Emergent approaches to the meta-analysis of multiple heterogeneous complex interventions.

BACKGROUND: Multiple interventions meta-analysis has been recommended in the methodological literature as a tool for evidence synthesis when a heterogeneous set of interventions is included in the same review—and, more recently, when a heterogeneous set of complex interventions is included. However, there is little guidance on the use of this method with complex interventions. This article suggests two approaches to model complexity and heterogeneity through this method. DISCUSSION: 'Clinically meaningful units' groups interventions by modality or similar theory of change, whereas 'components and dismantling' separates out interventions into combinations of components and either groups interventions by the combination of components they demonstrate or extracts effects for each identified component and, possibly, interactions between components. Future work in systematic review methodology should aim to understand how to develop taxonomies of components or theories of change that are internally relevant to the studies in these multiple interventions meta-analyses. SUMMARY: Despite little meaningful prior guidance to its use in this context, multiple interventions meta-analysis has the potential to be a useful tool for synthesising heterogeneous sets of complex interventions. Researchers should choose an approach in accordance with their specific aims in their systematic review

Lifestyle weight management programmes for children: A systematic review using Qualitative Comparative Analysis to identify critical pathways to effectiveness.

This study aimed to identify critical features of successful lifestyle weight management interventions for overweight children (0-11years). Eleven qualitative UK-based studies examining children's, parents' and providers' perspectives and experiences of programmes were synthesised to identify components felt to be critical. Studies for this views synthesis were identified from existing reviews and an update of one review's search, which was run in December 2015. The identified components were then explored in a synthesis of intervention evaluations (five 'most effective' and 15 'least effective') conducted in western Europe, North America, Australia or New Zealand. The intervention evaluations were identified from existing reviews and an update of one review's search, which was run in March 2016. This evaluation synthesis was carried out using Qualitative Comparative Analysis. Three important mechanisms were present in all the most effective interventions but absent in all the least effective: 1/ showing families how to change: a) providing child physical activity sessions, b) delivering practical behaviour change strategy sessions, c) providing calorie intake advice; 2/ ensuring all the family are on board: a) delivering discussion/education sessions for both children and parents, b) delivering child-friendly sessions, c) aiming to change behaviours across the whole family; 3/ enabling social support for both parents and children by delivering both child group sessions and parent group sessions. To conclude, programmes should ensure the whole family is on board the programme, that parents and children can receive social support and are not just told what to change, but shown how

Weight management programmes: Re-analysis of a systematic review to identify pathways to effectiveness.

BACKGROUND: Previous systematic reviews of weight management programmes (WMPs) have not been able to account for heterogeneity of effectiveness within programmes using top-down behavioural change taxonomies. This could be due to overlapping causal pathways to effectiveness (or lack of effectiveness) in these complex interventions. Qualitative comparative analysis (QCA) can help identify these overlapping pathways. METHODS: Using trials of adult WMPs with dietary and physical activity components identified from a previous systematic review, we selected the 10 most and 10 least effective interventions by amount of weight loss at 12 months compared to minimal treatment. Using intervention components suggested by synthesis of studies of programme user views, we labelled interventions as to the presence of these components and, using qualitative comparative analysis, developed pathways of component combinations that created the conditions sufficient for interventions to be most effective and least effective. RESULTS: Informed by the synthesis of views studies, we constructed 3 truth tables relating to quality of the user-provider relationship; perceived high need for guidance from providers; and quality of the relationship between peers in weight management programmes. We found effective interventions were characterized by opportunities to develop supportive relationships with providers or peers, directive provider-led goal setting and components perceived to foster self-regulation. CONCLUSIONS: Although QCA is an inductive method, this innovative approach has enabled the identification of potentially critical aspects of WMPs, such as the nature of relationships within them, which were previously not considered to be as important as more concrete content such as dietary focus

The importance of service-users' perspectives: A systematic review of qualitative evidence reveals overlooked critical features of weight management programmes.

BACKGROUND: Extensive research effort shows that weight management programmes (WMPs) targeting both diet and exercise are broadly effective. However, the critical features of WMPs remain unclear. OBJECTIVE: To develop a deeper understanding of WMPs critical features, we undertook a systematic review of qualitative evidence. We sought to understand from a service-user perspective how programmes are experienced, and may be effective, on the ground. SEARCH STRATEGY: We identified qualitative studies from existing reviews and updated the searches of one review. INCLUSION CRITERIA: We included UK studies capturing the views of adult WMP users. DATA EXTRACTION AND SYNTHESIS: Thematic analysis was used inductively to code and synthesize the evidence. MAIN RESULTS: Service users were emphatic that supportive relationships, with service providers or WMP peers, are the most critical aspect of WMPs. Supportive relationships were described as providing an extrinsic motivator or "hook" which helped to overcome barriers such as scepticism about dietary advice or a lack confidence to engage in physical activity. DISCUSSION AND CONCLUSIONS: The evidence revealed that service-users' understandings of the critical features of WMPs differ from the focus of health promotion guidance or descriptions of evaluated programmes which largely emphasize educational or goal setting aspects of WMPs. Existing programme guidance may not therefore fully address the needs of service users. The study illustrates that the perspectives of service users can reveal unanticipated intervention mechanisms or underemphasized critical features and underscores the value of a holistic understanding about "what happens" in complex psychosocial interventions such as WMPs

Interpretive analysis of 85 systematic reviews suggests narrative syntheses and meta-analyses are incommensurate in argumentation

Introduction. Using Toulmin’s argumentation theory, we analysed the texts of systematic reviews in the area of workplace health promotion to explore differences in the modes of reasoning embedded in reports of narrative synthesis as compared to reports of meta-analysis. Methods. We used framework synthesis, grounded theory and cross-case analysis methods to analyse 85 systematic reviews addressing intervention effectiveness in workplace health promotion. Results. Two core categories, or ‘modes of reasoning’, emerged to frame the contrast between narrative synthesis and meta-analysis: practical-configurational reasoning in narrative synthesis (‘what is going on here? what picture emerges?’) and inferential-predictive reasoning in meta-analysis (‘does it work, and how well? will it work again?’). Modes of reasoning examined quality and consistency of the included evidence differently. Meta-analyses clearly distinguished between warrant and claim, whereas narrative syntheses often presented joint warrant-claims. Conclusion. Narrative syntheses and meta-analyses represent different modes of reasoning. Systematic reviewers are likely to be addressing research questions in different ways with each method. It is important to consider narrative synthesis in its own right as a method and to develop specific quality criteria and understandings of how it is done, not merely as a complement to, or second-best option for, meta-analysis

The entomopathogenic fungus Beauveria bassiana reduces instantaneous blood feeding in wild multi-insecticide-resistant Culex quinquefasciatus mosquitoes in Benin, West Africa.

BACKGROUND: Mosquito-borne diseases are still a major health risk in many developing countries, and the emergence of multi-insecticide-resistant mosquitoes is threatening the future of vector control. Therefore, new tools that can manage resistant mosquitoes are required. Laboratory studies show that entomopathogenic fungi can kill insecticide-resistant malaria vectors but this needs to be verified in the field. METHODS: The present study investigated whether these fungi will be effective at infecting, killing and/or modifying the behaviour of wild multi-insecticide-resistant West African mosquitoes. The entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana were separately applied to white polyester window netting and used in combination with either a permethrin-treated or untreated bednet in an experimental hut trial. Untreated nets were used because we wanted to test the effect of fungus alone and in combination with an insecticide to examine any potential additive or synergistic effects. RESULTS: In total, 1125 female mosquitoes were collected during the hut trial, mainly Culex quinquefasciatus Say. Unfortunately, not enough wild Anopheles gambiae Giles were collected to allow the effect the fungi may have on this malaria vector to be analysed. None of the treatment combinations caused significantly increased mortality of Cx. quinquefasciatus when compared to the control hut. The only significant behaviour modification found was a reduction in blood feeding by Cx. quinquefasciatus, caused by the permethrin and B. bassiana treatments, although no additive effect was seen in the B. bassiana and permethrin combination treatment. Beauveria bassiana did not repel blood foraging mosquitoes either in the laboratory or field. CONCLUSIONS: This is the first time that an entomopathogenic fungus has been shown to reduce blood feeding of wild mosquitoes. This behaviour modification indicates that B. bassiana could potentially be a new mosquito control tool effective at reducing disease transmission, although further field work in areas with filariasis transmission should be carried out to verify this. In addition, work targeting malaria vector mosquitoes should be carried out to see if these mosquitoes manifest the same behaviour modification after infection with B. bassiana conidia

Tolerance of Artemia to static and shock pressure loading

Hydrostatic and hydrodynamic pressure loading has been applied to unicellular organisms for a number of years due to interest from food technology and extremophile communities. There is also an emerging interest in the response of multicellular organisms to high pressure conditions. Artemia salina is one such organism. Previous experiments have shown a marked difference in the hatching rate of these organisms after exposure to different magnitudes of pressure, with hydrostatic tests showing hatching rates at pressures up to several GPa, compared to dynamic loading that resulted in comparatively low survival rates at lower pressure magnitudes. In order to begin to investigate the origin of this difference, the work presented here has focussed on the response of Artemia salina to (quasi) one-dimensional shock loading. Such experiments were carried out using the plate-impact technique in order to create a planar shock front. Artemia cysts were investigated in this manner along with freshly hatched larvae (nauplii). The nauplii and cysts were observed post-shock using optical microscopy to detect motility or hatching, respectively. Hatching rates of 18% were recorded at pressures reaching 1.5 GPa, as determined with the aid of numerical models. Subjecting Artemia to quasi-one-dimensional shock loading offers a way to more thoroughly explore the shock pressure ranges these organisms can survive

How does reviewing the evidence change veterinary surgeons' beliefs regarding the treatment of ovine footrot? A quantitative and qualitative study

Footrot is a widespread, infectious cause of lameness in sheep, with major economic and welfare costs. The aims of this research were: (i) to quantify how veterinary surgeons’ beliefs regarding the efficacy of two treatments for footrot changed following a review of the evidence (ii) to obtain a consensus opinion following group discussions (iii) to capture complementary qualitative data to place their beliefs within a broader clinical context. Grounded in a Bayesian statistical framework, probabilistic elicitation (roulette method) was used to quantify the beliefs of eleven veterinary surgeons during two one-day workshops. There was considerable heterogeneity in veterinary surgeons’ beliefs before they listened to a review of the evidence. After hearing the evidence, seven participants quantifiably changed their beliefs. In particular, two participants who initially believed that foot trimming with topical oxytetracycline was the better treatment, changed to entirely favour systemic and topical oxytetracycline instead. The results suggest that a substantial amount of the variation in beliefs related to differences in veterinary surgeons’ knowledge of the evidence. Although considerable differences in opinion still remained after the evidence review, with several participants having non-overlapping 95% credible intervals, both groups did achieve a consensus opinion. Two key findings from the qualitative data were: (i) veterinary surgeons believed that farmers are unlikely to actively seek advice on lameness, suggesting a proactive veterinary approach is required (ii) more attention could be given to improving the way in which veterinary advice is delivered to farmers. In summary this study has: (i) demonstrated a practical method for probabilistically quantifying how veterinary surgeons’ beliefs change (ii) revealed that the evidence that currently exists is capable of changing veterinary opinion (iii) suggested that improved transfer of research knowledge into veterinary practice is needed (iv) identified some potential obstacles to the implementation of veterinary advice by farmers

A two-stage mechanism of viral RNA compaction revealed by single molecule fluorescence

Long RNAs often exist as multiple conformers in equilibrium. For the genomes of single-stranded RNA viruses, one of these conformers must include a compacted state allowing the RNA to be confined within the virion. We have used single molecule fluorescence correlation spectroscopy to monitor the conformations of viral genomes and sub-fragments in the absence and presence of coat proteins. Cognate RNA-coat protein interactions in two model viruses cause a rapid collapse in the hydrodynamic radii of their respective RNAs. This is caused by protein binding at multiple sites on the RNA that facilitate additional protein-protein contacts. The collapsed species recruit further coat proteins to complete capsid assembly with great efficiency and fidelity. The specificity in RNA-coat protein interactions seen at single-molecule concentrations reflects the packaging selectivity seen for such viruses in vivo. This contrasts with many in vitro reassembly measurements performed at much higher concentrations. RNA compaction by coat protein or polycation binding are distinct processes, implying that defined RNA-coat protein contacts are required for assembly

Cellular Inhibitor of Apoptosis (cIAP)-mediated ubiquitination of Phosphofurin Acidic Cluster Sorting protein 2 (PACS-2) negatively regulates Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) cytotoxicity

Lysosomal membrane permeabilization is an essential step in TRAIL-induced apoptosis of liver cancer cell lines. TRAIL-induced lysosomal membrane permeabilization is mediated by the multifunctional sorting protein PACS-2 and repressed by the E3 ligases cIAP-1 and cIAP-2. Despite the opposing roles for PACS-2 and cIAPs in TRAIL-induced apoptosis, an interaction between these proteins has yet to be examined. Herein, we report that cIAP-1 and cIAP-2 confer TRAIL resistance to hepatobiliary cancer cell lines by reducing PACS-2 levels. Under basal conditions, PACS-2 underwent K48-linked polyubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay. Single c-Iap-1 or c-Iap-2 gene knock-outs in mouse hepatocytes did not lead to PACS-2 accumulation. However, deletion of both cIAP-1 and cIAP-2 reduced PACS-2 ubiquitination, which increased PACS-2 levels and sensitized HuH-7 cells to TRAIL-induced lysosomal membrane permeabilization and apoptosis. Correspondingly, deletion of cIAPs sensitized wild-type, but not PACS-2-deficient hepatocarcinoma cells or Pacs-2-/- mouse hepatocytes to TRAIL-induced apoptosis. Together, these data suggest cIAPs constitutively downregulate PACS-2 by polyubiquitination and proteasomal degradation, thereby restraining TRAIL-induced killing of liver cancer cells. © 2014 Guicciardi et al