The TLR4 D299G and T399I SNPs Are Constitutively Active to Up-Regulate Expression of Trif-Dependent Genes

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Exploring patients’ experiences of analgesia after major lower limb amputation: A qualitative study

OBJECTIVES: To explore patient experiences, understanding and perceptions of analgesia following major lower limb amputation. DESIGN: Qualitative interview study, conducted as part of a randomised controlled feasibility trial. SETTING: Participants were recruited from two general hospitals in South Wales. PARTICIPANTS: Interview participants were patients enrolled in PLACEMENT (Perineural Local Anaesthetic Catheter aftEr Major lowEr limb amputatioN Trial): a randomised controlled feasibility trial comparing the use of perineural catheter (PNC) versus standard care for postoperative pain relief following major lower limb amputation. PLACEMENT participants who completed 5-day postoperative follow-up, were able and willing to participate in a face-to-face interview, and had consented to be contacted, were eligible to take part in the qualitative study. A total of 20 interviews were conducted with 14 participants: 10 male and 4 female. METHODS: Semi-structured, face-to-face interviews were conducted with participants over two time points: (1) up to 1 month and (2) at least 6 months following amputation. Interviews were audio-recorded, transcribed verbatim and analysed using a framework approach. RESULTS: Interviews revealed unanticipated benefits of PNC usage for postoperative pain relief. Participants valued the localised and continuous nature of this mode of analgesia in comparison to opioids. Concerns about opioid dependence and side effects of pain relief medication were raised by participants in both treatment groups, with some reporting trying to limit their intake of analgesics. CONCLUSIONS: Findings suggest routine placement of a PNC following major lower limb amputation could reduce postoperative pain, particularly for patient groups at risk of postoperative delirium. This method of analgesic delivery also has the potential to reduce preoperative anxiety, alleviate the burden of pain management and minimise opioid use. Future research could further examine the comparison between patient-controlled analgesia and continuous analgesia in relation to patient anxiety and satisfaction with pain management. TRIAL REGISTRATION NUMBER: ISRCTN: 85710690; EudraCT: 2016-003544-37

Multilingual construction of Communicative Development Inventories in Southern Africa

The Communicative Development Inventories (CDIs) are a set of validated, parent-completed questionnaires assessing children's vocabulary, gesture, and grammatical development. They have many benefits but in particular administration does not require a qualified psychologist or speech-language therapist, making them ideal for settings with poor access to professionals. In addition they are cheap to administer at scale, again benefitting low resource settings. Further, they are relatively easy to develop for languages that are not well described in terms of development, meaning they can be adapted easily to under-studied languages. The CDIs have previously been adapted for Asian (1), Indo-European (2), other European (3), Pacific Island (4) and some African languages (5,6). They have been used successfully in studies of health risks (nutrition, infection) in sub-Saharan Africa (7), again meaning they are useful for impoverished settings and child development issues prevalent in such settings. We are in process of developing CDIs for six languages spoken in Southern Africa (IsiXhosa, Setswana, Sesotho, Xitsonga, Afrikaans and South African English). We have developed a common method for each language starting with a long list of words taken from other CDIs, following on to parent/practitioner assessment of face validity of these words in their translations, and continuing to piloting, instrument reduction, and validation. Within validation we look at correlation with age, and relationship to other variables including family socio-economic status, and child language performance measured in the home or lab. We also apply these methods to the assessment of gesture using the CDI. Some of the languages to be studied are related to each other (of the Bantu group of African languages) and to two languages for which CDIs have been developed in East Africa (5); for these we will highlight common grammatical development to be examined that exists in all of the related languages. In the East African setting parents were found to be valid observers of their child's morpheme omissions so this is a particular focus for assessment of grammatical development. To date we have developed four pilot versions (IsiXhosa, Setswana, Sesotho, and Afrikaans). Vocabulary in isiXhosa is found to be significantly related to toddler age, mother education, and first-born status, among other known correlates of child language (8). In Sesotho, toddler vocabulary is also significantly related to age (9). In the other languages (Xitsonga and SA English) we have created pre-pilot word lists and carried out focus groups with parents enabling us to determine the acceptability of the words on our long-lists. We conclude that construction of CDIs in multiple (some unrelated) languages simultaneously is possible with rigorous application of the same methods to each language. Where languages are under-studied, we can benefit from previous research and descriptions of development in related languages. 1.Tardif, J. Child Lang. 36, (2009). 2.Caselli, J. Child Lang. 26, (1999); Bleses, J. Child Lang. 35, (2008). 3.Barrena, in A portrait of the young in the new multilingual Spain. (2008), vol. 9. 4.Reese, First Language 35, (2015). 5.Alcock, J. Child Lang. 42, (2015). 6.Prado, Journal of Health, Population and Nutrition 37, (2018). 7.Prado, J. Child Psychol.Psychi. 58, (2017); Alcock, BMC research notes 9, (2016). 8.Whitelaw, University of Cape Town (2018). 9.Horn, Cape Town (2018)

Electric resistivity of organic conductor K-(BEDT-TTF)2Cu2(CN)3

U ovom radu su proučavana svojstva električne otpornosti u temperaturnom rasponu od ~300K (sobne temperature) do ~20K (do kuda je dostupna aparatura davala pouzdane rezultate), organskog kristala κ-(BEDT-TTF)2Cu2(CN)3. Na temelju provedenih mjerenja ispitana su slaganja rezultata mjerenja s teorijom, odnosno s Arrheniusovim zakonom i teorijom preskoka promjenjivog dosega. U metodičkom dijelu rada predstavljen je jedan način kako bi se mogao održati istraživački tip nastave na temu električnog otpora u srednoj školi sa četverogodišnjim programom fizike.The subject of this study is electric resistivity in temperature range from ~300K (room temperature) to ~20K (temperature at which available apparatus was giving reliable results), organic crystal κ-(BEDT-TTF)2Cu2(CN)3. The study examines connection between measured results and the theory, respectively with Arrhenius law and theory of variable range hopping. Educational part shows an exploratory teaching method how to present electric resistance in high school within four year program of physics

High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo

NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is an important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role in NAFLD initiation and progression to the more serious condition of NASH (non-alcoholic steatohepatitis). Herein we hypothesize that mitochondrial defects induced by exposure to a HFD (high fat diet) contribute to a hypoxic state in liver and this is associated with increased protein modification by RNS (reactive nitrogen species). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories (1 cal≈4.184 J) from fat respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, NO (nitric oxide)-dependent control of respiration, and 3-NT (3-nitrotyrosine), a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triacylglycerols, increased CYP2E1 (cytochrome P450 2E1) and iNOS (inducible nitric oxide synthase) protein, and significantly enhanced hypoxia in the pericentral region of the liver. Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls. In addition, accumulation of 3-NT paralleled the hypoxia gradient in vivo and 3-NT levels were increased in mitochondrial proteins. Liver mitochondria from mice fed the HFD for 16 weeks exhibited depressed state 3 respiration, uncoupled respiration, cytochrome c oxidase activity, and mitochondrial membrane potential. These findings indicate that chronic exposure to a HFD negatively affects the bioenergetics of liver mitochondria and this probably contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins

Integrating qualitative research within a clinical trials unit: developing strategies and understanding their implementation in contexts

Background/aims: The value of using qualitative methods within clinical trials is widely recognised. How qualitative research is integrated within trials units to achieve this is less clear. This paper describes the process through which qualitative research has been integrated within Cardiff University’s Centre for Trials Research (CTR) in Wales, UK. We highlight facilitators of, and challenges to, integration. Methods: We held group discussions on the work of the Qualitative Research Group (QRG) within CTR. The content of these discussions, materials for a presentation in CTR, and documents relating to the development of the QRG were interpreted at a workshop attended by group members. Normalisation Process Theory (NPT) was used to structure analysis. A writing group prepared a document for input from members of CTR, forming the basis of this paper. Results: Actions to integrate qualitative research comprised: its inclusion in Centre strategies; formation of a QRG with dedicated funding/roles; embedding of qualitative research within operating systems; capacity building/training; monitoring opportunities to include qualitative methods in studies; maximising the quality of qualitative research and developing methodological innovation. Facilitators of these actions included: the influence of the broader methodological landscape within trial/study design and its promotion of the value of qualitative research; and close physical proximity of CTR qualitative staff/students allowing sharing of methodological approaches. Introduction of innovative qualitative methods generated interest among other staff groups. Challenges included: pressure to under-resource qualitative components of research, preference for a statistical stance historically in some research areas and funding structures, and difficulties faced by qualitative researchers carving out individual academic profiles when working across trials/studies. Conclusions: Given that CTUs are pivotal to the design and conduct of RCTs and related study types across multiple disciplines, integrating qualitative research into trials units is crucial if its contribution is to be fully realised. We have made explicit one trials unit’s experience of embedding qualitative research and present this to open dialogue on ways to operationalise and optimise qualitative research in trials. NPT provides a valuable framework with which to theorise these processes, including the importance of sense-making and legitimisation when introducing new practices within organisations

The BioMart community portal: an innovative alternative to large, centralized data repositories.

The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations

Protocol for the development of a core outcome set for stillbirth care research (iCHOOSE Study)

IntroductionStillbirth is associated with significant physical, psychosocial and economic consequences for parents, families, wider society and the healthcare system. There is emerging momentum to design and evaluate interventions for care after stillbirth and in subsequent pregnancies. However, there is insufficient evidence to inform clinical practice compounded by inconsistent outcome reporting in research studies. To address this paucity of evidence, we plan to develop a core outcome set for stillbirth care research, through an international consensus process with key stakeholders including parents, healthcare professionals and researchers.Methods and analysisThe development of this core outcome set will be divided into five distinct phases: (1) Identifying potential outcomes from a mixed-methods systematic review and analysis of interviews with parents who have experienced stillbirth; (2) Creating a comprehensive outcome long-list and piloting of a Delphi questionnaire using think-aloud interviews; (3) Choosing the most important outcomes by conducting an international two-round Delphi survey including high-income, middle-income and low-income countries; (4) Deciding the core outcome set by consensus meetings with key stakeholders and (5) Dissemination and promotion of the core outcome set. A parent and public involvement panel and international steering committee has been convened to coproduce every stage of the development of this core outcome set.Ethics and disseminationEthical approval for the qualitative interviews has been approved by Berkshire Ethics Committee REC Reference 12/SC/0495. Ethical approval for the think-aloud interviews, Delphi survey and consensus meetings has been awarded from the University of Bristol Faculty of Health Sciences Research Ethics Committee (Reference number: 116535). The dissemination strategy is being developed with the parent and public involvement panel and steering committee. Results will be published in peer-reviewed specialty journals, shared at national and international conferences and promoted through parent organisations and charities.PROSPERO registration numberCRD42018087748.</jats:sec

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist