1,117 research outputs found

    KH domains with impaired nucleic acid binding as a tool for functional analysis

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    In eukaryotes, RNA-binding proteins that contain multiple K homology (KH) domains play a key role in coordinating the different steps of RNA synthesis, metabolism and localization. Understanding how the different KH modules participate in the recognition of the RNA targets is necessary to dissect the way these proteins operate. We have designed a KH mutant with impaired RNA-binding capability for general use in exploring the role of individual KH domains in the combinatorial functional recognition of RNA targets. A double mutation in the hallmark GxxG loop (GxxG-to-GDDG) impairs nucleic acid binding without compromising the stability of the domain. We analysed the impact of the GDDG mutations in individual KH domains on the functional properties of KSRP as a prototype of multiple KH domain-containing proteins. We show how the GDDG mutant can be used to directly link biophysical information on the sequence specificity of the different KH domains of KSRP and their role in mRNA recognition and decay. This work defines a general molecular biology tool for the investigation of the function of individual KH domains in nucleic acid binding proteins

    Does the cancer drugs fund lead to faster uptake of cost-effective drugs? A time-trend analysis comparing England and Wales

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    BACKGROUND: The Cancer Drugs Fund (CDF) provides £200 million annually in England for ‘anti-cancer' drugs. METHODS: We used a controlled pre-/post-intervention design to compare IMS Health dispensing data for 15 cancer drugs (2007–2012) in England vs Wales, stratified by pre-CDF NICE drug approval status (rejected, mixed recommendations, recommended, not appraised). RESULTS: The CDF was associated with increased prescribing in England for three of five drugs rejected or with mixed NICE recommendations. The prescribing volume ratios (PVR) ranged from 1.29 (95% CI 1.00, 1.67) for sorafenib to 3.28 (2.59, 4.14) for bevacizumab (NICE rejected) and 0.93 (0.81, 1.06) and 1.35 (1.21, 1.49) for sunitinib and imatinib respectively (mixed recommendations). Post CDF prescribing in England increased for both drugs awaiting NICE appraisal pre-CDF (lapatinib PVR=7.44 (5.81, 9.54), panitumumab PVR=5.40 (1.20, 24.42)) and subsequently rejected. The CDF was not associated with increased prescribing in England of NICE-recommended drugs. The three most recently launched, subsequently recommended drugs were adopted faster in Wales (from pazopanib PVR=0.51 (0.28, 0.96) to abiraterone PVR=0.78 (0.61–0.99)). INTERPRETATION: These data indicate that the CDF is used to access drugs deemed not cost-effective by NICE. The CDF did not expedite access to new cost-effective cancer agents prior to NICE approval

    Results of an international survey on the investigation and endovascular management of cerebral vasospasm and delayed cerebral ischemia

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    Background: Delayed cerebral ischemia (DCI) is a major cause of morbidity and mortality in aneurysmal subarachnoid hemorrhage. Endovascular management of this condition offers a new hope in preventing adverse outcome; however, a uniform standard of practice is lacking owing to a paucity of clinical trials. We conducted an international survey on the use of investigative and endovascular techniques in the treatment of DCI to assess the variability of current practice. Methods: Neurovascular neurosurgeons and neuroradiologists were contacted through professional societies from America, United Kingdom, Europe, and Australasia. Members were invited to complete a 13-item questionnaire regarding screening techniques, first-line and second-line therapies in endovascular intervention, and the role of angioplasty. Answers were compared using χ2 testing for nonparametric data. Results: Data from 344 respondents from 32 countries were analyzed: 167 non-United States and 177 U.S. respondents. More than half of all clinicians had 10+ years of experience in units with a mixture of higher and lower case volumes. Daily transcranial Doppler ultrasonography was the most commonly used screening technique by both U.S. (70%) and non-U.S. (53%) practitioners. Verapamil was the most common first-line therapy in the United States, whereas nimodipine was most popular in non-U.S. countries. Angioplasty was performed by 83% of non-U.S. and 91% of U.S. clinicians in the treatment of vasospasm; however, more U.S. clinicians reported using angioplasty for distal vasospasm. Conclusions: Treatment practices for DCI vary considerably, with the greatest variability in the choice of agent for intra-arterial therapy. Our data demonstrate the wide variation of approaches in use at present. However, without further clinical trials and development of a uniform standard of best practice, variability in treatment and outcome for DCI is likely to continue

    A systematic review of the clinical effectiveness and cost-effectiveness of pharmacological and psychological interventions for the management of obsessive-compulsive disorder in children/adolescents and adults

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    BACKGROUND: Obsessive-compulsive disorder (OCD) is a relatively common and disabling condition. OBJECTIVES: To determine the clinical effectiveness, acceptability and cost-effectiveness of pharmacological and psychological interventions for the treatment of OCD in children, adolescents and adults. DATA SOURCES: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Trials Registers, which includes trials from routine searches of all the major databases. Searches were conducted from inception to 31 December 2014. REVIEW METHODS: We undertook a systematic review and network meta-analysis (NMA) of the clinical effectiveness and acceptability of available treatments. Outcomes for effectiveness included mean differences in the total scores of the Yale-Brown Obsessive-Compulsive Scale or its children's version and total dropouts for acceptability. For the cost-effectiveness analysis, we developed a probabilistic model informed by the results of the NMA. All analyses were performed using OpenBUGS version 3.2.3 (members of OpenBUGS Project Management Group; see www.openbugs.net ). RESULTS: We included 86 randomised controlled trials (RCTs) in our systematic review. In the NMA we included 71 RCTs (54 in adults and 17 in children and adolescents) for effectiveness and 71 for acceptability (53 in adults and 18 in children and adolescents), comprising 7643 and 7942 randomised patients available for analysis, respectively. In general, the studies were of medium quality. The results of the NMA showed that in adults all selective serotonin reuptake inhibitors (SSRIs) and clomipramine had greater effects than drug placebo. There were no differences between SSRIs, and a trend for clomipramine to be more effective did not reach statistical significance. All active psychological therapies had greater effects than drug placebo. Behavioural therapy (BT) and cognitive therapy (CT) had greater effects than psychological placebo, but cognitive-behavioural therapy (CBT) did not. BT and CT, but not CBT, had greater effects than medications, but there are considerable uncertainty and methodological limitations that should be taken into account. In children and adolescents, CBT and BT had greater effects than drug placebo, but differences compared with psychological placebo did not reach statistical significance. SSRIs as a class showed a trend for superiority over drug placebo, but the difference did not reach statistical significance. However, the superiority of some individual drugs (fluoxetine, sertraline) was marginally statistically significant. Regarding acceptability, all interventions except clomipramine had good tolerability. In adults, CT and BT had the highest probability of being most cost-effective at conventional National Institute for Health and Care Excellence thresholds. In children and adolescents, CBT or CBT combined with a SSRI were more likely to be cost-effective. The results are uncertain and sensitive to assumptions about treatment effect and the exclusion of trials at high risk of bias. LIMITATIONS: The majority of psychological trials included patients who were taking medications. There were few studies in children and adolescents. CONCLUSIONS: In adults, psychological interventions, clomipramine, SSRIs or combinations of these are all effective, whereas in children and adolescents, psychological interventions, either as monotherapy or combined with specific SSRIs, were more likely to be effective. Future RCTs should improve their design, in particular for psychotherapy or combined interventions. STUDY REGISTRATION: The study is registered as PROSPERO CRD42012002441. FUNDING DETAILS: The National Institute for Health Research Health Technology Assessment programme

    Depressive and subthreshold depressive symptomatology among older adults in a socioeconomically deprived area in Brazil

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    Depressive and subthreshold depressive symptomatology are common but often neglected in older adults. / Objective: This study aimed to assess rates of depressive and subthreshold depressive symptomatology, and the characteristics associated, among older adults living in a socioeconomically deprived area of Brazil. / Methods: This study is part of the PROACTIVE cluster randomised controlled trial. 3356 adults aged 60+ years and registered in 20 primary health clinics were screened for depressive symptomatology with the Patient Health Questionnaire-9 (PHQ-9). Depressive status was classified according to the total PHQ-9 score and the presence of core depressive symptoms (depressed mood and anhedonia) as follows: no depressive symptomatology (PHQ-9 score 0–4, or 5–9 but with no core depressive symptom); subthreshold depressive symptomatology (PHQ-9 score 5–9 and at least one core depressive symptom); and depressive symptomatology (PHQ-9 score ≥ 10). Sociodemographic information and self-reported chronic conditions were collected. Relative risk ratios and 95% CIs were obtained using a multinomial regression model. / Results: Depressive and subthreshold depressive symptomatology were present in 30% and 14% of the screened sample. Depressive symptomatology was associated with female gender, low socioeconomic conditions and presence of chronic conditions, whereas subthreshold depressive symptomatology was only associated with female gender and having hypertension. / Conclusions: Depressive and subthreshold depressive symptomatology is highly prevalent in this population registered with primary care clinics. Strategies managed by primary care non-mental health specialists can be a first step for improving this alarming and neglected situation among older adults

    Pedagogies for the 'dis‐engaged': diverse experiences of the young people’s Arts Award programme

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    Art education is often praised for its engaging programmes and inclusive pedagogies, with many initiatives created with the intention of widening access for those who are deemed to be lacking. This article investigates one such programme – the young people’s Arts Award, which is a nationally recognised qualification for young people aged 11–25. I call upon a range of pedagogies in order to critique the Arts Award within the context of informal and alternative education settings in the United Kingdom. Drawing on a 12‐month ethnographic study, the research was conducted across five diverse programmes which included youth work projects and alternative provision. I present two cases – ‘learning to be an artist’ and ‘learning to behave’ – which demonstrate a hierarchy of pedagogy in the application of this programme across these particular contexts. Artists’ Signature Pedagogies are used as an analytical framework to explore the affordances of working with artists through the programme. Further, I engage with the Pedagogy of Poverty to demonstrate that young people who were classified as ‘dis‐engaged’ were more likely to receive lower quality programmes, low‐level work and over‐regulated teaching. I argue that despite changes to the ways that young people access art education, there continues to be unequal opportunities. This finding is significant for not only creative practitioners and youth arts workers, but also arts education policy makers and programmers

    Prescribing patterns of dental practitioners in Australia from 2001 to 2012. Antimicrobials

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    Background: The development of antibiotic resistance by bacteria is of global concern. Inappropriate prescribing has the potential to exacerbate this issue. We aimed to examine the patterns of prescribing of antimicrobial medicines by dental practitioners in Australia from 2001 to 2012. Methods: Data were collected from Medicare Australia on prescriptions from dental practitioners dispensed to concessional beneficiaries between 2001 and 2012. We examined patterns of use over time. Results: There was an overall increase in number of prescriptions and in dispensed use (standardized by dose and population) of antibiotics and antifungals for the concessional population over the 12-year period. The use of dentally prescribed antibiotics increased 50%. Amoxicillin was the most commonly prescribed antibiotic accounting for 66% of all prescriptions in 2012. Generally, there was preferential prescribing of the highest dose formulations. The use of the two antifungals increased 30% over the study period with a preference for amphotericin B (74%) rather than nystatin. Conclusions: These data show a concerning increase in prescribing of antibiotics and antifungals by dentists in Australia. It would appear that Australian dentists may not be prescribing these medicines appropriately; however, further research is needed to understand prescribing behaviours and decision-making by dentists

    Offering self-sampling to cervical screening non-attenders in primary care

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    Objectives To assess the feasibility and acceptability of offering self-sampling for Human Papillomavirus (HPV) testing to cervical screening non-attenders when they consult primary care for any reason. Methods In a pilot implementation study, six general practices in London, UK, offered self-sampling kits during consultation to women aged 25–64 who were at least six months overdue for cervical screening (no cytology test recorded in the past 3.5 years if aged 25–49, or 5.5 years if aged 50–64). Eligible women were identified using an automated real-time search (during consultation) of the general practice electronic medical record system. Women collected samples either in clinic or at home (dry flocked swabs analysed using Roche Cobas®4800). Results Of approximately 5000 eligible women, 3131 consulted primary care between January and December 2014 (mean recruitment period 9.5 months). Of these, 21% (652) were offered kits, 14% (443) accepted, and 9% (292) returned a self-sample. The proportion of eligible women offered kits varied considerably among practices (11–36%). Sample return rates increased with kit offered rates ( r = 0.8, p = 0.04). Of 39 HPV positive women 85% (33) attended follow-up, including two with invasive cancers (stage 2A1 and 1A1). Conclusions Offering self-sampling to cervical screening non-attenders opportunistically in primary care is feasible. Return rates could be increased if more women were offered kits. A large trial is needed to identify how self-sampling is best integrated into the national screening programme, and to identify determinants of uptake. </jats:sec
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