| 1. |
- Kattge, Jens, et al.
(författare)
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TRY plant trait database - enhanced coverage and open access
- 2020
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Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Tidskriftsartikel (refereegranskat)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 2. |
- Begley, Cecily, 1954, et al.
(författare)
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Evaluation of an intervention to increase vaginal birth after caesarean section through enhanced women-centred care: The OptiBIRTH randomised trial (ISRCTN10612254)
- 2017
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Ingår i: 31th ICM Triennial Congress.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Vaginal birth after a previous caesarean (VBAC) is a safe alternative to repeat caesarean section (CS), is the preferred option of most women and may reduce overall CS rates.1 However, VBAC rates vary; e.g., rates in Germany, Ireland and Italy are considerably lower (29-36%) than those in the Netherlands, Sweden and Finland (45-55%). Purpose/Objective: To evaluate the effectiveness of an intervention to maximise VBAC rates. The OptiBIRTH Project was funded by a European Union Grant: FP7-HEALTH-2012-INNOVATION-1-HEALTH.2012.3.2-1. Agreement No:305208 Method: A cluster randomised trial was used. A sample size of 12 maternity units was required, each recruiting 120 consenting women, to detect an absolute 15% difference in successful VBACs (increase from 25% in control to 40% in intervention groups), using an ICC of 0.05, with power of >80% and an alpha of 0.05. To allow for loss to follow-up, 15 trial units were randomised across three countries with low VBAC rates (Germany, Ireland and Italy) and the trial commenced April 2014. An evidence-based intervention was introduced in all intervention sites. Control sites had usual care. Interim analysis by an independent Data Monitoring Committee at mid-point permitted continuation. Data were analysed using intention to treat. Key Findings: Recruitment closed October 2015, with the last babies born in December 2015, and data analysis will be completed in April 2016. The primary outcome, comparison of annual VBAC rates for each hospital before and after introduction of the intervention will be presented, and selected secondary outcomes for the recruited women including: mode of birth, perineal trauma, breastfeeding, uterine rupture, wound breakdown, perinatal mortality, Apgar scores, and admission to neonatal intensive care unit. Discussion: If the OptiBIRTH intervention increases VBAC rates safely, its introduction across Europe could prevent 160,000 unnecessary CSs every year, saving maternity services >€150 million annually and contributing to the normalisation of birth for thousands of women. References: 1 Cunningham et al (2010). National Institute of Health Consensus Development Conference Statement: Vaginal birth after caesarean. Obstet & Gynecol 115(6): 1279-1295. 2 EURO-PERISTAT 2008: CD006066.EURO-PERISTAT Project (2008). European Perinatal Health Report. (www.europeristat.com).
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| 3. |
- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 4. |
- Clarke, Mike, et al.
(författare)
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OptiBIRTH: a cluster randomised trial of acomplex intervention to increase vaginalbirth after caesarean section
- 2020
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Ingår i: BMC Pregnancy and Childbirth. - : Springer Science and Business Media LLC. - 1471-2393 .- 1471-2393.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite evidence supporting the safety of vaginal birth after caesarean section (VBAC), rates are lowin many countries.Methods: OptiBIRTH investigated the effects of a woman-centred intervention designed to increase VBAC ratesthrough an unblinded cluster randomised trial in 15 maternity units with VBAC rates < 35% in Germany, Ireland andItaly. Sites were matched in pairs or triplets based on annual birth numbers and VBAC rate, and randomised, 1:1 or 2:1, intervention versus control, following trial registration. The intervention involved evidence-based education ofclinicians and women with one previous caesarean section (CS), appointment of opinion leaders, audit/peer review,and joint discussions by women and clinicians. Control sites provided usual care. Primary outcome was annualhospital-level VBAC rates before the trial (2012) versus final year of the trial (2016). Between April 2014 and October2015, 2002 women were recruited (intervention 1195, control 807), with mode-of-birth data available for 1940women.Results: The OptiBIRTH intervention was feasible and safe across hospital settings in three countries. There was nostatistically significant difference in the change in the proportion of women having a VBAC between interventionsites (25.6% in 2012 to 25.1% in 2016) and control sites (18.3 to 22.3%) (odds ratio adjusted for differences betweenintervention and control groups (2012) and for homogeneity in VBAC rates at sites in the countries: 0.87, 95% CI:0.67, 1.14, p = 0.32 based on 5674 women (2012) and 5284 (2016) with outcome data. Among recruited womenwith birth data, 4/1147 perinatal deaths > 24 weeks gestation occurred in the intervention group (0.34%) and 4/782in the control group (0.51%), and two uterine ruptures (one per group), a rate of 1:1000.Conclusions: Changing clinical practice takes time. As elective repeat CS is the most common reason for CS inmultiparous women, interventions that are feasible and safe and that have been shown to lead to decreasingrepeat CS, should be promoted. Continued research to refine the best way of promoting VBAC is essential. Thismay best be done using an implementation science approach that can modify evidence-based interventions inresponse to changing clinical circumstances.Trial registration: The OptiBIRTH trial was registered on 3/4/2013. Trial registration number ISRCTN10612254.
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| 5. |
- Falster, Daniel, et al.
(författare)
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AusTraits, a curated plant trait database for the Australian flora
- 2021
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Ingår i: Scientific Data. - : Nature Portfolio. - 2052-4463. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- We introduce the AusTraits database - a compilation of values of plant traits for taxa in the Australian flora (hereafter AusTraits). AusTraits synthesises data on 448 traits across 28,640 taxa from field campaigns, published literature, taxonomic monographs, and individual taxon descriptions. Traits vary in scope from physiological measures of performance (e.g. photosynthetic gas exchange, water-use efficiency) to morphological attributes (e.g. leaf area, seed mass, plant height) which link to aspects of ecological variation. AusTraits contains curated and harmonised individual- and species-level measurements coupled to, where available, contextual information on site properties and experimental conditions. This article provides information on version 3.0.2 of AusTraits which contains data for 997,808 trait-by-taxon combinations. We envision AusTraits as an ongoing collaborative initiative for easily archiving and sharing trait data, which also provides a template for other national or regional initiatives globally to fill persistent gaps in trait knowledge.
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| 6. |
- Lu, Ying-Jie, et al.
(författare)
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Interleukin-17A mediates acquired immunity to pneumococcal colonization.
- 2008
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Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 4:9
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Tidskriftsartikel (refereegranskat)abstract
- Although anticapsular antibodies confer serotype-specific immunity to pneumococci, children increase their ability to clear colonization before these antibodies appear, suggesting involvement of other mechanisms. We previously reported that intranasal immunization of mice with pneumococci confers CD4+ T cell-dependent, antibody- and serotype-independent protection against colonization. Here we show that this immunity, rather than preventing initiation of carriage, accelerates clearance over several days, accompanied by neutrophilic infiltration of the nasopharyngeal mucosa. Adoptive transfer of immune CD4+ T cells was sufficient to confer immunity to naïve RAG1(-/-) mice. A critical role of interleukin (IL)-17A was demonstrated: mice lacking interferon-gamma or IL-4 were protected, but not mice lacking IL-17A receptor or mice with neutrophil depletion. In vitro expression of IL-17A in response to pneumococci was assayed: lymphoid tissue from vaccinated mice expressed significantly more IL-17A than controls, and IL-17A expression from peripheral blood samples from immunized mice predicted protection in vivo. IL-17A was elicited by pneumococcal stimulation of tonsillar cells of children or adult blood but not cord blood. IL-17A increased pneumococcal killing by human neutrophils both in the absence and in the presence of antibodies and complement. We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines.
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| 7. |
- Lundgren, Ingela, 1957, et al.
(författare)
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Clinicians' views of factors of importance for improving the rate of VBAC (vaginal birth after caesarean section) : a study from countries with low VBAC rates.
- 2016
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Ingår i: BMC Pregnancy and Childbirth. - : Springer Science and Business Media LLC. - 1471-2393 .- 1471-2393. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Caesarean section (CS) rates are increasing worldwide and the most common reason is repeat CS following previous CS. For most women a vaginal birth after a previous CS (VBAC) is a safe option. However, the rate of VBAC differs in an international perspective. Obtaining deeper knowledge of clinicians' views on VBAC can help in understanding the factors of importance for increasing VBAC rates. Focus group interviews with clinicians and women in three countries with high VBAC rates (Finland, Sweden and the Netherlands) and three countries with low VBAC rates (Ireland, Italy and Germany) are part of "OptiBIRTH", an ongoing research project. The study reported here aims to explore the views of clinicians from countries with low VBAC rates on factors of importance for improving VBAC rates.METHODS: Focus group interviews were held in Ireland, Italy and Germany. In total 71 clinicians participated in nine focus group interviews. Five central questions about VBAC were used and interviews were analysed using content analysis. The analysis was performed in each country in the native language and then translated into English. All data were then analysed together and final categories were validated in each country.RESULTS: The findings are presented in four main categories with several sub-categories: 1) "prameters for VBAC", including the importance of the obstetric history, present obstetric factors, a positive attitude among those who are centrally involved, early follow-up after CS and antenatal classes; 2) "organisational support and resources for women undergoing a VBAC", meaning a successful VBAC requires clinical expertise and resources during labour; 3) "fear as a key inhibitor of successful VBAC", including understanding women's fear of childbirth, clinicians' fear of VBAC and the ways that clinicians' fear can be transferred to women; and 4) "shared decision making - rapport, knowledge and confidence", meaning ensuring consistent, realistic and unbiased information and developing trust within the clinician-woman relationship.CONCLUSIONS: The findings indicate that increasing the VBAC rate depends on organisational factors, the care offered during pregnancy and childbirth, the decision-making process and the strategies employed to reduce fear in all involved.
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| 8. |
- Lundgren, Ingela, 1957, et al.
(författare)
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How can the VBAC rates be improved – according to midwives and obstetricians in six European countries.
- 2017
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Ingår i: 31th ICM Trienníal Congress 18-22 June 2017.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: The most common reason for caesarean section (CS) is repeat CS following previous CS. Vaginal birth after CS (VBAC) rates vary widely in different healthcare settings and countries. Interview studies with clinicians and women in three countries with high VBAC rates (Finland, Sweden and the Netherlands) and three countries with low VBAC rates (Ireland, Italy and Germany) are part of ‘OptiBIRTH’, a research project funded by EU aiming to increase VBAC rates across Europe through enhanced woman-centred maternity care. Purpose/Objective: To investigate the views of clinicians on factors of importance for improving VBAC rates. Method: Individual interviews and focus group interviews with clinicians in six countries with high and low VBAC rates were conducted during 2012–2013. 115 clinicians participated: 61 midwives and 54 physicians. Five questions about VBAC were used and interviews were analysed using content analysis. The analysis was performed in each country in the native language, translated into English, analysed together, and finally categories were validated in each country. Key Findings: According to midwives and obstetricians from countries with high VBAC rates, the important factors for improving the VBAC rate are a common approach, obstetricians’ final decision on the mode of birth, support during birth, and the strengthening of women’s trust in VBAC. Therefore the structure of the maternity care system in the country, cooperation between midwives and obstetricians, and the care offered during pregnancy and birth should be focused. Findings from the low VBAC countries will be presented at the conference and shows similarities in some aspects but also major differences. Discussion: Similarities and differences between factors of importance for improving the VBAC rate are related to both the care structure, and the views and attitudes of midwives and physicians, which has implications for the care of women post CS.
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| 9. |
- Nelson, Michelle H., et al.
(författare)
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The Bispecific Tumor Antigen-Conditional 4-1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies
- 2023
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Ingår i: Molecular Cancer Therapeutics. - 1538-8514. ; 22:1, s. 89-101
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Tidskriftsartikel (refereegranskat)abstract
- 4-1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4-1BB on tumor-specific cytotoxic T cells makes 4-1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4-1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4-1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4-1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4-1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4-1BB-mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.
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| 10. |
- Nilsson, Christina, 1959, et al.
(författare)
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Vaginal Birth After Caesarean: Views of women from countries with low VBAC rates
- 2017
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Ingår i: Women and Birth. - : Elsevier BV. - 1871-5192 .- 1878-1799. ; 30:6, s. 481-490
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Tidskriftsartikel (refereegranskat)abstract
- Problem and background: Vaginal birth after caesarean section is a safe option for the majority of women. Seeking women´s views can be of help in understanding factors of importance for achieving vaginal birth in countries where the vaginal birth rates after caesarean is low. Aim: To investigate women’s views on important factors to improve the rate of vaginal birth after caesarean in countries where vaginal birth rates after caesarean rates are low. Methods: A qualitative study using content analysis. Data were gathered through focus groups and individual interviews with 51 women, in their native languages, in Germany, Ireland and Italy. The women were asked five questions about vaginal birth after caesarean. Data were translated to English, analysed together and finally validated in each country. Findings: Important factors for the women were that all involved in caring for them were of the same opinion about vaginal birth after caesarean section, thet they experience shared decision-making with clinicians supportive of vaginal birth, receive correct information, are sufficently prepared for a vaginal birth, and experience a culture that supports vaginal birth after caesarean section. Discussion and conclusion: Women’s decision-making about vaginal birth after caesarean in these countries involves a complex, multidimensional interplay of medical, psychological, social, cultural, personal and practical considerations. Further research is needed to explore if the information deficit women report negatively affects their ability to make informed choices, and to understand what matters most to women when making decisions about vaginal birth after caesarean as a mode of birth.
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| 11. |
- Rader, Romina, et al.
(författare)
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Non-bee insects are important contributors to global crop pollination.
- 2016
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 113:1, s. 146-151
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Tidskriftsartikel (refereegranskat)abstract
- Wild and managed bees are well documented as effective pollinators of global crops of economic importance. However, the contributions by pollinators other than bees have been little explored despite their potential to contribute to crop production and stability in the face of environmental change. Non-bee pollinators include flies, beetles, moths, butterflies, wasps, ants, birds, and bats, among others. Here we focus on non-bee insects and synthesize 39 field studies from five continents that directly measured the crop pollination services provided by non-bees, honey bees, and other bees to compare the relative contributions of these taxa. Non-bees performed 25-50% of the total number of flower visits. Although non-bees were less effective pollinators than bees per flower visit, they made more visits; thus these two factors compensated for each other, resulting in pollination services rendered by non-bees that were similar to those provided by bees. In the subset of studies that measured fruit set, fruit set increased with non-bee insect visits independently of bee visitation rates, indicating that non-bee insects provide a unique benefit that is not provided by bees. We also show that non-bee insects are not as reliant as bees on the presence of remnant natural or seminatural habitat in the surrounding landscape. These results strongly suggest that non-bee insect pollinators play a significant role in global crop production and respond differently than bees to landscape structure, probably making their crop pollination services more robust to changes in land use. Non-bee insects provide a valuable service and provide potential insurance against bee population declines.
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| 12. |
- Sinclair, Marlene, et al.
(författare)
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A systematic literature review of computer-based behavioural change interventions to inform the design of an online VBAC intervention for the OptiBIRTH European randomized trial.
- 2017
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Ingår i: Evidence Based Midwifery. - 1479-4489. ; 15:1, s. 5-13
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The aim of this research was o systematically review computer-based, behavior change (BC) interventions during pregnancy and their design components in order to determine their best application within the context of the OptiBIRTH intervention. Design: A systematic literature review was undertaken using the Cochrane collaboration guidelines for systematic reviews of health promotion and public health interventions. Literature searches were conducted in; Ovid MEDLINE, PubMed, Cochrane Library, Embase, PsycINFO, from database inception to June 2015. Cochrane Risk of Bias criteria was applied to assess the methodological quality of the papers and a taxonomy of BC techniques was used to appraise the interventions. PICO. Participants included healthy pregnant women who were ≥18 years old. The types of intervention used were computer-based interventions designed to facilitate a BC approach in a sample of pregnant women. The comparison was routine antenatal care. The primary outcome included improved health behavior(s), as an indicator of the intention behind the intervention design. Results. A total of 343 papers were identified through database-searching and hand- searching methods; 80 duplicates were removed. From the remaining 263, 244 did not explicitly address the subject under review. Therefore, 19 full text articles were assessed for eligibility; 16 did not meet eligibility criteria and were excluded at this stage. This resulted in a total of three studies being selected for inclusion in this review (Jackson et al, 2011; Tzilos et al, 2011; Tsoh et al, 2010). The computer-based interventions were designed to bring about BC in relation to alcohol consumption, smoking or diet and exercise during pregnancy. Interventions delivered varied between two types; purely computer-delivered (Tzilos et al. 2011) or a combination of both computer plus face-to-face input (Jackson et al, 2011; Tsoh et al. 2010). Techniques used included motivational interviewing, problem solving cognitive dissonance and goal setting. Types of measurement outcomes varied but were all self-reported behavioral outcomes. Statistically significant improvements in behavioral outcomes were seen in the interventions by Jackson et al (2011) and Tsoh et al (2011), but not in the intervention by Tzilos et al (2011). The GRADE analysis identified that all studies combined lacked blinding and relied on self-reported data increasing risk of bias. Conclusion. This systematic review reports on the best available evidence and theory to design an online component of a complex intervention for use in an RCT to enhance women´s shared decision-making experience about vaginal births after caesarean (VBAC). The review reports the differences between the observed BC approach and that of a decision-making being focused on a more healthy option. As a result, techniques designed to create dissonance are considered appropriate. Shared decision-making, however, is conceptually different, in that the goal is to facilitate a woman in discovering the best direction of travel for her as person. Therefore, the authors argue that it is crucial for healthcare professionals designing complex healthcare interventions (either BC techniques or shared decision-making) to ensure that a person´s self-determination is respected through having access to relevant and understandable information and healthcare professionals who understand a woman´s motivation. However, it is not possible to draw firm conclusions from three studies and there is a requirement for further research.
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| 13. |
- Sinclair, Marlene, et al.
(författare)
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Assisting women in autonomous decision making about vaginal birth after C section (VBAC): Designing motivational Apps in OptiBIRTH cluster randomised trial (ISRCTN10612254
- 2017
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Ingår i: 31th ICM Triennial Congress 18-22 June 2017.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Optibirth is a funded FP7 research programme using a cluster randomised trial in Ireland, Germany and Italy, with 15 clusters of 94 women per cluster. The aim of OptiBIRTH is to evaluate the effectiveness of a complex intervention aimed at increased VBAC rates through enhanced women-centred care1 .The intervention consisted of motivationally enhanced, evidence-based, educational information for women and clinicians for use in face to face and online modes. Purpose/Objective: This paper reports the design process associated with creating three interrelated mobile apps, as part of a complex intervention, to enable women with a previous caesarean section to decide autonomously between a repeat caesarean section and a vaginal birth. The emphasis has been on using technology creatively and effectively maximizing optimality bearing in mind the needs of the new “Z” generation. Method: Focus groups were undertaken across six European countries to illicit women’s need for information about caesarean section and VBAC. Motivational theory underpinned the development of subsequent e-learning materials to enhance woman-led-decision-making. Ethical approval was obtained from Trinity College University, Dublin. Following analysis of focus group data, consultation with experts and exploration of technological solutions, three electronic applications were designed. Following three iterations, the Apps were reviewed for content, motivational design and functionality by Irish, German and Italian midwifery experts and translated into German and Italian. Key Findings: The following interrelated Apps were designed to provide women and health professionals with rapid access to women’s perceptions of their previous birth experience and their current decision-making-in-progress: “My birth story” uses a wordle to communicate past birth experience “My birth thoughts” enables women to communicate their current decision making “My Birth plan” generates a personalised birth plan Discussion: Discussion will focus on challenges facing midwives including, embedding the Apps into a motivationally-designed portal, staff support and training, timeline, cultural differences and translation issues
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| 14. |
- Wheeler, Eleanor, et al.
(författare)
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Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis
- 2017
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Ingår i: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI0.55-0.74) of African American adults with T2Dto remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
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