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Abstract Background Accidental hypothermia, recognized by core temperature below 35 °C, is a lethal condition with a mortality rate up to 25%. Hypothermia-induced cardiac dysfunction causing increased total peripheral resistance and reduced cardiac output contributes to the high mortality rate in this patient group. Recent studies, in vivo and in vitro, have suggested levosimendan, milrinone and isoprenaline as inotropic treatment strategies in this patient group. However, these drugs may pose increased risk of ventricular arrhythmias during hypothermia. Our aim was therefore to describe the effects of levosimendan, milrinone and isoprenaline on the action potential in human cardiomyocytes during hypothermia. Methods Using an experimental in vitro-design, levosimendan, milrinone and isoprenaline were incubated with iCell2 hiPSC-derived cardiomyocytes and cellular action potential waveforms and contraction were recorded from monolayers of cultured cells. Experiments were conducted at temperatures from 37 °C down to 26 °C. One-way repeated measures ANOVA was performed to evaluate differences from baseline recordings and one-way ANOVA was performed to evaluate differences between drugs, untreated control and between drug concentrations at the specific temperatures. Results Milrinone and isoprenaline both significantly increases action potential triangulation during hypothermia, and thereby the risk of ventricular arrhythmias. Levosimendan, however, does not increase triangulation and the contractile properties also remain preserved during hypothermia down to 26 °C. Conclusions Levosimendan remains a promising candidate drug for inotropic treatment of hypothermic patients as it possesses ability to treat hypothermia-induced cardiac dysfunction and no increased risk of ventricular arrhythmias is detected. Milrinone and isoprenaline, on the other hand, appears more dangerous in the hypothermic setting.

Abstract Background During hospital relocations, it is important to support healthcare professionals becoming familiar with new settings. Simulation-based training seems promising and in situ simulation has been suggested as a beneficial educational tool to prepare healthcare professionals for relocation. This study aimed to investigate the impact of a simulation-based training intervention on health professionals´ readiness to work in their new environment, as well as investigate sick leave before and after relocation. Methods The study was a controlled intervention study implemented at a university hospital in Denmark. Simulation was used to prepare employees for workflows prior to relocation. Before relocation, 1199 healthcare professionals participated in the in situ simulation-based training program. Questionnaires on readiness to perform were distributed to participants at pre-, post-, and follow-up (6 months) measurement. In addition, data on participants’ sick leave was gathered from a business intelligence portal. To compare dependent and independent groups, paired and unpaired t tests were performed on mean score of readiness to perform and sick leave. Results Compared to the control group, healthcare professionals participating in the intervention felt significantly more ready to work in a new hospital environment. As a measure of psychological wellbeing, register data indicated no difference in sick leave, when comparing intervention and control groups before and after participating in the in situ simulation-based training program. Conclusions Healthcare professionals felt significantly more ready to work in a new environment, after participating in the in situ simulation-based training program, indicating that the intervention supported healthcare professionals during relocations. This may mitigate feelings of uncertainty; however, further research is needed to explore such effects. Trial registration The study was approved by The Regional Ethics Committee (no. 1-16-02-222-22).

Abstract Background Rewarming from hypothermia is associated with severe complications, one of which is hypothermia-induced cardiac dysfunction. This condition is characterized by decreased cardiac output accompanied by increased total peripheral resistance. This contributes to mortality rate approaching 40%. Despite this, no pharmacological interventions are recommended for these patients below 30 °C. Raising the intracellular levels of cAMP and/or cGMP, through PDE3- and PDE5-inhibitors respectively, have showed the ability to alleviate hypothermia-induced cardiac dysfunction in vivo. Drugs that raise levels of both cAMP and cGMP could therefore prove beneficial in patients suffering from hypothermia-induced cardiac dysfunction. Methods The unselective PDE-inhibitor pentoxifylline was investigated to determine its ability to reach the intracellular space, inhibit PDE3 and PDE5 and inhibit cellular efflux of cAMP and cGMP at temperatures 37, 34, 30, 28, 24 and 20 °C. Recombinant human PDE-enzymes and human erythrocytes were used in the experiments. IC50-values were calculated at all temperatures to determine temperature-dependent changes. Results At 20 °C, the IC50-value for PDE5-mediated enzymatic breakdown of cGMP was significantly increased compared to normothermia (IC50: 39.4 µM ± 10.9 µM vs. 7.70 µM ± 0.265 µM, p-value = 0.011). No other significant changes in IC50-values were observed during hypothermia. Conclusions This study shows that pentoxifylline has minimal temperature-dependent pharmacodynamic changes, and that it can inhibit elimination of both cAMP and cGMP at low temperatures. This can potentially be effective treatment of hypothermia-induced cardiac dysfunction. Trial registration: Not applicable.

Introduction: Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiovascular dysfunction, which could lead to shock. Current guidelines do not recommend any pharmacological treatment at core temperatures below 30°C, due to lack of knowledge. However, previous in vivo studies have shown promising results when using phosphodiesterase 3 (PDE3) inhibitors, which possess the combined effects of supporting cardiac function and alleviating the peripheral vascular resistance through changes in cyclic nucleotide levels. This study therefore aims to investigate whether PDE3 inhibitors milrinone, amrinone, and levosimendan are able to modulate cyclic nucleotide regulation in hypothermic settings.Materials and methods: The effect of PDE3 inhibitors were studied by using recombinant phosphodiesterase enzymes and inverted erythrocyte membranes at six different temperatures—37°C, 34°C, 32°C, 28°C, 24°C, and 20°C- in order to evaluate the degree of enzymatic degradation, as well as measuring cellular efflux of both cAMP and cGMP. The resulting dose-response curves at every temperature were used to calculate IC50 and Ki values.Results: Milrinone IC50 and Ki values for cGMP efflux were significantly lower at 24°C (IC50: 8.62 ± 2.69 µM) and 20°C (IC50: 7.35 ± 3.51 µM), compared to 37°C (IC50: 22.84 ± 1.52 µM). There were no significant changes in IC50 and Ki values for enzymatic breakdown of cAMP and cGMP.Conclusion: Milrinone, amrinone and levosimendan, were all able to suppress enzymatic degradation and inhibit extrusion of cGMP and cAMP below 30°C. Our results show that these drugs have preserved effect on their target molecules during hypothermia, indicating that they could provide an important treatment option for hypothermia-induced cardiac dysfunction.

Deamidation evaluation and mitigation is an important aspect of therapeutic antibody developability assessment. We investigated the structure and function of the Asn-Gly deamidation in a human anti-CD52 IgG1 antibody light chain complementarity-determining region 1, and risk mitigation through protein engineering. Antigen binding affinity was found to decrease about 400-fold when Asn33 was replaced with an Asp residue to mimic the deamidation product, suggesting significant impacts on antibody function. Other variants made at Asn33 (N33H, N33Q, N33H, N33R) were also found to result in significant loss of antigen binding affinity. The co-crystal structure of the antigen-binding fragment bound to a CD52 peptide mimetic was solved at 2.2Å (PDB code 6OBD), which revealed that Asn33 directly interacts with the CD52 phosphate group via a hydrogen bond. Gly34, but sits away from the binding interface, rendering it more amendable to mutagenesis without affecting affinity. Saturation mutants at Gly34 were prepared and subjected to forced deamidation by incubation at elevated pH and temperature. Three mutants (G34R, G34K and G34Q) showed increased resistance to deamidation by LC-MS peptide mapping, while maintaining high binding affinity to CD52 antigen measured by Biacore. A complement -dependent cytotoxicity assay indicated that these mutants function by triggering antibody effector function. This study illustrates the importance of structure-based design and extensive mutagenesis to mitigate antibody developability issues.

[This corrects the article DOI: 10.1371/journal.pone.0227365.].

BACKGROUND:Metabolites of the kynurenine pathway (mKP) relate to important aspects of heart failure pathophysiology, such as inflammation, energy-homeostasis, apoptosis, and oxidative stress. We aimed to investigate whether mKP predict mortality in patients with heart failure. METHODS:The study included 202 patients with heart failure (73.8% with coronary artery disease (CAD)), propensity score matched to 384 controls without heart disease, and 807 controls with CAD (71%). All underwent coronary angiography and ventriculography at baseline. Plasma mKP, pyridoxal 5'phosphate (PLP) and CRP were measured at baseline. Case-control differences were assessed by logistic regression and survival by Cox regression, adjusted for age, gender, smoking, diabetes, ejection fraction, PLP, eGFR and CRP. Effect measures are reported per standard deviation increments. RESULTS:Higher plasma levels of kynurenine, 3- hydroxykynurenine (HK), quinolinic acid (QA), the kynurenine-tryptophan-ratio (KTR) and the ratio of HK to xanthurenic acid (HK/XA) were detected in heart failure compared to both control groups. The mortality rate per 1000 person-years was 55.5 in patients with heart failure, 14.6 in controls without heart disease and 22.2 in CAD controls. QA [HR 1.80, p = 0.013], HK [HR 1.77, p = 0.005], HK/XA [HR 1.67, p < 0.001] and KTR [HR 1.55, p = 0.009] were associated with increased mortality in patients with heart failure, while XA [HR 0.68-0.80, p = 0.013-0.037] were associated with lower mortality in all groups. HK and HK/XA had weak associations with increased mortality in CAD-controls. CONCLUSION:Elevated plasma levels of mKP and metabolite ratios are associated with increased mortality, independent of CAD, in patients with heart failure.

BACKGROUND:Development of motor competencies and learning of movements in children is dependent on varied physical activity (PA). After-school programs (ASP) might provide opportunities for young schoolchildren to participate in PA. The aim of the current study was to investigate the PA of first graders in ASP and to consider its contribution to the development of motor competencies and the learning of movements. METHODS:The study was performed utilizing a mixed methods design. A total of 42 first graders were sampled from 14 ASPs in Norway. Direct observations of the children's activities were conducted for the duration of one entire ASP day. PA intensity was measured using ActiGraph accelerometers. Qualitative data were analyzed using qualitative content analysis, while the Mann-Whitney U test and the Wilcoxon signed-rank test were used to analyze the quantitative data. RESULTS:The median PA time among the observed children was 61.5 minutes. The median stationary time was 75.9 minutes. There was considerable variation within the sample. Girls were significantly more engaged in stationary behavior than boys. Frequent changes in activity type and intensity were typical features of the children's ASP day. PA duration and intensity were significantly higher outdoors than indoors. Adult-managed time had longer periods of stationary behavior than child-managed time. The PA at all intensity levels contained barrier-breaking movements-especially at light intensity levels. CONCLUSION:Most of the first graders studied were engaged in a variety of activity types of different duration and intensity levels, favorable for the development of motor competencies and for the learning of movements. Hence, it is reasonable to highlight that light PA, in combination with moderate and vigorous PA, is also of great importance for children during the time they spend in ASP. Ultimately, there is a need for staff members who can also stimulate varied PA among the most stationary children.

Det virker å være stor enighet om at norske boliger er dyre, og at dette er stort problem. Vi mener at absolutte priser må ses i sammenheng med rente- og inntektsnivå. I denne analysen benytter vi sykepleierindeksen for å forsøke å svare på om bolig er dyrt eller ikke.

Persons with diabetes have increased risk of depression, however, studies addressing whether the risk varies by age and type of antidiabetic treatment have yielded conflicting results. The aim of this study was to investigate if the association between diabetes and depression varied by type of antidiabetic treatment in a large community based sample of middle-aged (40-47 years) and older adults (70-72 years).Data from 21845 participants in the Hordaland Health Study (HUSK) were analyzed in a cross-sectional design. Diabetes was assessed by self-report and classified as un-medicated, treated by oral antidiabetic agents or by insulin. Depression was defined as a score ≥ 8 on the depression subscale of the Hospital Anxiety and Depression Scale and/or self-reported use of antidepressant agents. Associations between diabetes and depression were estimated using logistic regression.Persons in their forties with diabetes had a doubled prevalence of depression (OR: 1.96 (95% C.I.: 1.35, 2.83)) compared to persons without diabetes, while a lower and non-significant association was found among persons in their seventies. Persons in their forties with orally treated diabetes had about three times higher prevalence of depression (OR: 2.92 (95% C.I.: 1.48, 5.77)) after adjustment for gender, BMI, physical activity, alcohol consumption and education, compared to non-diabetic persons in the same age-group. No association between depression and insulin or un-medicated diabetes was found.Clinicians should be aware that persons in their forties with orally treated diabetes are at a marked increased risk of depression.

The purpose of this research was to examine the ways that a metaphor could help describe and make sense of the facilitation practices of a teacher educator who collaborated in a self-study of teacher education practice project with colleagues in Norway, and an international critical friend. Our research question was: 'How does the metaphor of orchestration offer an understanding and elaboration of the complex and dynamic processes of facilitating teacher educator professional development through self-study of teacher education practices?' Data generation involved three layers composed of reflective diaries written troughout and at the end of the data generation, and audio records of pair and group meetings. The metaphor of orchestration provided insight into the ways the facilitator initiated and tried to steer dynamic and uncontrollable teaching and research practices while providing some concrete examples of how metaphors might be manifested in the practices of facilitators of professional development.

Background: The current interest in models-based practice (MBP) as an innovation and framework has necessitated deeper understanding of both what MBP is and how teacher educators teach pre-service teachers about innovative approaches such as MBP. Despite several studies of individual teacher educators enacting MBP, there are few examples of how several teacher educators might go about implementing MBP in physical education teacher education (PETE) programmes. Purpose: The purpose of this study was to develop an understanding of how a collaborative approach to teaching pre-service teachers MBP can support coherence in PETE modules. The study was guided by the question: How do teacher educators teaching in one PETE module negotiate their experience of teaching about teaching as they implement MBP? Method: This collaborative self-study of teacher education practices was conducted in a Norwegian PETE department and involved five teacher educators. The particular setting for the study was one module (what might be described elsewhere as a course or unit of study) that Lasse, Berit, Anders, and Mats were to teach to first year pre-service teachers in one PETE programme (13 females and 37 males). In addition to teaching the module, the four teacher educators acted as critical friends to one another, while Tim (who was based in Canada) offered a second layer of critical friendship to group members both individually and collectively. Data generation included two primary sources: audio records of our meetings in different configurations (21 meetings and approximately 35 hours audio) and our reflective diaries (total of 10 entries and 20 pages). Data analysis involved a five-step dialogic process of 'thinking with' Loughran's (2006. "Developing a Pedagogy of Teacher Education: Understanding Teaching and Learning About Teaching." London: Routledge) concept of developing a pedagogy of teacher education (Jackson, A. Y., and L. A. Mazzei. 2012. "Thinking with Theory in Qualitative Research: Viewing Data Across Multiple Perspectives." London: Routledge). Results: This study provides insights into the affordances of taking a collaborative approach to teaching about teaching MBP and how such a collaborative approach facilitated implementation individually and collectively. Furthermore, the study highlights the ways the several collaborative processes and structures produced the development of a shared language and vision for teaching about teaching MBP. This shared vision led to coherence in how we talked and taught about MBP with each other and with pre-service teachers. These visions helped make our individual and collective practices and their articulation coherent to ourselves and to one another, and also to the pre-service teachers whom we taught. Conclusion: Our understanding is that the development of coherent PETE programmes and the modules within those programmes requires at least: (i) a professional group of teacher educators who are willing to share their understanding, challenges, and uncertainties with one another and with pre-service teachers, (ii) an inquiry-oriented stance towards researching group and departmental beliefs and practices, and (iii) a desire to better understand and share the development of new understandings with colleagues at departmental, national, and/or international levels.