympathoblasts. Methods To investigate clonal development of neuroblastoma cell states, we performed haplotype-specific analysis of human tumor samples using single-cell multi-omics, including joint DNA/RNA sequencing of sorted single cells (DNTR-seq). Samples were also assessed using immunofluorescence stainings and fluorescence in-situ hybridization (FISH). Results Beyond adrenergic tumor cells, we identify subpopulations of aneuploid SCP-like cells, characterized by clonal expansion, whole-chromosome 17 gains, as well as expression programs of proliferation, apoptosis, and a non-immunomodulatory phenotype. Conclusion Aneuploid pre-malignant SCP-like cells represent a novel feature of NB. Genetic evidence and tumor phylogeny suggest that these clones and malignant adrenergic populations originate from aneuploidy-prone cells of migrating neural crest or SCP origin, before lineage commitment to sympatho-adrenal cell states. Our findings expand the phenotypic spectrum of NB cell states. Considering the multipotency of SCPs in development, we suggest that the transformation of fetal SCPs may represent one possible mechanism of tumor initiation in NB with chromosome 17 aberrations as a characteristic element.

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes.

Background The concept of an occupational pattern in occupational therapy and occupational science has evolved with varying definitions, ranging from activity patterns to patterns of daily occupation.Aims This study aimed to explore the concept of occupational pattern, develop an updated definition of the concept, and theoretically validate the concept’s definition.Method Walker and Avant’s concept analysis method was used, where both theoretical frameworks and peer-reviewed scientific literature were searched and synthesized to clarify and define the concept. Furthermore, seven occupational therapists theoretically validated the concept.Findings The analysis included forty-nine references from various research contexts and theoretical perspectives. The synthesis yielded a conceptualization of the concept of occupational pattern, outlining it into three overarching categories: ‘content in an individual’s occupational pattern’, ‘designing an occupational pattern’, and ‘balancing the occupational pattern’.Implications An updated operational definition of the multifaceted concept of an occupational pattern now exists, with practical implications for enhancing the education of occupational therapy students and guiding the utilization of the concept. Moreover, it holds significance for instrument development and outcome measurement in research; especially in lifestyle intervention studies within the field of occupational therapy.

Rice paddy soils have high organic carbon (OC) storage potential, but predicting OC stocks in these soils is difficult due to the complex OC stabilization mechanisms under fluctuating redox conditions. Especially in temperate climates, these mechanisms remain understudied and comparisons to OC stocks under natural vegetation are scarce. Semi-natural forests could have similar or higher OC inputs than rice paddies, but in the latter mineralization under anoxic conditions and interactions between OC and redox-sensitive minerals (in particular Fe oxyhydroxides, hereafter referred to as Fe oxides) could promote OC stabilization. Moreover, management-induced soil redox cycling in rice paddies can interact with pre-existing pedogenetic differences of soils having different degrees of evolution. To disentangle these drivers of soil OC stocks, we focused on a soil age gradient in Northern Italy with a long (30 + years) history of rice cultivation and remnant semi-natural forests. Irrespective of soil age, soils under semi-natural forest and paddy land-use showed comparable OC stocks. While, in topsoil, stocks of crystalline Fe and short-ranged Fe and Al oxides did not differ between land-uses, under paddy management more OC was found in the mineral-associated fraction. This hints to a stronger redox-driven OC stabilization in the paddy topsoil compared to semi-natural forest soils that might compensate for the presumed lower OC inputs under rice cropping. Despite the higher clay contents over the whole profile and more crystalline pedogenetic Fe stocks in the topsoil in older soils, OC stocks were higher in the younger soils, in particular in the 50–70 cm layer, where short-range ordered pedogenetic oxides were also more abundant. These patterns might be explained by differences in hydrological flows responsible for the translocation of Fe and dissolved OC to the subsoil, preferentially in the younger, coarse-textured soils. Taken together, these results indicate the importance of the complex interplay between redox-cycling affected by paddy-management and soil-age related hydrological properties.

The objective was to reflect on the experience of working collaboratively across education programmes, departments, and faculties from the perspective of university teachers at a higher education institution. Nine teachers from five programmes working together to develop a new curriculum for interprofessional education (IPE) participated in a focus group discussion. Data were analysed using thematic analysis. Findings suggest that teacher experiences can be understood in terms of teamwork processes valued from both professional and IPE experiential variations within the group. Since findings illustrate pedagogical collaboration across department and faculty boundaries, they can inspire teachers who are planning a similar process.

Implants made of magnesium (Mg) are increasingly employed in patients to achieve osteosynthesis while degrading in situ. Since Mg implants and Mg2+ have been suggested to possess anti-inflammatory properties, the clinically observed soft tissue inflammation around Mg implants is enigmatic. Here, using a rat soft tissue model and a 1–28 d observation period, we determined the temporo-spatial cell distribution and behavior in relation to sequential changes of pure Mg implant surface properties and Mg2+ release. Compared to nondegradable titanium (Ti) implants, Mg degradation exacerbated initial inflammation. Release of Mg degradation products at the tissue-implant interface, culminating at 3 d, actively initiated chemotaxis and upregulated mRNA and protein immunomodulatory markers, particularly inducible nitric oxide synthase and toll-like receptor-4 up to 6 d, yet without a cytotoxic effect. Increased vascularization was demonstrated morphologically, preceded by high expression of vascular endothelial growth factor. The transition to appropriate tissue repair coincided with implant surface enrichment of Ca and P and reduced peri-implant Mg2+ concentration. Mg implants revealed a thinner fibrous encapsulation compared with Ti. The detailed understanding of the relationship between Mg material properties and the spatial and time-resolved cellular processes provides a basis for the interpretation of clinical observations and future tailoring of Mg implants.

A genetic predisposition to central nervous system (CNS) toxicity induced by antimicrobial drugs (antibiotics, antivirals, antifungals, and antiparasitic drugs) has been suspected. Whole genome sequencing of 66 cases and 833 controls was performed to investigate whether antimicrobial drug-induced CNS toxicity was associated with genetic variation. The primary objective was to test whether antimicrobial-induced CNS toxicity was associated with seventeen efflux transporters at the blood-brain barrier. In this study, variants or structural elements in efflux transporters were not significantly associated with CNS toxicity. Secondary objectives were to test whether antimicrobial-induced CNS toxicity was associated with genes over the whole genome, with HLA, or with structural genetic variation. Uncommon variants in and close to three genes were significantly associated with CNS toxicity according to a sequence kernel association test combined with an optimal unified test (SKAT-O). These genes were LCP1 (q = 0.013), RETSAT (q = 0.013) and SFMBT2 (q = 0.035). Two variants were driving the LCP1 association: rs6561297 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]) and the regulatory variant rs10492451 (p = 1.15x10-6, OR: 4.60 [95% CI: 2.51-8.46]). No common genetic variant, HLA-type or structural variation was associated with CNS toxicity. In conclusion, CNS toxicity due to antimicrobial drugs was associated with uncommon variants in LCP1, RETSAT and SFMBT2.

IntroductionChronic infections are a major clinical challenge in hard-to-heal wounds and implanted devices. Pseudomonas aeruginosa is a common causative pathogen that produces numerous virulence factors. Due to the increasing problem of antibiotic resistance, new alternative treatment strategies are needed. Quorum sensing (QS) is a bacterial communication system that regulates virulence and dampens inflammation, promoting bacterial survival. QS inhibition is a potent strategy to reduce bacterial virulence and alleviate the negative impact on host immune response.AimThis study investigates how secreted factors from P. aeruginosa PAO1, cultured in the presence or absence of the QS inhibitor sodium salicylate (NaSa), influence host immune response.Material and methodsIn vitro, THP-1 macrophages and neutrophil-like HL-60 cells were used. In vivo, discs of titanium were implanted in a subcutaneous rat model with local administration of P. aeruginosa culture supernatants. The host immune response to virulence factors contained in culture supernatants (+/-NaSa) was characterized through cell viability, migration, phagocytosis, gene expression, cytokine secretion, and histology.ResultsIn vitro, P. aeruginosa supernatants from NaSa-containing cultures significantly increased THP-1 phagocytosis and HL-60 cell migration compared with untreated supernatants (-NaSa). Stimulation with NaSa-treated supernatants in vivo resulted in: (i) significantly increased immune cell infiltration and cell attachment to titanium discs; (ii) increased gene expression of IL-8, IL-10, ARG1, and iNOS, and (iii) increased GRO-α protein secretion and decreased IL-1β, IL-6, and IL-1α secretion, as compared with untreated supernatants.ConclusionIn conclusion, treating P. aeruginosa with NaSa reduces the production of virulence factors and modulates major immune events, such as promoting phagocytosis and cell migration, and decreasing the secretion of several pro-inflammatory cytokines.

Abstract Pyrophosphate-containing calcium phosphate implants promote osteoinduction and bone regeneration. The role of pyrophosphate for inflammatory cell-mesenchymal stem cell (MSC) cross-talk during osteogenesis is not known. In the present work, the effects of lipopolysaccharide (LPS) and pyrophosphate (PPi) on primary human monocytes and on osteogenic gene expression in human adipose-derived MSCs were evaluated in vitro, using conditioned media transfer as well as direct effect systems. Direct exposure to pyrophosphate increased nonadherent monocyte survival (by 120% without LPS and 235% with LPS) and MSC viability (LDH) (by 16–19% with and without LPS). Conditioned media from LPS-primed monocytes significantly upregulated osteogenic genes (ALP and RUNX2) and downregulated adipogenic (PPAR-γ) and chondrogenic (SOX9) genes in recipient MSCs. Moreover, the inclusion of PPi (250 μM) resulted in a 1.2- to 2-fold significant downregulation of SOX9 in the recipient MSCs, irrespective of LPS stimulation or culture media type. These results indicate that conditioned media from LPS-stimulated inflammatory monocytes potentiates the early MSCs commitment towards the osteogenic lineage and that direct pyrophosphate exposure to MSCs can promote their viability and reduce their chondrogenic gene expression. These results are the first to show that pyrophosphate can act as a survival factor for both human MSCs and primary monocytes and can influence the early MSC gene expression. Graphical abstract

This study aims to increase the understanding of how learning environments have been developed for newly arrived immigrant pupils in need of special educational support measures according to special educators. In this way, knowledge can be deepened about obstacles and opportunities in the school system regarding the development of learning environments, which can have an impact on these pupils' learning. Free text responses from an e-questionnaire were analyzed through conventional content analysis. The analysis revealed varied descriptions of what characterizes the development of learning environments at schools. For example, many respondents described what characterizes as general adaptations as a kind of one size fits all solutions. Special educators also described support for language learning and language understanding in small groups, training for school staff and enhanced collaborations. The characterization of special educators´ descriptions is deepened and discussed with regard to obstacles and opportunities in the school system. To deepen the understanding, the results from this study are analyzed together with previous research and Skrtic's (1991; 2005) concept of the school system, reflecting school bureaucracies and adhocracy. The obstacles in the development of learning environments are found in special solutions, lack of efforts and unclear areas of responsibility, while successes are found in training for school staff and enhanced collaborations in joint professional work.

BackgroundDiet and physical activity (PA) are modifiable risk factors thought to influence the risk of ischemic stroke (IS). However, few studies have examined their effect on different subtypes of IS.AimTo examine components of overall diet quality and different types of PA in relation to the risk of atherothrombotic IS (aIS).Materials and methodsThe study population included 23,797 participants (mean age 58 years; 63% women) from the Malmö Diet and Cancer Study cohort. Participants were enrolled between 1991 and 1996 and followed until end of 2016 (median follow-up 21.5 years). Incident aIS events were identified using national registries (total cases 1,937). Measures of PA (total, leisure-time, occupational, and domestic) were assessed using a baseline questionnaire and dietary intakes were estimated using a modified diet history method. Overall diet quality was assessed using a diet quality index. Intake of key food groups and beverages associated with overall diet quality were investigated separately. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression models adjusting for confounders.ResultsA high diet quality with high intake of fruit and vegetables, fish and shellfish and low intake of sugar-sweetened beverages and red and processed meat compared to a low diet quality was associated with lower risk of aIS (HR = 0.82, 95% CI = 0.69–0.97; p = 0.015). Leisure-time PA was associated with reduced risk of aIS (HR = 0.95 per SD increase in MET-hours/week, 95% CI = 0.91–0.99; p = 0.028) with null associations observed for total, occupational and domestic PA level. We observed no significant interaction between diet and PA on the risk of aIS. The standardized 20-year risk of aIS among subjects with low leisure-time PA and low diet quality was 8.1% compared to 6.1% among those with high leisure-time PA and high diet quality.ConclusionSeveral components of a healthy diet and being physically active may reduce the risk of aIS, however, the absolute risk reduction observed was modest. A high diet quality seemed to have a risk reducing effect regardless of level of PA suggesting that individuals with a sedentary lifestyle may still gain some positive health benefits through a healthy diet.

Abstract Background Forest harvesting changes forest habitat and impacts forest dependent species. Uneven-aged management is often considered better for biodiversity than even-aged management, but there is an ongoing discourse over the benefits and disadvantages of different silvicultural systems. This systematic review contributes to the public discussion and provides evidence for policy making by synthesising current evidence on impacts of even-aged and uneven-aged forest management on biodiversity in boreal forests of Fennoscandia and European Russia. In this review even-aged and uneven-aged forest management are compared directly to each other as well as to natural forest to provide a broad basis for public discussion. Methods Both peer-reviewed and grey literature were searched in bibliographical databases, organizational webpages and internet search engines in English, Finnish, Swedish and Russian. Articles were screened for relevance by their title/abstract and again by full text. The inclusion of studies was assessed against pre-defined criteria published in an a priori protocol. A narrative synthesis and meta-analysis were conducted to describe the evidence base and to compare species richness and abundance between differently managed forests. The influence of habitat specialism, taxon, years since harvesting, deadwood availability and harvesting intensity on species richness and abundance were also tested. Review findings Searching identified 43,621 articles of which 137 articles with 854 studies had independent data and were included in the narrative synthesis. Of those, 547 studies were included in the meta-analysis. The most studied taxa were arthropods, vascular plants, bryophytes, fungi, and lichens. Results showed that forests with less disturbance (uneven-aged and mature even-aged) host more forest dependent species than young even-aged forests ( 80 years old). Uneven-aged forest had similar number of species and individuals than natural forest whereas even-aged forest had less species than natural forest. Open habitat species and their individuals were more numerous in young even-aged forests and forests undergone retention harvest. Effect sizes found were mostly large indicating strong and uniform impact of forest management based on species’ habitat preferences. In addition to habitat specialism, years since harvest explained some of the differences found in species richness and abundance due to increase of open habitat species in the early successional stages and forest dependent species in late successional stages. Taxon had limited explanatory power. Conclusions Habitat preferences determine species’ response to different harvesting methods and the magnitude of effect is large. Less disturbance from harvesting is better for forest dependent species whereas opposite is true for open habitat species. Uneven-aged and mature even-aged forests (> 80 years old) are important to maintain biodiversity in boreal forests. However, the results also highlight that natural forests are needed to ensure the future of forest dependent species in Fennoscandia and European Russia. Given that a broader set of biodiversity aspects are to be protected, best overall biodiversity impacts for a variety of species at landscape level can be achieved by ensuring that there is a mosaic of different forests within landscapes.

Abstract Background In boreal zone forest management is changing and degrading forest habitats, which has caused declines in biodiversity. To mitigate these harmful effects in production forests, small-scale habitats with high biodiversity values have been protected within them. These habitats include woodland key habitats, and other small habitat patches protected by voluntary conservation actions. In this systematic review we synthesize the evidence on the value of small protected habitat patches (SPHP) within production forest landscapes for biodiversity. Review question: Are small protected habitat patches within boreal production forests effective in conserving species richness, abundance, and community composition? Methods Both peer-reviewed and grey literature were searched from bibliographical databases, organizational websites and internet search engines in English, Finnish, Swedish and Russian. Articles were screened at two stages (title/abstract and full text) and the validity of the included studies were assessed. Screening and validity assessment were based on predetermined criteria. After data extraction, narrative and quantitative syntheses were conducted. Influences of effect modifiers were tested, and sensitivity analyses were conducted. Review findings During the searches 19,458 articles were found. After duplicate removal and title/abstract screening 336 articles remained. During full text screening 41 articles were included and 35 of them (174 studies) were included in narrative synthesis. 28 articles with 127 studies had suitable data for meta-analysis. SPHPs had significantly higher species richness compared to production forests. When compared to natural forests, there was no significant difference. Forest management in areas surrounding SPHPs did not have impact on species richness of these patches. Individual abundance was significantly higher in SPHPs compared to natural or production forests. There was significantly more dead wood in SPHPs compared to production forests, but when compared to natural forests there was no significant difference. Community composition was different between SPHPs and both production and natural forests. Conclusions The findings of this review show that small protected patches within production forests are important part of biodiversity conservation. They cannot substitute larger protected areas but supplement the protected area network. However, there were gaps both in geographical distribution of the studies as well as in the selection of target species of the studies. Therefore, generalization of the results must be done carefully.

Abstract Background Several studies show that the enhanced recovery after surgery (ERAS) program reduces complications postoperatively and leads to faster recovery and shorter hospital stays. However, little is known about patients’ self-reported health in an enhanced recovery context. The aim of this study was firstly to describe patient experiences of health within the concept of ERAS after colorectal (CR) surgery during a hospital stay and within 2 weeks of discharge. Secondly, to explore whether the ASA classification/co-morbidity, sex, and surgical method affect the patient’s experience of health. Methods Data were collected through the ERAS-HEALTH questionnaire, including two open-ended questions, and through telephone interviews postoperatively. Qualitative and quantitative analysis was used. Patients undergoing CR surgery (n = 80) were included from October 2016 to June 2018. Results The patients had mainly positive experiences of their hospital stay as well as most of them felt comfortable coming home. However, experienced state of health is affected by factors like surgical method and co-morbidity. Improvements were desired concerning information, food/food intake, pain management, and environment. At home, the patients experienced a lack of information about food/food intake and ostomy care. Decreased appetite and difficulties with micturition were also described. The most troublesome symptom was postoperative fatigue (POF). Analysis of the ERAS-HEALTH questionnaire showed that patients with higher co-morbidity and those who underwent open surgery have a significantly worse experience of their health compared with patients who underwent laparoscopy. However, it seems that the surgical method affects postoperative health to a greater extent than co-morbidity. Conclusions The patients reported many positive aspects and challenges when being cared for within the ERAS program. However, several improvements are needed to satisfy patient wishes regarding their care both in hospital and at home. Laparoscopic surgery affects patient state of health positively in several respects compared with open surgery.

Abstract Background The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer. Results To analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Conclusions Our analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions.

Abstract Background Forest harvesting is the main driver of habitat degradation and biodiversity loss in forests of the boreal zone. To mitigate harmful effects, small-scale habitats with high biodiversity values have been protected within production forests. These include woodland key habitats, and other small-scale habitat patches protected by voluntary conservation action. This article describes a protocol for a systematic review to synthesize the value of small habitat patches left within production landscapes for biodiversity. The topic for this systematic review arose from a discussion with the Finnish forestry sector and was further defined in a stakeholder workshop. Research question: Do small protected habitat patches within production forests provide value for biodiversity conservation in boreal forests? Animal, plant and fungal diversities are addressed as well as the amount of deadwood within the habitat patches as proxy indicators for biodiversity. Methods The literature, both peer-reviewed and grey, will be searched from bibliographical databases, organizational websites and internet search engines in English, Finnish, Swedish and Russian. Article screening will be done at two stages (title/abstract and full-text). The validity of the studies included will be evaluated against validity criteria and studies will be categorized based on their risk of bias. To describe the findings a narrative synthesis will be conducted. If there is enough quantitative data retrieved from the studies, a meta-analysis will be conducted.

This article describes an intervention to design and test a method for employee-driven innovation and a model for learning among managers and development leaders. The empirical basis for the intervention focused on personal assistants in the home service within a municipality in Sweden. The intervention was carried out using action research in on a series of workshops with a group of employees, managers, development leaders. Using a “stage” and “stands” theatre metaphor, employees engaged in collective, innovative learning “on the stage” combined with observations and reflections from managers and development leaders “in the stands”. This article contributes a method that can generate creative ideas among the employees and a model that can stimulate experience-based learning through observations. The intervention also shows that action research can be used to develop and test methods and models.

Abstract Background Biodiversity is vital for human well-being, but is threatened by human actions world-wide. In the boreal zone, harvesting and management of forests on an industrial scale is the most important factor driving habitat change and degradation. Over time different forest management regimes have been implemented but their impact on biodiversity at different spatial and temporal scales has not been systematically reviewed although non-systematic reviews on the topic exist. The aim of this article is to describe a protocol for a systematic review to synthesise and compare the impacts of two different forest management systems on biodiversity at different spatial and temporal scales. The topic for the systematic review arose from the discussions with the Finnish forestry sector and was further defined in a stakeholder workshop. Research questions addressed by the systematic review protocol are: (1) What are the stand-level effects of even-aged and uneven-aged forest management on boreal forest biodiversity in Fennoscandia and European Russia? (2) What is the effect of these same forest management systems on biodiversity at landscape level? Methods Animal, plant, and fungal diversity is addressed. Bibliographic databases and organizational websites will be searched, and internet search engines will be utilized to find relevant literature. The searches will be conducted in English, Finnish, Swedish, and Russian. Articles will be screened regarding the inclusion and exclusion criteria at title, abstract, and full-text stage. The validity of included studies will be evaluated against appraisal criteria and studies categorized based on their risk of bias. A narrative synthesis will be conducted to describe the findings. If enough quantitative data can be retrieved from the studies, a meta-analysis will be conducted.

Improving the effectiveness of anti-cancer immunotherapy remains a major clinical challenge. Cytotoxic T cell infiltration is crucial for immune-mediated tumor rejection, however, the suppressive tumor microenvironment impedes their recruitment, activation, maturation and function. Nevertheless, solid tumors can harbor specialized lymph node vasculature and immune cell clusters that are organized into tertiary lymphoid structures (TLS). These TLS support naïve T cell infiltration and intratumoral priming. In many human cancers, their presence is a positive prognostic factor, and importantly, predictive for responsiveness to immune checkpoint blockade. Thus, therapeutic induction of TLS is an attractive concept to boost anti-cancer immunotherapy. However, our understanding of how cancer-associated TLS could be initiated is rudimentary. Exciting new reagents which induce TLS in preclinical cancer models provide mechanistic insights into the exquisite stromal orchestration of TLS formation, a process often associated with a more functional or “normalized” tumor vasculature and fueled by LIGHT/LTα/LTβ, TNFα and CC/CXC chemokine signaling. These emerging insights provide innovative opportunities to induce and shape TLS in the tumor microenvironment to improve immunotherapies.

Summary: Due to limited current therapies, metastases are the primary cause of mortality in cancer patients. Here, we employ a fusion compound of the cytokine LIGHT and a vascular targeting peptide (LIGHT-VTP) that homes to angiogenic blood vessels in primary tumors. We show in primary mouse lung cancer that normalization of tumor vasculature by LIGHT-VTP prevents cancer cell intravasation. Further, LIGHT-VTP efficiently targets pathological blood vessels in the pre-metastatic niche, reducing vascular hyper-permeability and extracellular matrix (ECM) deposition, thus blocking metastatic lung colonization. Moreover, we demonstrate that mouse and human metastatic melanoma deposits are targetable by VTP. In overt melanoma metastases, LIGHT-VTP normalizes intra-metastatic blood vessels and increases GrzB+ effector T cells. Successful treatment induces high endothelial venules (HEVs) and lymphocyte clusters, which sensitize refractory lung metastases to anti-PD-1 checkpoint inhibitors. These findings demonstrate an important application for LIGHT-VTP therapy in preventing metastatic development as well as exerting anti-tumor effects in established metastases. : Treatment options for metastatic cancer are limited. He et al. develop a cytokine therapy that specifically targets leaky blood vessels in the pre-metastatic niche and established lung metastases. Treatment repairs vessel leakiness, prevents outgrowth of circulating cancer cells, and also sensitizes already established lung metastases for checkpoint inhibition. Keywords: metastasis, angiogenesis, vessel normalization, tertiary lymph node structures, immunotherapy, high endothelial venules, pre-metastatic niche, peptide tumor targeting

Abstract Background The initiation of growth cessation and dormancy represent critical life-history trade-offs between survival and growth and have important fitness effects in perennial plants. Such adaptive life-history traits often show strong local adaptation along environmental gradients but, despite their importance, the genetic architecture of these traits remains poorly understood. Results We integrate whole genome re-sequencing with environmental and phenotypic data from common garden experiments to investigate the genomic basis of local adaptation across a latitudinal gradient in European aspen (Populus tremula). A single genomic region containing the PtFT2 gene mediates local adaptation in the timing of bud set and explains 65% of the observed genetic variation in bud set. This locus is the likely target of a recent selective sweep that originated right before or during colonization of northern Scandinavia following the last glaciation. Field and greenhouse experiments confirm that variation in PtFT2 gene expression affects the phenotypic variation in bud set that we observe in wild natural populations. Conclusions Our results reveal a major effect locus that determines the timing of bud set and that has facilitated rapid adaptation to shorter growing seasons and colder climates in European aspen. The discovery of a single locus explaining a substantial fraction of the variation in a key life-history trait is remarkable, given that such traits are generally considered to be highly polygenic. These findings provide a dramatic illustration of how loci of large-effect for adaptive traits can arise and be maintained over large geographical scales in natural populations.

Aging skeletal muscle shows declining numbers and activity of satellite cells. Here, Franco et al. show that in satellite cells of the human leg muscle vastus lateralis, somatic mutations accumulate with age and that these mutations become enriched in exons and promoters of genes involved in muscle function.

Atherosclerotic cardiovascular disease (ACVD) is the leading cause of death worldwide. This study aimed to investigate the association between diet and lifestyle factors, beyond traditional risk factors, and the risk of incident ACVD. The Malmö Diet and Cancer study included 30,446 middle-aged individuals. Baseline examinations including a dietary assessment, questionnaire and interviews, were performed between 1991–1996. After excluding individuals with prevalent cardiovascular disease and atrial fibrillation or flutter, 26,990 participants remained. In a previously developed diet quality index, adherence to recommended intake of saturated fat (SFA), polyunsaturated fat (PUFA), fish and shellfish, fiber, vegetables and fruit, and sucrose results in one point per dietary component, with a maximum diet score of six points. Diagnosis of incident ACVD was based on validated diagnoses of coronary artery disease, atherothrombotic ischemic stroke, carotid artery disease or peripheral artery disease. Multivariable Cox regression analysis adjusting for established risk factors was performed to assess hazard ratios (HR) with 95% confidence intervals (CI). After a median follow-up of 21.1 years, 5858 (21.7%) individuals diagnosed with ACVD unrelated to atrial fibrillation or flutter were identified. Higher diet score (HR 0.94/point increase; 95% CI 0.91–0.97; p < 0.001), intake of fish and shellfish (HR 0.95/standard deviation (SD) increment, 95% CI 0.93–0.98), fiber (HR 0.93/SD increment, 95% CI 0.89–0.98) and SFA (HR 0.96/SD increment, 95% CI 0.92–0.99) consumption were associated with decreased risk for incident ACVD. High leisure-time physical activity (HR 0.82, 95% CI 0.74–0.91) was associated with reduced risk and obesity (HR 1.17, 95% CI 1.08–1.27) with increased risk of incident ACVD. The present study strengthens current recommendations of improving diet quality and increasing physical activity in preventing ACVD.

Risk factors for ischemic stroke is suggested to differ by etiologic subtypes. The purpose of this study was to examine the associations between modifiable and non-modifiable risk factors and atherothrombotic stroke (i.e., excluding cardioembolic stroke), and to examine if the potential benefit of modifiable lifestyle factors differs among subjects with and without predisposing comorbidities. After a median follow-up of 21.2 years, 2339 individuals were diagnosed with atherothrombotic stroke out of 26,547 study participants from the Malmö Diet and Cancer study. Using multivariable Cox regression, we examined non-modifiable (demographics and family history of stroke), semi-modifiable comorbidities (hypertension, dyslipidemia, diabetes mellitus and atherosclerotic disease), and modifiable (smoking, body mass index, diet quality, physical activity, and alcohol intake) risk factors in relation to atherothrombotic stroke. Higher age, male gender, family history of stroke, and low educational level increased the risk of atherothrombotic stroke as did predisposing comorbidities. Non-smoking (hazard ratio (HR) = 0.62, 95% confidence interval (CI) 0.56–0.68), high diet quality (HR = 0.83, 95% CI 0.72–0.97) and high leisure-time physical activity (HR = 0.89, 95% CI 0.80–0.98) decreased the risk of atherothrombotic ischemic stroke independent of established risk factors, with non-significant associations with body mass index and alcohol intake. The effect of the lifestyle factors was independent of predisposing comorbidities at baseline. The adverse effects of several cardiovascular risk factors were confirmed in this study of atherothrombotic stroke. Smoking cessation, improving diet quality and increasing physical activity level is likely to lower risk of atherothrombotic stroke in the general population as well as in patient groups at high risk.

One of the most prominent features of digital music services is the provision of personalized music recommendations that come about through the profiling of users and audiences. Based on a range of "bot experiments," this article investigates if, and how, gendered patterns in music recommendations are provided by the streaming service Spotify. While our experiments did not give any strong indications that Spotify assigns different taste profiles to male and female users, the study showed that male artists were highly overrepresented in Spotify's music recommendations; an issue which we argue prompts users to cite hegemonic masculine norms within the music industries. Although the results should be approached as historically and contextually contingent, we argue that they point to how gender and gendered tastes may be constituted through the interplay between users and algorithmic knowledge-making processes, and how digital content delivery may maintain and challenge gender relations and gendered power differentials within the music industries. Seen through the lens of critical research on software, music and gender performativity, the experiments thus provide insights into how gender is shaped and attributed meaning as it materializes in contemporary music streams.

Abstract Background Histopathological diagnosis is important for prognostication and choice of treatment in patients with cancer in the lung. Metastases to the lungs are common and need to be distinguished from primary lung cancer. Furthermore, cases with synchronous or metachronous primary lung cancers (although infrequent) are often handled differently than cases with lung cancer with intrapulmonary metastasis or relapse, respectively. In some cases, morphology and immunohistochemical staining is not sufficient for certain diagnosis. Methods The present study included six cases where molecular genetic analysis in form of pyrosequencing or targeted next-generation sequencing was of value for certain diagnosis of selected tumours in the lung. Results Two of the included cases were rare metastases to the lung; colorectal cancer with IHC profile consistent with primary lung cancer and malignant adenomyoepithelioma of the breast, respectively, where molecular genetic analysis was of aid for proving the relationship to the primary tumour. The other four cases were multiple lung adenocarcinomas where molecular genetic analysis was of aid to distinguish between intrapulmonary metastasis and synchronous tumour. Conclusions Comparison of molecular genetic profile may be an important tool for determination of relationship between tumours in some situations and should always be considered in unclear cases. Further studies on concordance and discordance of molecular genetic profiles between spatially or temporally different tumours with common origin may be helpful for improved diagnostics of pulmonary tumours.

Normalization of the tumor vasculature is an emerging concept shown to improve anti-cancer therapy. However, there are currently no clinical interventions that effect long-lasting normalization. Here, we have developed a strategy for normalization by specific intratumoral delivery of LIGHT/TNFSF14. Importantly, normalization occurs by induced expression of contractile markers in intratumoral pericytes, which in turn re-establishes tight pericyte-vessel alignment. Restoring vessel integrity improves tumor perfusion and acts as adjuvant to chemo- and immunotherapy. Mechanistically, intratumoral LIGHT induces pericyte differentiation and normalization via Rho kinase signaling. Minute amounts of LIGHT act in a paracrine fashion to trigger an amplifying cascade involving transforming growth factor β (TGF-β) from peri-vascular macrophages. That these effects can be reproduced by adoptive transfer of LIGHT-stimulated macrophages alone demonstrates their central role in regulating pericyte differentiation. Our findings highlight a crucial role of pericyte contractile properties in vascular normalization, effected by macrophage signaling, thus providing so far unexplored anti-cancer opportunities.

One of the most prominent features of digital music services is the provision of personalized music recommendations that come about through the profiling of users and audiences. Based on a range of “bot experiments,” this article investigates if, and how, gendered patterns in music recommendations are provided by the streaming service Spotify. While our experiments did not give any strong indications that Spotify assigns different taste profiles to male and female users, the study showed that male artists were highly overrepresented in Spotify’s music recommendations; an issue which we argue prompts users to cite hegemonic masculine norms within the music industries. Although the results should be approached as historically and contextually contingent, we argue that they point to how gender and gendered tastes may be constituted through the interplay between users and algorithmic knowledge-making processes, and how digital content delivery may maintain and challenge gender relations and gendered power differentials within the music industries. Seen through the lens of critical research on software, music and gender performativity, the experiments thus provide insights into how gender is shaped and attributed meaning as it materializes in contemporary music streams.

The aim of the article is to explore the location and the meaning given to the rainbow flag in places outside the hegemonic center. Through three case studies in the global North and South, held together by a multi-ethnographic approach, as well as a certain theoretical tension between the rainbow flag as a boundary object and/or a floating signifier, we seek to study where the flag belongs, to whom it belongs, with particular focus on how. The three case studies, which are situated in a city in the Global South (Buenos Aires), in a conflict war zone in the Middle East (the West Bank) and in a racialised neighbourhood in the Global North (Sweden), share despite their diversity a peripheral location to hegemonic forms of knowledge production regimes. Central to our analysis is how the rainbow flag is given a multitude of original and radical different meanings that may challenge the colonial/Eurocentric notions which up to a certain extent are embedded in the rainbow flag.

BackgroundDiabetes mellitus (DM) and cardiovascular disease are associated with dyslipidemia, but the detailed lipid molecular pattern in both diseases remains unknown. Methods and ResultsWe used shotgun mass spectrometry to determine serum levels of 255 molecular lipids in 316 controls, 171 DM, and 99 myocardial infarction (MI) events from a cohort derived from the Malmö Diet and Cancer study. Orthogonal projections to latent structures analyses were conducted between the lipids and clinical parameters describing DM or MI. Fatty acid desaturases (FADS) and elongation of very long chain fatty acid protein 5 (ELOVL5) activities were estimated by calculating product to precursor ratios of polyunsaturated fatty acids in complex lipids. FADS genotypes encoding these desaturases were then tested for association with lipid levels and ratios. Differences in the levels of lipids belonging to the phosphatidylcholine and triacylglyceride (TAG) classes contributed the most to separating DM from controls. TAGs also played a dominating role in discriminating MI from controls. Levels of C18:2 fatty acids in complex lipids were lower both in DM and MI versus controls (DM, P=0.004; MI, P=6.0E‐06) at least due to an acceleration in the metabolic flux from C18:2 to C20:4 (eg, increased estimated ELOVL5: DM, P=0.02; MI, P=0.04, and combined elongase‐desaturase activities: DM, P=3.0E‐06; MI, P=2.0E‐06). Minor allele carriers of FADS genotypes were associated with increased levels of C18:2 (P≤0.007) and lower desaturase activity (P≤0.002). ConclusionsWe demonstrate a possible relationship between decreased levels of C18:2 in complex lipids and DM or MI. We thereby highlight the importance of molecular lipids in the pathogenesis of both diseases.

Amelogenesis imperfecta (AI) is a hereditary developmental disorder affecting the enamel of teeth. Affected patients present with tooth hypersensitivity, rapid tooth wear, or fractures of enamel as well as alterations in color and shape, all of which compromise esthetic appearance and masticatory function. Chronic conditions in childhood severely impact the whole family, affecting normal family routines and/or increasing the family’s financial burden. The aim of this study was to explore experiences and the impact on daily life of being a parent to a child with severe forms of amelogenesis imperfecta. Parents of children and adolescents with AI participated in an interview with a psychologist. The transcribed interviews were analyzed using thematic analysis. The parents talked about several concerns about having a child with AI. Four main themes emerged from the interviews: Feelings associated with passing on a hereditary disorder, knowledge decreases stress, unfamiliarity with the diagnosis, and psychosocial stress. In these main categories we identified several subthemes. Feelings associated with passing on a hereditary disorder included the subtheme of guilt/shame; knowledge decreases stress included knowledge about diagnosis in the family and support from dental health care professionals; Unfamiliarity with diagnosis included missed diagnosis, fear of not getting correct treatment, and insufficient pain control; finally, the subtheme Psychosocial stress included fear of child being bullied and emergency dental visits. The findings show that parents of children with severe amelogenesis imperfecta report similar experiences as do parents of children with other chronic and rare diseases.

Background: The Nordic countries collaborate in setting recommendations for intake of nutrients by publishing the Nordic Nutrition Recommendations (NNR). Studies exploring how well the Nordic population adheres to the NNR are limited and none are available for the metabolic syndrome (MetS) subgroup. Individuals with MetS are a large part of the adult Nordic population and their diet's nutritional quality is of great importance as it can affect the progression of MetS. Objective: To evaluate nutritional intake in a cohort of Nordic adults with MetS or MetS risk factors and their adherence to the NNR. Design: A multi-centre study was carried out in six centres in four Nordic countries (SYSDIET CoE). Participants (n=175) were 30–65 years of age, with BMI 27–38 kg/m2 and had at least two criteria for MetS. The NNR was used to evaluate the baseline nutrient intake calculated from the participants’ 4-day food diaries using national nutrient databases. Results: Less than 20% of participants consumed ≤10 E% from saturated fat as recommended in the NNR. Recommended intake (RI) of polyunsaturated fat was met by approximately one-third of participants. Only 20% of men and 26% of women met the RI of dietary fibre. Intake below the defined lower intake level of 2.5 µg/day for vitamin D was observed in nearly 20% of participants. The daily median intake of salt was 8.8 g for men and 6.7 g for women. Conclusion: Dietary quality of this Nordic population with Mets or MetS risk factors is unsatisfactory and characterised by high intakes of SFA and sodium and low intakes of PUFA and dietary fibre. Vitamin D intake was below RI level in a large part of the population. Authorities in the Nordic countries are encouraged to develop intervention programmes for high-risk groups.

The responses of Arabidopsis accessions and characterized genotypes were used to explore components in the early defense responses to the soilborne fungus Verticillium longisporum. V. longisporum susceptibility was found to be a complex trait, in which different disease phenotypes, such as stunting, altered flowering time, weight loss, and chlorosis were perceived differently across genotypes. A Bay-0 × Shahdara recombinant inbred line population was used to identify two loci on chromosomes 2 and 3 of Bay-0 origin that caused enhanced chlorosis after V. longisporum challenge. Furthermore, the observation that a mutation in RFO1 in Col-0 resulted in susceptibility whereas the natural rfo1 allele in Ty-0 showed a high degree of resistance to the pathogen supports the hypothesis that several resistance quantitative trait loci reside among Arabidopsis accessions. Analysis of mutants impaired in known pathogen response pathways revealed an enhanced susceptibility in ein2-1, ein4-1, ein6-1, esa1-1, and pad1-1, but not in other jasmonic acid (JA)-, ethylene (ET)-, or camalexin-deficient mutants, suggesting that V. longisporum resistance is regulated via a hitherto unknown JA- and ET-associated pathway. Pretreatments with the ET precursor 1-aminocyclo-propane-1-carboxylic acid (ACC) or methyl jasmonate (MeJA) caused enhanced resistance to V. longisporum. Mutants in the salicylic acid (SA) pathway (eds1-1, NahG, npr1-3, pad4-1, and sid2-1) did not show enhanced susceptibility to V. longisporum. In contrast, the more severe npr1-1 allele displayed enhanced V. longisporum susceptibility and decreased responses to ACC or MeJA pretreatments. This shows that cytosolic NPR1, in addition to SA responses, is required for JA- and ET-mediated V. longisporum resistance. Expression of the SA-dependent PR-1 and PR-2 and the ET-dependent PR-4 were increased 7 days postinoculation with V. longisporum. This indicates increased levels of SA and ET in response to V. longisporum inoculation. The R-gene signaling mutant ndr1-1 was found to be susceptible to V. longisporum, which could be complemented by ACC or MeJA pretreatments, in contrast to the rfo1 T-DNA mutant, which remained susceptible, suggesting that RFO1 (Fusarium oxysporum resistance) and NDR1 (nonrace specific disease resistance 1) activate two distinct signaling pathways for V. longisporum resistance.

This article explores the benefits of political discourse theory in the analysis of self harm video blogs. It is argued that a reworked concept of ‘dislocation’ (e.g. Laclau 1985, 1990; Glynos & Howarth 2007) can shed light on the chaotic experiences prior to the act of self harm, and it is further claimed that this act, as well as the practice of video blogging, can be seen as responses to the dislocatory experience. On the explicit level, the videos often challenge the stigma of self harm, and especially the stigma of self injury scars. However, drawing on Glynos and Howarth’s four dimensions of social practices (social, political, ethical, ideological), the article demonstrates how many of the video blogs simultaneously contest and conform to this stigmatisation. It is suggested that a categorisation according to the four dimensions can be used as a first step in the analysis ofsocial practices.

The aim of this article is to examine the construction of psychiatry and patienthood in personal accounts of self-harm. Drawing on interviews and dialogues from Internet message boards, I show that the relationship between psychiatry and the self-harming patient is often critically framed. Psychiatry is said to pay too much attention to acts of self-harm instead of trying to understand the patient's thoughts and feelings. This particular construction of psychiatry enables different identities for the patients. On the one hand, they are defined in terms of their problematic behaviours and thus positioned as entirely pathological. On the other hand, this also opens up for agency and acts of resistance against the asymmetrical power relations in psychiatric care.

In this article I discuss how a certain mood — in this case a complex one, summarized in the word suffering — takes material, physical and linguistic shape, and how the feeling, expressed through certain aesthetics, becomes the means for social positioning. My focus is on young people in specific subcultures, where suffering is regarded as something attractive and desirable. Giving physical shape to suffering is for these people a way to present themselves as unique and different from the mainstream culture with its "superficial happiness". At the same time, there is a hierarchy within these subcultural settings, where the ones with the most "cred" have the highest rank. Cred is a sort of symbolic capital which is principally about being authentic. To stand out as suffering in an authentic way, you need to find a balance between showing too much or too little. Irony is an important part of this balancing act.

Librarians may exclude people accidentally. This is so because there is a widespread use of classifications and subject headings reflecting the heterosexual norm. Critical classification theory tackles this norm for the reason that it affects the retrieval of gay literature. In order to allow a reconsideration of this exclusive practice in the LIS community I challenge two main questions: Firstly, how does the heterosexual norm appear in classification systems and subject headings lists? And secondly, what are the consequences of that practice for the retrieval of gay literature?This paper focuses on the professional practise in Swedish public libraries. If subject cataloguing prevents Lesbians, Gays, Bisexuals and Transgender (LGBT) finding their literatures, then Swedish public libraries are upholders of the exclusive heterosexual norm in society.