Correction: Optimising a person-centred approach to stopping medicines in older people with multimorbidity and polypharmacy using the DExTruS framework: a realist review (BMC Medicine, (2022), 20, 1, (297), 10.1186/s12916-022-02475-1)

The original article [1] contained an error in the spelling of co-author, Michelle Maden’s name which has since been corrected

Optimising a person-centred approach to stopping medicines in older people with multimorbidity and polypharmacy using the DExTruS framework: a realist review

Background: Tackling problematic polypharmacy requires tailoring the use of medicines to individual circumstances and may involve the process of deprescribing. Deprescribing can cause anxiety and concern for clinicians and patients. Tailoring medication decisions often entails beyond protocol decision-making, a complex process involving emotional and cognitive work for healthcare professionals and patients. We undertook realist review to highlight and understand the interactions between different factors involved in deprescribing and to develop a final programme theory that identifies and explains components of good practice that support a person-centred approach to deprescribing in older patients with multimorbidity and polypharmacy. Methods: The realist approach involves identifying underlying causal mechanisms and exploring how, and under what conditions they work. We conducted a search of electronic databases which were supplemented by citation checking and consultation with stakeholders to identify other key documents. The review followed the key steps outlined by Pawson et al. and followed the RAMESES standards for realist syntheses. Results: We included 119 included documents from which data were extracted to produce context-mechanism-outcome configurations (CMOCs) and a final programme theory. Our programme theory recognises that deprescribing is a complex intervention influenced by a multitude of factors. The components of our final programme theory include the following: a supportive infrastructure that provides clear guidance around professional responsibilities and that enables multidisciplinary working and continuity of care, consistent access to high-quality relevant patient contextual data, the need to support the creation of a shared explanation and understanding of the meaning and purpose of medicines and a trial and learn approach that provides space for monitoring and continuity. These components may support the development of trust which may be key to managing the uncertainty and in turn optimise outcomes. These components are summarised in the novel DExTruS framework. Conclusion: Our findings recognise the complex interpretive practice and decision-making involved in medication management and identify key components needed to support best practice. Our findings have implications for how we design medication review consultations, professional training and for patient records/data management. Our review also highlights the role that trust plays both as a central element of tailored prescribing and a potential outcome of good practice in this area

Synergy in Efficacy of Fungal Entomopathogens and Permethrin against West African Insecticide-Resistant Anopheles gambiae Mosquitoes

Background Increasing incidences of insecticide resistance in malaria vectors are threatening the sustainable use of contemporary chemical vector control measures. Fungal entomopathogens provide a possible additional tool for the control of insecticide-resistant malaria mosquitoes. This study investigated the compatibility of the pyrethroid insecticide permethrin and two mosquito-pathogenic fungi, Beauveria bassiana and Metarhizium anisopliae, against a laboratory colony and field population of West African insecticide-resistant Anopheles gambiae s.s. mosquitoes. Methodology/Findings A range of fungus-insecticide combinations was used to test effects of timing and sequence of exposure. Both the laboratory-reared and field-collected mosquitoes were highly resistant to permethrin but susceptible to B. bassiana and M. anisopliae infection, inducing 100% mortality within nine days. Combinations of insecticide and fungus showed synergistic effects on mosquito survival. Fungal infection increased permethrin-induced mortality rates in wild An. gambiae s.s. mosquitoes and reciprocally, exposure to permethrin increased subsequent fungal-induced mortality rates in both colonies. Simultaneous co-exposure induced the highest mortality; up to 70.3±2% for a combined Beauveria and permethrin exposure within a time range of one gonotrophic cycle (4 days). Conclusions/Significance Combining fungi and permethrin induced a higher impact on mosquito survival than the use of these control agents alone. The observed synergism in efficacy shows the potential for integrated fungus-insecticide control measures to dramatically reduce malaria transmission and enable control at more moderate levels of coverage even in areas where insecticide resistance has rendered pyrethroids essentially ineffective

Evaluating the impact of screening plus eave tubes on malaria transmission compared to current best practice in central Côte d'Ivoire : A two armed cluster randomized controlled trial

Background: Access to long-lasting insecticidal nets (LLINs) has increased and malaria has decreased globally, but malaria transmission remains high in parts of sub-Saharan Africa and insecticide resistance threatens current progress. Eave tubes are a new tool for the targeted delivery of insecticides against mosquitoes attempting to enter houses. The primary objective of this trial is to test whether screening plus eave tubes (SET) provides protection against malaria, on top of universal coverage with LLINs in an area of intense pyrethroid resistance. The trial will also assess acceptability and cost-effectiveness of the intervention. Methods/design: A two-armed, cluster randomized controlled trial will be conducted to evaluate the effect of SET on clinical malaria incidence in children living in central Côte d'Ivoire. Forty villages will be selected based on population size and the proportion of houses suitable for modification with SET. Using restricted randomization, half the villages will be assigned to the treatment arm (SET + LLINs) and the remainder will be assigned to the control arm (LLINs only). In both arms, LLINs will be distributed and in the treatment arm, householders will be offered SET. Fifty children aged six months to eight years old will be enrolled from randomly selected households in each of the 40 villages. Cohorts will be cleared of malaria parasites at the start of the study and one year after recruitment, and will be monitored for clinical malaria case incidence by active case detection over two years. Mosquito densities will be assessed using CDC light traps and human landing catches and a subset of Anopheles mosquitoes will be examined for parity status and tested for sporozoite infection. Acceptability of SET will be monitored using surveys and focus groups. Cost-effectiveness analysis will measure the incremental cost per case averted and per disability-adjusted life year (DALY) averted of adding SET to LLINs. Economic and financial costs will be estimated from societal and provider perspective using standard economic evaluation methods. Discussion: This study will be the first evaluation of the epidemiological impact of SET. Trial findings will show whether SET is a viable, cost-effective technology for malaria control in Côte d'Ivoire and possibly elsewhere. Trial registration: ISRCTN18145556, registered on 01 February 2017 - retrospectively registered

Fine scale spatial investigation of multiple insecticide resistance and underlying target-site and metabolic mechanisms in Anopheles gambiae in central Côte d’Ivoire

Routine monitoring of occurrence, levels and mechanisms of insecticide resistance informs effective management strategies, and should be used to assess the effect of new tools on resistance. As part of a cluster randomised controlled trial evaluating a novel insecticide-based intervention in central Côte d’Ivoire, we assessed resistance and its underlying mechanisms in Anopheles gambiae populations from a subset of trial villages. Resistance to multiple insecticides in An. gambiae s.s. and An. coluzzii was detected across villages, with dose–response assays demonstrating extremely high resistance intensity to the pyrethroid deltamethrin (> 1,500-fold), and mortality following exposure to pyrethroid-treated bednets was low (< 30% mortality in cone bioassays). The 1014F kdr mutation was almost fixed (≥ 90%) in all villages but the 1575Y kdr-amplifying mutation was relatively rare (< 15%). The carbamate and organophosphate resistance-associated Ace-1 G119S mutation was also detected at moderate frequencies (22–43%). Transcriptome analysis identified overexpression of P450 genes known to confer pyrethroid resistance (Cyp9K1, Cyp6P3, and Cyp6M2), and also a carboxylesterase (COEAE1F) as major candidates. Cyp6P3 expression was high but variable (up to 33-fold) and correlated positively with deltamethrin resistance intensity across villages (r2 = 0.78, P = 0.02). Tools and strategies to mitigate the extreme and multiple resistance provided by these mechanisms are required in this area to avoid future control failures

Public Stigma of Autism Spectrum Disorder at School: Implicit Attitudes Matter

This study examines the public stigma of children with autism spectrum disorder (ASD) by their school-aged peers, focusing on both explicit and implicit attitudes. The twofold aims were to provide a broader picture of public stigma and to explore age-related changes in attitudes. Students completed an explicit measure of the public stigma and an implicit measure of attitudes after watching a video displaying children with ASD vs. typically developing (TD) children. Both measures showed more negative perceptions towards children with ASD compared to TD children. However, while explicit attitudes improved with age, implicit attitudes remained constantly negative. This finding suggests that both explicit and implicit attitudes should be considered when promoting an inclusive climate at school

A new era for understanding amyloid structures and disease

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention

A history of the problems of philosophy,

vol. I. Introduction. pt. I. Psychology.--vol. II. pt. II. Ethics. pt. III. Metaphysics. pt. IV. Theodicy.Mode of access: Internet

Optimising a whole-person-centred approach to stopping medicines in older people with multimorbidity and polypharmacy: the TAILOR Medication Synthesis

Background: Tackling problematic polypharmacy requires tailoring the use of medicines to individual needs and circumstances. This may involve stopping medicines (deprescribing); but patients and clinicians report uncertainty on how best to do this. The TAILOR medication synthesis sought to help us understand how best to support deprescribing in older people living with multimorbidity and polypharmacy. Objectives: We identified two research questions. 1) What evidence exists to support the safe, effective and acceptable stopping of medication in this patient group? 2) How, for whom and in what contexts can safe and effective tailoring of clinical decisions related to medication use work to produce desired outcomes? We thus described three objectives: a) to undertake a robust scoping review of the literature on stopping medicines in this group to describe what is being done, where and for what effect; b) to undertake a realist synthesis review to construct a programme theory that describes ‘best practice’ and helps explain the heterogeneity of deprescribing approaches; and c) to translate findings into resources to support tailored prescribing in clinical practice. Data sources: Experienced information specialists conducted comprehensive searches in MEDLINE, CINAHL, Web of Science, EMBASE, The Cochrane Library (CDSR, CENTRAL), Joanna Briggs Database of Systematic Reviews and Implementation Reports, Google and Google Scholar (targeted searches). Review methods: The scoping review followed the five steps described by the Johanna Briggs Institute methodology for conducting a scoping review . The realist review followed the methodological and publication standards for realist reviews described by the RAMESES group. PPI partners ensured our analysis retained a patient-centred focus. Results: Our scoping review identified 9528 abstracts: 8847 removed at screening, 662 at full text review. Leaving 20 studies (published between 2009-2020) which examined the effectiveness, safety and acceptability of deprescribing in adults (≥50 years) with polypharmacy (≥5 prescribed medications) and multi-morbidity (≥2 conditions). Our analysis revealed that deprescribing under research conditions mapped well to expert guidance on the steps needed for good clinical practice. Our findings offer evidence-informed support to clinicians for the safety, clinician acceptability and potential effectiveness of clinical decision making that demonstrates a structured approach to deprescribing decisions. Our realist review identified 2602 references with 119 included in the final analysis. Analysis described 34 Context-Mechanism-Outcomes-Configurations describing the knowledge work of tailored prescribing under 8 headings related to organisational, healthcare provider and patient factors, and interventions to improve deprescribing. We conclude that robust tailored deprescribing requires attention to providing an enabling infrastructure, access to data, tailored explanations, and trust. Limitations: Scoping review - strict application of our definition of multimorbidity may have impacted on relevance to clinical practice. The realist review was limited by the data(evidence) available. Conclusions: Our combined reviews recognise deprescribing as a complex intervention; provide support for the safety of structured approaches to deprescribing; but highlight the need to integrate patient-centred and contextual factors into best-practice models. Future work: TAILOR has informed new funded research tackling deprescribing in sleep management, and professional education. Further research is being developed to implement tailored prescribing into routine primary care practice. Study registrations: PROSPERO 2018 CRD42018107544; PROSPERO 2018 CRD42018104176 Study funding: NIHR HTA 17/69/0