Antifungal agents for invasive candidiasis in non-neutropenic critically ill adults: What do the guidelines recommend?

Objectives: Recommendations in clinical practice guidelines (CPG) may differ and cause confusion. Our objective was to appraise CPGs for antifungal treatment of invasive candidiasis (IC) in non-neutropenic critically-ill adult patients. Methods: We systematically searched the literature for CPGs published between 2008 and 2018. We assessed the quality of each guideline using six domains of the AGREE II instrument. We extracted and compared recommendations for different treatment strategies and assessed content quality.Results: Of 19 guidelines, the mean overall AGREE II score was 58%. The domain 'clarity of presentation' received the highest scores (88%) and 'applicability' the lowest (18%). CPGs provided detailed recommendations on antifungal prophylaxis (n = 10), with fluconazole recommended as initial prophylaxis in all seven CPGs citing a specific drug. Echinocandin was recommended as the initial drug in all 16 CPGs supporting empirical/pre-emptive treatment; and in 18 of 19 for targeted invasive candidiasis treatment. However, it remains unclear when to initiate prophylaxis, empirical or pre-emptive therapy or when to step down. Conclusions: The methodological quality of CPGs for antifungal treatment of IC in non-neutropenic critically-ill patients is suboptimal. Some treatment recommendations were inconsistent across indications and require local guidance to help clinicians make better informed decisions

Long term impact of the WHI studies on information-seeking and decision-making in menopause symptoms management: a longitudinal analysis of questions to a medicines call centre

Abstract Background While women are taking a greater role in decisions about menopause symptom management, the legacy of the Women’s Health Initiative (WHI) studies persist. Despite hormone therapy (HT) being effective in reducing all-cause mortality, many women seeking relief of menopausal symptoms exaggerate HT harms and overstate the perceived benefits or ignore the risks of alternative therapies. We aimed to explore the longitudinal impact of the widely-publicised WHI 2002 study on women’s information-seeking and describe determinants of decision-making about managing menopausal symptoms. Methods In a longitudinal analysis of both quantitative and qualitative data, we explored consumer questions about menopause-related medicines received by two Australian medicines call centres (1996–2010) before, during, and after WHI 2002. We analysed calls by age and gender of caller and patient, their relationship, postcode, enquiry type, and motivation to help-seek. We compared calls regarding HT and herbal medicines (HM) with the rest of calls, and thematically analysed question narratives across the three time-periods. Results There were 1,829 menopause-related calls received of over this time-period, with a call surge, primarily from women in their mid-fifties, in the two months after the WHI 2002 publication. Two in three calls were motivated by negative media reports as women sought support for decision-making, primarily reassurance to cease HT. While HT safety concerns persisted for eight years post-publication, the nature of information-seeking changed over time. Callers subsequently sought reassurance to use menopause treatments together with their other medicines; and pursued HT substitutes, including HM, in response to HT product discontinuation. Conclusions Women sought information or reassurance to support a decision, based on dynamic changes in internal (symptom or risk intolerance, attitude towards menopause and treatment preferences) and external factors (perceived source trust and changes in treatment availability). In assessing HT benefit versus risk, women tend to overestimate risk with HT safety concerns persisting over time. Decision-making in managing menopause symptoms is complex and dynamic. Reassurance to reach or justify decisions from a perceived trusted source can support informed decision-making

Patient-based benefit-risk assessment of medicines: development, refinement, and validation of a content search strategy to retrieve relevant studies

INTRODUCTION: Poor indexing and inconsistent use of terms and keywords may prevent efficient retrieval of studies on the patient-based benefit-risk assessment (BRA) of medicines. We aimed to develop and validate an objectively derived content search strategy containing generic search terms that can be adapted for any search for evidence on patient-based BRA of medicines for any therapeutic area. METHODS: We used a robust multistep process to develop and validate the content search strategy: (1) we developed a bank of search terms derived from screening studies on patient-based BRA of medicines in various therapeutic areas, (2) we refined the proposed content search strategy through an iterative process of testing sensitivity and precision of search terms, and (3) we validated the final search strategy in PubMed by firstly using multiple sclerosis as a case condition and secondly computing its relative performance versus a published systematic review on patient-based BRA of medicines in rheumatoid arthritis. RESULTS: We conceptualized a final search strategy to retrieve studies on patient-based BRA containing generic search terms grouped into two domains, namely the patient and the BRA of medicines (sensitivity 84%, specificity 99.4%, precision 20.7%). The relative performance of the content search strategy was 85.7% compared with a search from a published systematic review of patient preferences in the treatment of rheumatoid arthritis. We also developed a more extended filter, with a relative performance of 93.3% when compared with a search from a published systematic review of patient preferences in lung cancer

Optimising recruitment to the HAND-1 RCT feasibility study:integration 1 of the QuinteT Recruitment Intervention (QRI)

© 2020, The Author(s). Background: Recruitment to randomised controlled trials (RCTs) can be challenging, with most trials not reaching recruitment targets. Randomised feasibility studies can be set up prior to a main trial to identify and overcome recruitment obstacles. This paper reports on an intervention—the QuinteT Recruitment Intervention (QRI)—to optimise recruitment within a randomised feasibility study of surgical treatments for patients with Dupuytren’s contracture (the HAND-1 study). Methods: The QRI was introduced in 2-phases: phase 1 sought to understand the recruitment challenges by interviewing trial staff, scrutinising screening logs and analysing audio-recorded patient consultations; in phase 2 a tailored plan of action consisting of recruiter feedback and training was delivered to address the identified challenges. Results: Two key recruitment obstacles emerged: (1) issues with the recruitment pathway, in particular methods to identify potentially eligible patients and (2) equipoise of recruiters and patients. These were addressed by liaising with centres to share good practice and refine their pathway and by providing bespoke feedback and training on consent discussions to individual recruiters and centres whilst recruitment was ongoing. The HAND-1 study subsequently achieved its recruitment target. Conclusions: Transferable lessons learnt from the QRI in the feasibility study will be implemented in the definitive RCT, enabling a “head start” in the tackling of wider issues around screening methods and consent discussions in the set up/early recruitment study phases, with ongoing QRI addressing specific issues with new centres and recruiters. Findings from this study are likely to be relevant to other surgical and similar trials that are anticipated to encounter issues around patient and recruiter equipoise of treatments and variation in recruitment pathways across centres. The study also highlights the value of feasibility studies in fine-tuning design and conduct issues for definitive RCTs. Embedding a QRI in an RCT, at feasibility or main stage, offers an opportunity for a detailed and nuanced understanding of key recruitment challenges and the chance to address them in “real-time” as recruitment proceeds

Connecting the dots: Potential of data integration to identify regulatory snps in late-onset alzheimer's disease GWAS findings

Late-onset Alzheimer's disease (LOAD) is a multifactorial disorder with over twenty loci associated with disease risk. Given the number of genome-wide significant variants that fall outside of coding regions, it is possible that some of these variants alter some function of gene expression rather than tagging coding variants that alter protein structure and/or function. RegulomeDB is a database that annotates regulatory functions of genetic variants. In this study, we utilized RegulomeDB to investigate potential regulatory functions of lead single nucleotide polymorphisms (SNPs) identified in five genome-wide association studies (GWAS) of risk and age-at onset (AAO) of LOAD, as well as SNPs in LD (r2≥0.80) with the lead GWAS SNPs. Of a total 614 SNPs examined, 394 returned RegulomeDB scores of 1-6. Of those 394 variants, 34 showed strong evidence of regulatory function (RegulomeDB score ,3), and only 3 of them were genome-wide significant SNPs (ZCWPW1/ rs1476679, CLU/rs1532278 and ABCA7/rs3764650). This study further supports the assumption that some of the non-coding GWAS SNPs are true associations rather than tagged associations and demonstrates the application of RegulomeDB to GWAS data.©2014 Rosenthal et al

Active children through individual vouchers – evaluation (ACTIVE): protocol for a mixed method randomised control trial to increase physical activity levels in teenagers

BackgroundMany teenagers are insufficiently active despite the health benefits of physical activity (PA). There is strong evidence to show that inactivity and low fitness levels increase the risk of non-communicable diseases such as coronary heart disease (CHD), type 2 diabetes and breast and colon cancers (Lee et al. Lancet 380:219–29, 2012). A major barrier facing adolescents is accessibility (e.g. cost and lack of local facilities). The ACTIVE project aims to tackle this barrier through a multi-faceted intervention, giving teenagers vouchers to spend on activities of their choice and empowering young people to improve their fitness and PA levels.DesignACTIVE is a mixed methods randomised control trial in 7 secondary schools in Swansea, South Wales. Quantitative and qualitative measures including PA (cooper run test (CRT), accelerometery over 7 days), cardiovascular (CV) measures (blood pressure, pulse wave analysis) and focus groups will be undertaken at 4 separate time points (baseline, 6 months,12 months and follow-up at 18 months). Intervention schools will receive a multi-component intervention involving 12 months of £20 vouchers to spend on physical activities of their choice, a peer mentor scheme and opportunities to attend advocacy meetings. Control schools are encouraged to continue usual practice. The primary aim is to examine the effect of the intervention in improving cardiovascular fitness.DiscussionThis paper describes the protocol for the ACTIVE randomised control trial, which aims to increase fitness, physical activity and socialisation of teenagers in Swansea, UK via a voucher scheme combined with peer mentoring. Results can contribute to the evidence base on teenage physical activity and, if effective, the intervention has the potential to inform future physical activity interventions and policy