Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy

<p>Background: Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials.</p> <p>Methods and Findings: Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93–1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93–1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82–1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (<2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76–1.10]).</p> <p>Conclusions: In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).</p&gt

Mobile Consumer Behavior in Fashion m-Retail: An Eye Tracking Study to Understand Gender Differences

© 2020 ACM. With exponential adoption of mobile devices, consumers increasingly use them for shopping. There is a need to understand the gender differences in mobile consumer behavior. This study used mobile eye tracking technology and mixed-method approach to analyze and compare how male and female mobile fashion consumers browse and shop on smartphones. Mobile eye tracking glasses recorded fashion consumers' shopping experiences using smartphones for browsing and shopping on the actual fashion retailer's website. 14 participants successfully completed this study, half of them were males and half females. Two different data analysis approaches were employed, namely a novel framework of the shopping journey, and semantic gaze mapping with 31 Areas of Interest (AOI) representing the elements of the shopping journey. The results showed that male and female users exhibited significantly different behavior patterns, which have implications for mobile website design and fashion m-retail. The shopping journey map framework proves useful for further application in market research

Spatial Localisation of Actin Filaments across Developmental Stages of the Malaria Parasite

Actin dynamics have been implicated in a variety of developmental processes during the malaria parasite lifecycle. Parasite motility, in particular, is thought to critically depend on an actomyosin motor located in the outer pellicle of the parasite cell. Efforts to understand the diverse roles actin plays have, however, been hampered by an inability to detect microfilaments under native conditions. To visualise the spatial dynamics of actin we generated a parasite-specific actin antibody that shows preferential recognition of filamentous actin and applied this tool to different lifecycle stages (merozoites, sporozoites and ookinetes) of the human and mouse malaria parasite species Plasmodium falciparum and P. berghei along with tachyzoites from the related apicomplexan parasite Toxoplasma gondii. Actin filament distribution was found associated with three core compartments: the nuclear periphery, pellicular membranes of motile or invasive parasite forms and in a ring-like distribution at the tight junction during merozoite invasion of erythrocytes in both human and mouse malaria parasites. Localisation at the nuclear periphery is consistent with an emerging role of actin in facilitating parasite gene regulation. During invasion, we show that the actin ring at the parasite-host cell tight junction is dependent on dynamic filament turnover. Super-resolution imaging places this ring posterior to, and not concentric with, the junction marker rhoptry neck protein 4. This implies motor force relies on the engagement of dynamic microfilaments at zones of traction, though not necessarily directly through receptor-ligand interactions at sites of adhesion during invasion. Combined, these observations extend current understanding of the diverse roles actin plays in malaria parasite development and apicomplexan cell motility, in particular refining understanding on the linkage of the internal parasite gliding motor with the extra-cellular milieu

System Dynamics modelling to formulate policy interventions to optimise antibiotic prescribing in hospitals

© 2020 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Multiple strategies have been used in the National Health System (NHS) in England to reduce inappropriate antibiotic prescribing and consumption in order to tackle antimicrobial resistance. These strategies have included, among others, restricting dispensing, introduction of prescribing guidelines, use of clinical audit, and performance reviews as well as strategies aimed at changing the prescribing behaviour of clinicians. However, behavioural interventions have had limited effect in optimising doctors’ antibiotic prescribing practices. This study examines the determinants of decision-making for antibiotic prescribing in hospitals in the NHS. A system dynamics model was constructed to capture structural and behavioural influences to simulate doctors’ prescribing practices. Data from the literature, patient records, healthcare professional interviews and survey responses were used to parameterise the model. The scenario simulation shows maximum improvements in guideline compliance are achieved when compliance among senior staff is increased, combined with fast laboratory turnaround of blood cultures, and microbiologist review. Improving guideline compliance of junior staff alone has limited impact. This first use of system dynamics modelling to study antibiotic prescribing decision-making demonstrates the applicability of the methodology for design and evaluation of future policies and interventions.Peer reviewe

Multifactorial Origins of Heart and Gut Defects in nipbl-Deficient Zebrafish, a Model of Cornelia de Lange Syndrome

nipbl-deficient zebrafish provide evidence that heart and gut defects in Cornelia de Lange Syndrome are caused by combined effects of multiple gene expression changes that occur during early embryonic development

Evaluation of a web-based intervention to reduce antibiotic prescribing for LRTI in six European countries: quantitative process analysis of the GRACE/INTRO randomised controlled trial.

To reduce the spread of antibiotic resistance, there is a pressing need for worldwide implementation of effective interventions to promote more prudent prescribing of antibiotics for acute LRTI. This study is a process analysis of the GRACE/INTRO trial of a multifactorial intervention that reduced antibiotic prescribing for acute LRTI in six European countries. The aim was to understand how the interventions were implemented and to examine effects of the interventions on general practitioners' (GPs') and patients' attitudes

A realist evaluation of a physical activity participation intervention for children and youth with disabilities: What works, for whom, in what circumstances, and how?

Background: The need to identify strategies that facilitate involvement in physical activity for children and youth with disabilities is recognised as an urgent priority. This study aimed to describe the association between context, mechanisms and outcome(s) of a participation-focused physical activity intervention to understand what works, in what conditions, and how. Methods: This study was designed as a realist evaluation. Participant recruitment occurred through purposive and theoretical sampling of children and parents participating in the Local Environment Model intervention at Beitostolen Healthsports Centre in Norway. Ethnographic methods comprising participant observation, interviews, and focus groups were employed over 15 weeks in the field. Data analysis was completed using the context-mechanism-outcome framework of realist evaluation. Context-mechanism-outcome connections were generated empirically from the data to create a model to indicate how the program activated mechanisms within the program context, to enable participation in physical activity. Results: Thirty one children with a range of disabilities (mean age 12y 6 m (SD 2y 2 m); 18 males) and their parents (n=44; 26 mothers and 18 fathers) participated in the study. Following data synthesis, a refined program theory comprising four context themes, five mechanisms, and six outcomes, were identified. The mechanisms (choice, fun, friends, specialised health professionals, and time) were activated in a context that was safe, social, learning-based and family-centred, to elicit outcomes across all levels of the International Classification of Functioning, Disability and Health. Conclusions: The interaction of mechanisms and context as a whole facilitated meaningful outcomes for children and youth with disabilities, and their parents. Whilst optimising participation in physical activity is a primary outcome of the Local Environment Model, the refined program theory suggests the participation-focused approach may act as a catalyst to promote a range of outcomes. Findings from this study may inform future interventions attempting to enable participation in physical activity for children and youth with disabilities

A global agenda for advancing freshwater biodiversity research

This manuscript is a contribution of the Alliance for Freshwater Life (www.allianceforfreshwaterlife.org). We thank Nick Bond, Lisa Bossenbroek, Lekima Copeland, Dean Jacobsen, Maria Cecilia Londo?o, David Lopez, Jaime Ricardo Garcia Marquez, Ketlhatlogile Mosepele, Nunia Thomas-Moko, Qiwei Wei and the authors of Living Waters: A Research Agenda for the Biodiversity of Inland and Coastal Waters for their contributions. We also thank Peter Thrall, Ian Harrison and two anonymous referees for their valuable comments that helped improve the manuscript. Open access funding enabled and organised by Projekt DEAL

Binding Site Turnover Produces Pervasive Quantitative Changes in Transcription Factor Binding between Closely Related Drosophila Species

Genome-wide comparison of transcription factor binding between related Drosophila species highlights how sequence changes affect the biochemical events that underlie animal development

A Zebrafish Model of Roberts Syndrome Reveals That Esco2 Depletion Interferes with Development by Disrupting the Cell Cycle

The human developmental diseases Cornelia de Lange Syndrome (CdLS) and Roberts Syndrome (RBS) are both caused by mutations in proteins responsible for sister chromatid cohesion. Cohesion is mediated by a multi-subunit complex called cohesin, which is loaded onto chromosomes by NIPBL. Once on chromosomes, cohesin binding is stabilized in S phase upon acetylation by ESCO2. CdLS is caused by heterozygous mutations in NIPBL or cohesin subunits SMC1A and SMC3, and RBS is caused by homozygous mutations in ESCO2. The genetic cause of both CdLS and RBS reside within the chromosome cohesion apparatus, and therefore they are collectively known as “cohesinopathies”. However, the two syndromes have distinct phenotypes, with differences not explained by their shared ontology. In this study, we have used the zebrafish model to distinguish between developmental pathways downstream of cohesin itself, or its acetylase ESCO2. Esco2 depleted zebrafish embryos exhibit features that resemble RBS, including mitotic defects, craniofacial abnormalities and limb truncations. A microarray analysis of Esco2-depleted embryos revealed that different subsets of genes are regulated downstream of Esco2 when compared with cohesin subunit Rad21. Genes downstream of Rad21 showed significant enrichment for transcriptional regulators, while Esco2-regulated genes were more likely to be involved the cell cycle or apoptosis. RNA in situ hybridization showed that runx1, which is spatiotemporally regulated by cohesin, is expressed normally in Esco2-depleted embryos. Furthermore, myca, which is downregulated in rad21 mutants, is upregulated in Esco2-depleted embryos. High levels of cell death contributed to the morphology of Esco2-depleted embryos without affecting specific developmental pathways. We propose that cell proliferation defects and apoptosis could be the primary cause of the features of RBS. Our results show that mutations in different elements of the cohesion apparatus have distinct developmental outcomes, and provide insight into why CdLS and RBS are distinct diseases