A scoping review of risk factors and transmission routes associated with human giardiasis outbreaks in high-income settings

The flagellated pathogen Giardia duodenalis is one of the leading causes of parasitic gastrointestinal illness worldwide. In many higher income countries, such as the United Kingdom, the disease is often perceived as being travel-related, likely leading to the under-reporting of sporadic cases and outbreaks. A summary of the literature describing outbreaks and risk factors in higher income countries is necessary to improve our understanding of this pathogen and identify existing knowledge gaps. Initial literature searches were carried out in September 2016 and updated at regular intervals until November 2021, using appropriate search terms in Medline, Embase and PubMed databases. A total of 75 papers met the inclusion criteria, revealing that the consumption of contaminated water and contact with young children of diaper-wearing age were the most common transmission routes leading to outbreaks of giardiasis. Of the ten studies where food was primarily associated with outbreaks, food handlers accounted for eight of these. Another reported transmission route was direct contact with fecal material, which was reported in six studies as the primary transmission route. Travel-associated giardiasis was considered the sole transmission route in two studies, whereas multiple transmission routes contributed to giardiasis outbreaks in eleven studies. The evidence around zoonotic transmission was less clear and hampered by the lack of robust and regularly applied parasite molecular typing techniques. This literature review summarizes the findings of Giardia outbreak investigations and epidemiological studies in high-income countries. Transmission routes are identified and discussed to highlight the associated risk factors. These data also indicate gaps in our current knowledge that include the need for robust, in-depth molecular studies and have underscored the importance of water as a transmission route for Giardia cysts. These future molecular studies will improve our understanding of Giardia epidemiology and transmission pathways in higher income countries to prevent spread of this significantly under-reported pathogen

Molecular characterisation of Giardia duodenalis from human and companion animal sources in the United Kingdom using an improved triosephosphate isomerase molecular marker

Giardia duodenalis is a protozoan parasite known for its ability to cause gastrointestinal disease in human and non-human mammals. In the UK, the full impact of this parasite has yet to be fully explored, due to the limited testing which has been undertaken in humans and the low-resolution assemblage-typing methods currently available. Rather than being primarily a travel-associated condition, a recent study has highlighted that an endemic Giardia cycle is present in the UK, although the source of human disease is unclear in the majority of cases. This study focussed on the improvement of one of the commonly used assemblage-typing assays, a nested topoisomerase phosphate (tpi) PCR, to increase the amplification success rate across both human and companion animal samples. After comparing published primers to full Giardia reference genomes, this marker protocol was optimised and then deployed to test a substantial number of human (n ​= ​79) and companion animal (n ​= ​174) samples to gain an insight into the molecular epidemiology of Giardia in the UK. One assemblage A1 and eleven assemblage A2 genotypes were detected in humans, along with and 25 assemblage B genotypes. Assemblage A1 genotypes, known to be human-infective, were found in three feline and one canine sample, while one feline sample contained assemblage A2. Additionally, four feline samples contained assemblage B, which is recognised as potentially human-infective. This study demonstrates the presence of potentially human-infective Giardia genotypes circulating in the companion animal population, notably with 17.4% (8/46) of feline-derived Giardia strains being potentially zoonotic. Using a modified tpi-based genotyping assay, this work highlights the potential for domestic pets to be involved in the endemic transmission of giardiasis in the UK and underlines the need for appropriate hygiene measures to be observed when interacting with both symptomatic and asymptomatic animals. It also serves to underline the requirement for further studies to assess the zoonotic risk of Giardia associated with companion animals in high-income countries

A Critical Review of Adverse Effects to the Kidney: Mechanisms, Data Sources and In Silico Tools to Assist Prediction

Introduction: The kidney is a major target for toxicity elicited by pharmaceuticals and environmental pollutants. Standard testing which often does not investigate underlying mechanisms has proven not to be an adequate hazard assessment approach. As such, there is an opportunity for the application of computational approaches that utilise multi-scale data based on the Adverse Outcome Pathway (AOP) paradigm, coupled with an understanding of the chemistry underpinning the molecular initiating event (MIE) to provide a deep understanding of how structural fragments of molecules relate to specific mechanisms of nephrotoxicity. Aims covered: The aim of this investigation was to review the current scientific landscape related to computational methods, including mechanistic data, AOPs, publicly available knowledge bases and current in silico models, for the assessment of pharmaceuticals and other chemicals with regard to their potential to elicit nephrotoxicity. A list of over 250 nephrotoxicants enriched with, where possible, mechanistic and AOP-derived understanding was compiled. Expert opinion: Whilst little mechanistic evidence has been translated into AOPs, this review identified a number of data sources of in vitro, in vivo and human data that may assist in the development of in silico models which in turn may shed light on the inter-relationships between nephrotoxicity mechanisms

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Monthly variation in the probability of presence of adult Culicoides populations in nine European countries and the implications for targeted surveillance

Background: Biting midges of the genus Culicoides (Diptera: Ceratopogonidae) are small hematophagous insects responsible for the transmission of bluetongue virus, Schmallenberg virus and African horse sickness virus to wild and domestic ruminants and equids. Outbreaks of these viruses have caused economic damage within the European Union. The spatio-temporal distribution of biting midges is a key factor in identifying areas with the potential for disease spread. The aim of this study was to identify and map areas of neglectable adult activity for each month in an average year. Average monthly risk maps can be used as a tool when allocating resources for surveillance and control programs within Europe. Methods : We modelled the occurrence of C. imicola and the Obsoletus and Pulicaris ensembles using existing entomological surveillance data from Spain, France, Germany, Switzerland, Austria, Denmark, Sweden, Norway and Poland. The monthly probability of each vector species and ensembles being present in Europe based on climatic and environmental input variables was estimated with the machine learning technique Random Forest. Subsequently, the monthly probability was classified into three classes: Absence, Presence and Uncertain status. These three classes are useful for mapping areas of no risk, areas of high-risk targeted for animal movement restrictions, and areas with an uncertain status that need active entomological surveillance to determine whether or not vectors are present. Results: The distribution of Culicoides species ensembles were in agreement with their previously reported distribution in Europe. The Random Forest models were very accurate in predicting the probability of presence for C. imicola (mean AUC = 0.95), less accurate for the Obsoletus ensemble (mean AUC = 0.84), while the lowest accuracy was found for the Pulicaris ensemble (mean AUC = 0.71). The most important environmental variables in the models were related to temperature and precipitation for all three groups. Conclusions: The duration periods with low or null adult activity can be derived from the associated monthly distribution maps, and it was also possible to identify and map areas with uncertain predictions. In the absence of ongoing vector surveillance, these maps can be used by veterinary authorities to classify areas as likely vector-free or as likely risk areas from southern Spain to northern Sweden with acceptable precision. The maps can also focus costly entomological surveillance to seasons and areas where the predictions and vector-free status remain uncertain

Weight loss in a UK commercial all meal provision study: a randomised controlled trial

Background: Effective approaches are needed to address the increasing prev- alence of overweight and obesity. The present study investigated whether all meal provision was a more effective and acceptable method for weight loss than a self-directed diet. Methods: This randomised controlled trial recruited 112 men and women with a body mass index in the range 27–35 kg m–2, who had no comorbidi- ties, from the local area of Hull. Participants were randomised to receive either meal provision or follow a self-directed diet for a 12-week period that resulted in an estimated 2928 kJ day␣1 (700 kcal day␣1) deficit. A dietitian supervised both dietary interventions. Results: At 12 weeks [mean (SEM)], percentage weight loss in the meal provision group was 6.6% (0.5%) compared to 4.3% (0.6%) for those on the self-directed diet. In terms of clinically relevant weight loss, 61% of par- ticipants lost 5% or more of their body weight with meal provision com- pared to 22% on the self-directed diet (P < 0.001). Weight loss was associated with wellbeing in both groups. Attrition was less apparent with 7% of those participants receiving meal provision withdrawing from the study compared to 41% of those following the self-directed diet (P < 0.001). Conclusions: Meal provision was a more effective and accepted method for weight loss over a 12-week period compared to a self-directed diet. This may in part represent the difference between being given the meal provision food free of charge. However, longer-term maintenance studies need to be undertaken to ascertain their effects on the maintenance of weight loss

Identification of mutations in distinct regions of p85 alpha in urothelial cancer.

Bladder cancers commonly show genetic aberrations in the phosphatidylinositol 3-kinase signaling pathway. Here we have screened for mutations in PIK3R1, which encodes p85α, one of the regulatory subunits of PI3K. Two hundred and sixty-four bladder tumours and 41 bladder tumour cell lines were screened and 18 mutations were detected. Thirteen mutations were in C-terminal domains and are predicted to interfere with the interaction between p85α and p110α. Five mutations were in the BH domain of PIK3R1. This region has been implicated in p110α-independent roles of p85α, such as binding to and altering the activities of PTEN, Rab4 and Rab5. Expression of these mutant BH-p85α forms in mouse embryonic fibroblasts with p85α knockout indicated that all forms, except the truncation mutants, could bind and stabilize p110α but did not increase AKT phosphorylation, suggesting that BH mutations function independently of p110α. In a panel of 44 bladder tumour cell lines, 80% had reduced PIK3R1 mRNA expression relative to normal urothelial cells. This, along with mutation of PIK3R1, may alter BH domain functioning. Our findings suggest that mutant forms of p85α may play an oncogenic role in bladder cancer, not only via loss of ability to regulate p110α but also via altered function of the BH domain

Fetzer Franklin Fund Metascience 2019 Symposium: The Emerging Field of Research on the Scientific Process Participant Survey Summary, Highlights from Post-Survey Interviews of Selected Participants

Summary of post-event evaluation (survey and participant interviews) of Metascience 2019 Symposium (https://www.metascience2019.org/), presented by Fetzer Franklin Fund (https://www.fetzer-franklin-fund.org/) September 5th-8th, 2019 at Stanford University

Development of an <i>in Silico</i> Profiler for Mitochondrial Toxicity

This study outlines the analysis of mitochondrial toxicity for a variety of pharmaceutical drugs extracted from Zhang et al. ((2009) <i>Toxicol. In Vitro</i>, <i>23</i>, 134–140). These chemicals were grouped into categories based upon structural similarity. Subsequently, mechanistic analysis was undertaken for each category to identify the molecular initiating event driving mitochondrial toxicity. The mechanistic information elucidated during the analysis enabled mechanism-based structural alerts to be developed and combined together to form an <i>in silico</i> profiler. This profiler is envisaged to be used to develop chemical categories based upon similar mechanisms as part of the adverse outcome pathway paradigm. Additionally, the profiler could be utilized in screening large data sets in order to identify chemicals with the potential to induce mitochondrial toxicity