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Doxorubicin is a widely used anticancer drug that causes dose-related cardiotoxicity. The exact mechanisms of doxorubicin toxicity are still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose doxorubicin treatments. Here, we developed an in vitro model of long-term low-dose administration of doxorubicin utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Moreover, given that current strategies for prevention and management of doxorubicin-induced cardiotoxicity fail to prevent cancer patients developing heart failure, we also investigated whether the GATA4-targeted compound 3i-1000 has cardioprotective potential against doxorubicin toxicity both in vitro and in vivo. The final doxorubicin concentration used in the chronic toxicity model in vitro was chosen based on cell viability data evaluation. Exposure to doxorubicin at the concentrations of 1–3 µM markedly reduced (60%) hiPSC-CM viability already within 48 h, while a 14-day treatment with 100 nM doxorubicin concentration induced only a modest 26% reduction in hiPCS-CM viability. Doxorubicin treatment also decreased DNA content in hiPSC-CMs. Interestingly, the compound 3i-1000 attenuated doxorubicin-induced increase in pro-B-type natriuretic peptide (proBNP) expression and caspase-3/7 activation in hiPSC-CMs. Moreover, treatment with 3i-1000 for 2 weeks (30 mg/kg/day, i.p.) inhibited doxorubicin cardiotoxicity by restoring left ventricular ejection fraction and fractional shortening in chronic in vivo rat model. In conclusion, the results demonstrate that long-term exposure of hiPSC-CMs can be utilized as an in vitro model of delayed doxorubicin-induced toxicity and provide in vitro and in vivo evidence that targeting GATA4 may be an effective strategy to counteract doxorubicin-induced cardiotoxicity.

The comparison of solution processed organic photovoltaics with two roll-to-roll coated electron transport layers (ETL), as well as printed grid or solid back electrodes provides insight into the future of R2R fabricated architectures. The variation in performance of the R2R slot-die coated zinc oxide (ZnO) versus the tin oxide (SnO2), showed a clear dependence on the spectrum of the illumination source. It was found that under indoor light conditions (200–1000 lux LED and fluorescent sources) the SnO2 outperformed the ZnO with highest efficiencies near 13% and 10% respectively. This is in contrast to results obtained under 1 Sun (AM 1.5) in which the cells fabricated with a ZnO ETL had a higher power conversion efficiency than those prepared with SnO2. The results also confirm the significance of the layout of the printed silver back contact; in which cells with the grid structure outperformed those with full coverage by approximately 35% for ZnO and just under 10% for SnO2 (all light conditions). The combination of a R2R coating and S2S printing process to prepare modules with 8 cells in series (PET/ITO/SnO2/PV2001:PCBM/PEDOT:PSS/silver grid) resulted in a PCE of 13.4% under indoor office light conditions.

Tella Lantta,1 Raija Kontio,1–3 Michael Daffern,4 Clive E Adams,5 Maritta Välimäki1,6,7 1Department of Nursing Science, University of Turku, Turku, Finland; 2Helsinki University, Helsinki, Finland; 3Helsinki University Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland; 4Centre for Forensic Behavioural Science (CFBS), Swinburne University of Technology, Melbourne, VIC, Australia; 5Institute of Mental Health, University of Nottingham, Nottingham, UK; 6Turku University Hospital, Turku, Finland; 7School of Nursing, The Hong Kong Polytechnic University, Hong Kong Purpose: This paper aims to explore the acceptability of Dynamic Appraisal of Situational Aggression (DASA) from the perspective of patients, its actual use by mental health nurses, and the predictive validity of the DASA instrument. Methods: A feasibility study design incorporating quantitative and qualitative components was used. The study was conducted in three mental health inpatient units at three hospitals in southern Finland. Quantitative data were used to explore demand (nurses’ actual use of the DASA), limited efficacy (predictive validity), and acceptability (measured through patients’ participation in the project). Qualitative data were collected to enhance the understanding of acceptability by describing patients’ perceptions of the strengths and weaknesses of the DASA. Results: Nurses used the DASA for most patient assessments. The predictive validity of the DASA was outstanding or excellent, depending on the type of aggression predicted, although the patient recruitment ratio was low. Patients reported both strengths and weaknesses of the DASA, providing complementary information regarding the instrument’s acceptability and clinical application. Conclusion: The DASA accurately predicts inpatient aggression. The patients’ preferences and concerns regarding risk assessment have been noted. More patient involvement in risk assessment research and violence prevention efforts is required. Keywords: patient participation, nurses, violence, risk assessment, psychiatric hospitals, multi-method approach

Suhteitus on tärkeä betonin valmistuksen suunnitelma, jolla pyritään saamaan tuoreelle ja kovettuneella betonille halutut ominaisuudet. Tässä työssä on keskitytty betonin suhteituksen laskemiseen ryhmittelyn, luokittelun ja regression kautta. Puristuslujuus on betonin tärkein ominaisuus ja se toimii tässä työssä vastearvona luokittelussa ja regressiossa. Puristuslujuuden vastearvoja tutkitaan ennustemuuttujien eli prediktorien avulla. Ennustemuuttujina ovat esimerkiksi sementtimäärä, vesimäärä, kiviainesmäärä ja erilaisten lisäaineiden määrä. Ryhmittelyllä analysoidaan ensin näytteitä parhaiden havaintojen esille kaivamiseksi ja mahdollisten harhaisuuksien poistamiseksi. Suhteitusta voidaan suorittaa reaaliaikaisesti betoniasemalla mutta tämän tutkimuksen perusteella voidaan suhteitus ottaa yhdeksi suunnittelun osa-alueeksi. Tällöin on kuitenkin oltava betonissa reagoivien osa-aineiden käytöstä aikaisempaa tietoa, jonka avulla laskenta suoritetaan ja päätökset tehdään. Aineiston käsittely voidaan suorittaa monellakin työkalulla, mutta tässä työssä käytetään Matlab-ohjelmistoa ryvästämis-, luokittelu- ja regressioanalyysien suorittamiseksi. Työkalussa on valmiina monia valmiita toimintoja laskennan suorittamiseksi ja tulosten esittämiseksi havainnollisesti. Reseptien suunnittelijan antamaa suhteitusta siis verrataan eri menetelmien kautta muodostettuihin suhteituksiin ja annetaan korjausehdotus tai kommentti suhteitukseen, mikäli siihen on tarvetta. Kehitettyjä menetelmiä voidaan käyttää esimerkiksi betonin valmistuksen opetuksessa siten, että rakennesuunnittelu, työmaa sekä muut osapuolet luovat menestyksekkään betoniketjun. Lisäksi, menetelmät voitaisiin toteuttaa osaksi reaaliaikaisen suhteituksen prosessia. Concrete mix design is an important part of manufacturing planning aiming to achieve certain desired properties for the fresh and hardened concrete. This work focuses on the concrete mix design via clustering, classification and regression. The most important feature of hardened concrete is compressive strength. In this study, the response values of concrete compressive strength are examined with predictors. The predictive variables are for example the amount of cement, water, aggregates and various additives. With clustering the data is preprocessed before applying classification and regression. The preprocessing leads to best data samples and finding outliers. The concrete mix design can be performed in real-time at a batching plant, but it should also be taken as one action in the normal design work. Before we can get any results and make decisions, we must have historical information about the behavior of the materials. The data processing can be done in many ways, but now we focus on clustering, classification and linear regression methods with Matlab software. This software has many built-in functions and methods to perform calculations and to present the results graphically. The existing mix design can be compared to the mix design created via statistical approach. The results shall be reviewed and action taken, if needed. The results of this thesis can be used by designers, site and other relevant stakeholders involved in creating the successful concrete chain and also for training purposes. The methods developed in this thesis can be used as a part of the real-time process in batching plant.

Transcription factors are pivotal regulators of gene transcription, and many diseases are associated with the deregulation of transcriptional networks. In the heart, the transcription factors GATA4 and NKX2-5 are required for cardiogenesis. GATA4 and NKX2-5 interact physically, and the activation of GATA4, in cooperation with NKX2-5, is essential for stretch-induced cardiomyocyte hypertrophy. Here, we report the identification of four small molecule families that either inhibit or enhance the GATA4–NKX2-5 transcriptional synergy. A fragment-based screening, reporter gene assay, and pharmacophore search were utilized for the small molecule screening, identification, and optimization. The compounds modulated the hypertrophic agonist-induced cardiac gene expression. The most potent hit compound, N-[4-(diethylamino)phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide (3, IC₅₀ = 3 μM), exhibited no activity on the protein kinases involved in the regulation of GATA4 phosphorylation. The identified and chemically and biologically characterized active compound, and its derivatives may provide a novel class of small molecules for modulating heart regeneration.

Purpose To evaluate the effects of lanreotide Autogel on patient-reported outcomes and association with biochemical control, using PRIMARYS data. Methods PRIMARYS was a 1-year, open-label study of lanreotide Autogel (Depot in USA) 120 mg every 4 weeks in 90 treatment-naïve patients with acromegaly. Symptoms were assessed using Patient-assessed Acromegaly Symptom Questionnaire (PASQ) and health-related quality of life (HRQoL) using the AcroQoL questionnaire. Correlations between PASQ and AcroQoL scores, and between PASQ/AcroQoL and growth hormone (GH)/insulin-like growth factor-1 (IGF-1) levels were also evaluated (post hoc). Results Acromegaly symptoms and HRQoL significantly improved from week 12 to week 48, with modest correlations at week 48 between PASQ total score (R = –0.55, p 50 % of baseline standard deviation) in PASQ total score and >40 % achieved a MID in AcroQoL global score (post hoc). Changes in PASQ scores were similar in biochemically controlled (GH levels ≤2.5 μg/L and normal IGF-1 levels) and uncontrolled groups, while changes in global and psychological AcroQoL scores were greater in the controlled group. There was no correlation between changes in PASQ or AcroQoL scores and changes in GH or IGF-1 levels. Conclusions Primary treatment with lanreotide Autogel over 1 year was associated with rapid and sustained improvements in clinical signs and symptoms and HRQoL in patients with acromegaly. Improvements in HRQoL, but not symptoms, were greater in those achieving biochemical control (ClinicalTrials.gov: NCT00690898; EudraCT: 2007–000155–34). Electronic supplementary material The online version of this article (doi:10.1007/s11102-015-0693-y) contains supplementary material, which is available to authorized users.

Tässä työssä on keskitytty betonin suhteituksen laskemiseen lineaarisen regression kautta. Suhteitus on tärkeä betonin valmistuksen suunnitelma, jolla pyritään saamaan tuoreelle ja kovettuneella betonille halutut ominaisuudet. Puristuslujuus on betonin tärkein ominaisuus ja se toimii tässä työssä vastearvona. Puristuslujuuden vastearvoja tutkitaan ennustemuuttujien eli prediktorien avulla. Ennustemuuttujina ovat esimerkiksi sementtimäärä, vesimäärä, kiviainesmäärä ja erilaisten lisäaineiden määrä. Suhteitusta voidaan suorittaa reaaliaikaisesti betoniasemalla mutta mielestäni se tulisi ottaa yhdeksi suunnittelun osa-alueeksi. Tällöin on kuitenkin oltava betonissa reagoivien osa-aineiden käytöstä aikaisempaa tietoa, jonka avulla laskenta suoritetaan ja päätökset tehdään. Aineiston käsittelyä voidaan tehdä monellakin tavalla mutta nyt keskitytään lineaarisella regressiolla laskettaviin menetelmiin Matlab-ohjelmalla. Matlab-ohjelmassa on valmiina monia valmiita toimintoja laskennan suorittamiseksi ja tulosten esittämiseksi havainnollisesti. This work is focused on the concrete mix design calculation via linear regression. Concrete mix-design is important manufacturing plan, which aims to get desired properties into fresh and hardened concrete. Compressive strength of hardened concrete is the most important feature. Response values of concrete compressive strength are examined with predictors. Predictive variables are for example the amount of cement, water, aggregates and various additives. Concrete mix-design work can be performed in real-time in batching plant, but it should be taken as one action on normal design work. Before we can get any results and make decisions, we must have previous information about the behavior of the materials. The data processing can be done in many ways, but now we focus on the linear regression methods with a software Matlab. Matlab program has many ready-made functions and methods to perform calculations and present the results graphically.

Aims: Transcription factor GATA4 is a dosage sensitive regulator of heart development and alterations in its level or activity lead to congenital heart disease (CHD). GATA4 has also been implicated in cardiac regeneration and repair. GATA4 action involves combinatorial interaction with other cofactors such as NKX2‐5, another critical cardiac regulator whose mutations also cause CHD. Despite its critical importance to the heart and its evolutionary conservation across species, the structural basis of the GATA4‐NKX2‐5 interaction remains incompletely understood. Methods and results: A homology model was constructed and used to identify surface amino acids important for the interaction of GATA4 and NKX2‐5. These residues were subjected to site-directed mutagenesis, and the mutant proteins were characterized for their ability to bind DNA and to physically and functionally interact with NKX2‐5. The studies identify 5 highly conserved amino acids in the second zinc finger (N272, R283, Q274, K299) and its C–terminal extension (R319) that are critical for physical and functional interaction with the third alpha helix of NKX2‐5 homeodomain. Integration of the experimental data with computational modeling suggests that the structural arrangement of the zinc finger–homeodomain resembles the architecture of the conserved DNA binding domain of nuclear receptors. Conclusions: The results provide novel insight into the structural basis for protein-protein interactions between two important classes of transcription factors. The model proposed will help to elucidate the molecular basis for disease causing mutations in GATA4 and NKX2‐5 and may be relevant to other members of the GATA and NK classes of transcription factors.

Context: Methodological shortcomings often compromise investigations into the effects of primary somatostatin-analog treatment on tumor size in acromegaly. There are also limited data for the long-acting lanreotide formulation. Objective: The aim of the study was to better characterize the effects of primary lanreotide Autogel treatment on tumor size in patients with GH-secreting macroadenomas. Design: PRIMARYS was a 48-week, multicenter, open-label, single-arm study. Setting: The study was conducted at specialist endocrine centers. Patients: Treatment-naïve acromegalic patients with GH-secreting macroadenomas participated in the study. Intervention: Lanreotide Autogel 120 mg was administered sc every 28 days (without dose titration). Outcome Measures: The primary endpoint was the proportion of patients with clinically significant (≥20%) tumor volume reduction (TVR) at week 48/last post-baseline value available using central assessments from three readers. The null hypothesis (H0) for the primary endpoint was that the proportion with TVR was ≤55%. Secondary endpoints included: TVR at other time points, GH and IGF-1, acromegalic symptoms, quality of life (QoL), and safety. Results: Sixty-four of 90 (71.1%) patients completed the study. Clinically significant TVR at 48 weeks/last post-baseline value available was achieved by 62.9% (95% confidence interval, 52.0, 72.9) of 89 patients in the primary analysis (intention-to-treat population; H0 not rejected) and 71.9–75.3% in sensitivity (n = 89) and secondary analyses (n = 63) (H0 rejected). At 12 weeks, 54.1% had clinically significant TVR. Early and sustained improvements also occurred in GH and IGF-1, acromegalic symptoms, and QoL. No patients withdrew due to gastrointestinal intolerance. Conclusions: Primary treatment with lanreotide Autogel, administered at 120 mg (highest available dose) without dose titration, in patients with GH-secreting macroadenomas provides early and sustained reductions in tumor volume, GH and IGF-1, and acromegalic symptoms, and improves QoL.

Aims and objectives. The aim of this study was to investigate, using Rasch model analysis, the measurement invariance of the item ratings of the Individualised Care Scale. Background. Evidence of reliability is needed in cross-cultural comparative studies. To be used in different cultures and languages, the items must function the same way. Design. A methodological and comparative design. Methods. Secondary analysis of data, gathered in 2005-2006 from a cross-cultural survey using the Individualised Care Scale from Finnish, Greek, Swedish and English predischarge hospitalised orthopaedic and trauma patients (n=1093), was used. The Rasch model, which produces calibrations (item locations and rank) and item fit statistics, was computed using the Winstep program. Results. The rank of average Individualised Care Scale item calibrations (-2·26-1·52) followed a generally similar trend (Infit≤1·3), but slight differences in the item rank by country were found and some item misfit was identified within the same items. There was some variation in the order and location of some Individualised Care Scale items for individual countries, but the overall pattern of item calibration was generally corresponding. Conclusions. The Rasch model provided information about the appropriateness, sensitivity and item function in different cultures providing more in-depth information about the psychometric properties of the Individualised Care Scale instrument. Comparison of the four versions of the Individualised Care Scale - patient revealed general correspondence in the item calibration patterns although slight differences in the rank order of the items were found. Some items showed also a slight misfit. Based on these results, the phrasing and targeting of some items should be considered. Relevance to clinical practice. The Individualised Care Scale - Patient version can be used in cross-cultural studies for the measurement of patients' perceptions of individualised care. Information obtained with the use of the Individualised Care Scale in clinical nursing practice is important, and valid measures are needed in evaluating patients' assessment of individualised care, one indicator of care quality. © 2012 Blackwell Publishing Ltd.

This paper reports results from a large recent study of the public domain in the European Union. Based on a combination of catalogue, commercial and survey data we present detailed fi gures both on the prices (and price di fferences) of in copyright and public domain material and on the usage of that material. Combined with the estimates for the size of the EU public domain presented in the companion paper Pollock and Stepan (2009) our results allow us to provide the fi rst quantitative estimate for the `value' of the public domain (i.e. welfare gains from its existence) in any jurisdiction.

Aim. This paper is a report of a study of internationally-based differences in nurses' perceptions of individualized care in orthopaedic surgical in-patient wards. Background. Individualized care is valued in healthcare policy, practice and ethical statements as an indicator of care quality. However, nurses' assessments of individualized care are limited and comparative cross-cultural studies on individualized nursing care are lacking. Methods. A descriptive comparative survey was used to sample orthopaedic surgical nurses (n=1163) working in 91 inpatient wards in 34 acute hospitals in Finland, Cyprus, Greece, Portugal, Sweden, Turkey and the United States of America. Data were collected between March and November 2009 using the Individualized Care Scale-Nurse and analysed using descriptive and inferential statistics. Results. Nurses in different countries perceived that they supported patients' individuality generally and provided individualized care during nursing activities. Although the highest scores were in support of patients' individuality in the clinical situation both through nursing provision and nurses' perceptions of individuality, there were between-country differences within these scores. Generally, the Greek and American nurses gave the highest scores and the Turkish, Cypriot and Portuguese nurses the lowest. Conclusions. Between-country differences found may be attributed to differing roles of nurses, care processes, healthcare systems and/or the ways nursing care is defined and organized. As this was the first time the Individualized Care Scale-Nurse was used in an international context, the results are formative and indicate the need to continue studies in this area. © 2011 Blackwell Publishing Ltd.

Rationale: Cross-cultural comparative studies using reliable and valid instruments can increase awareness of the differences and similarities between health worker's ability to respond to patients' individual needs within different health systems. This will enable a better understanding of cultural perspectives in individualized nursing care. Aim: To describe the translation and adaptation process of the Individualized Care Scale (ICS) and examine its reliability and validity in a cross-cultural study. Design: A cross-sectional comparative study. Settings: Twenty-seven orthopaedic and trauma in-patient units at 14 hospitals in 5 countries. Participants: A total of 1126 patients were included in the study: Finland (n = 425), Greece (n = 315), Sweden (n = 218), UK (n = 135) and USA (n = 33). Methods: A systematic forward- and back-translation procedure using bilingual techniques, a committee approach, pretest techniques and pilot testing were used with a convenience sample to produce a valid ICS for each participating group. Psychometric evaluation of the adapted ICS was based on means, SD, missing data analysis, Cronbach's alpha coefficients and average inter-item correlations. Construct validity was examined using sub-scale correlations to total scales and principal components analysis. Results: The use of the range of options and the sub-scale mean scores ranging from 2.72 to 4.30 demonstrated the sensitivity of the scale. Cronbach's alpha coefficients (0.77-0.97) and average inter-item correlations (0.37-0.77) were acceptable. The sub-scale correlations to total scales were high (0.83-0.97). The underlying theoretical construct of the ICS was demonstrated by the explained variances ranging from 58% to 79%. Conclusions: The ICS shows promise as a tool for evaluating individualized care in European cultures. The international expansion of an existing instrument developed for one country facilitates comparative studies across countries. There is a need to further test the construct validity and appropriateness of the ICS in different settings in European and nonwestern cultures. © 2010 The Authors. Journal compilation © 2010 Nordic College of Caring Science.

Aim. To compare English, Finnish, Greek and Swedish orthopaedic and trauma patients' perceptions of nursing care received during hospitalisation. Background. Patient perceptions are important when evaluating nursing care delivery. Evaluations usually take place sub-nationally though European citizens may be treated throughout the European Union. International comparative studies are possible because of the universal nature and philosophical roots of quality in nursing care. They are needed to assist in improving care outcomes. Design. A cross-sectional, comparative study design was used. Method. The Schmidt Perception of Nursing Care Survey was used to obtain data from orthopaedic and trauma patients in acute hospitals in four countries: Finland (n = 425, response rate 85%), Greece (n = 315, 86%), Sweden (n = 218, 73%) and UK (n = 135, 85%). Data were first analysed using descriptive statistics, then between-country comparisons were computed inferentially using a one-way analysis of variance and a univariate analysis of covariance. Results. Between-country differences were found in patients' perceptions of the nursing care received. Over the whole Schmidt Perception of Nursing Care Survey the Swedish and Finnish patients gave their care the highest assessments and the Greek patients the lowest. The same trend was seen in each of the four sub-scales: Seeing The Individual Patient, Explaining, Responding and Watching. Responding was given the highest assessments in each participating country and Seeing the Individual Patient the lowest except in Greece. Conclusions. Further research is needed to consider whether the between-country differences found are caused by differences between cultures, nursing practices, roles of healthcare personnel or patients in the different countries. The Schmidt Perception of Nursing Care Survey is suitable for the assessment of European orthopaedic and trauma patients' perceptions of nursing care received during hospitalisation. Relevance to clinical practice. The results are useful in evaluating and developing nursing care in hospitals from different European countries. © 2009 Blackwell Publishing Ltd.

Background: Although individualised nursing care is considered a core value in nursing in different countries, international comparative studies in this area are rare. In Western countries, common hospitalised patients, e.g. orthopaedic patients, often perceive health care as impersonal rather than individualised; a term which may also have different connotations in different cultures. Objectives: To describe and compare orthopaedic and trauma patients' perceptions of individuality in their care in four European countries. Design: A cross-sectional comparative study. Settings: 24 orthopaedic and trauma wards in 13 acute care hospitals. Participants: Data were collected from orthopaedic and trauma patients in Finland (n = 425, response rate 85%), Greece (n = 315, 86%), Sweden (n = 218, 73%) and UK (n = 135, 58%) between March 2005 and December 2006. Methods: Questionnaire survey data using the Individualised Care Scale (ICS) were obtained and analysed using descriptive and inferential statistics including frequencies, percentages, means, standard deviations, 95% confidence intervals (CI), one-way analysis of variance (ANOVA), χ2 statistics and univariate analysis of covariance (ANCOVA). Results: Patients perceived that nurses generally supported their individuality during specific nursing interventions and perceived individuality in their care. There were some between-country differences in the results. Patients' individuality in the clinical situation and in decisional control over their care were also generally well supported and taken into account. However, patients' personal life situation was not supported well through nursing interventions and these patients perceived lower levels of individualised care. Conclusions: North-South axis differences in patients' perceptions of individualised care may be attributed to the way nursing care is defined and organised in different European countries. Differences may be due to the differences in regional samples, and so no firm conclusions can be made. Further research will be needed to examine the effect of patient characteristics' and health care organisation variables in association with patients' perceptions of individualised care. © 2008 Elsevier Ltd. All rights reserved.

Objective: To analyze the effects of informational support, desire for behavioral involvement in health decision-making (behavioral involvement), opportunities to make decisions, and independence on subjective health status in surgical patients. A theoretical model of self-determination was applied and tested. Methods: The data were collected by structured questionnaires with a sample of 1,454 surgical patients in five European countries. LISREL analyses were used to test the theoretical causal model of self-determination. Results: Patients' perceptions of informational support received from nursing professionals and their desired involvement in health decision-making affected patients' opportunities to make decisions and further their independence level, which in turn affected patients' subjective health status. Conclusions: Understanding of factors that increase self-determination in patients can help health care professionals to promote patients' well-being. ©2004 Sigma Theta Tau International.