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Primate malarias: Diversity, distribution and insights for zoonotic Plasmodium
Protozoans within the genus Plasmodium are well-known as the causative agents of malaria in humans. Numerous Plasmodium species parasites also infect a wide range of non-human primate hosts in tropical and sub-tropical regions worldwide. Studying this diversity can provide critical insight into our understanding of human malarias, as several human malaria species are a result of host switches from non-human primates. Current spillover of a monkey malaria, Plasmodium knowlesi, in Southeast Asia highlights the permeability of species barriers in Plasmodium. Also recently, surveys of apes in Africa uncovered a previously undescribed diversity of Plasmodium in chimpanzees and gorillas. Therefore, we carried out a meta-analysis to quantify the global distribution, host range, and diversity of known non-human primate malaria species. We used published records of Plasmodium parasites found in non-human primates to estimate the total diversity of non-human primate malarias globally. We estimate that at least three undescribed primate malaria species exist in sampled primates, and many more likely exist in unstudied species. The diversity of malaria parasites is especially uncertain in regions of low sampling such as Madagascar, and taxonomic groups such as African Old World Monkeys and gibbons. Presence–absence data of malaria across primates enables us to highlight the close association of forested regions and non-human primate malarias. This distribution potentially reflects a long coevolution of primates, forest-adapted mosquitoes, and malaria parasites. The diversity and distribution of primate malaria are an essential prerequisite to understanding the mechanisms and circumstances that allow Plasmodium to jump species barriers, both in the evolution of malaria parasites and current cases of spillover into humans
Help-Seeking among People with Symptoms of Lung or Colorectal Cancer: Experience and social context
The UK has some of the poorest cancer outcomes in Europe, commonly attributed to diagnostic delays. The patient interval appears to be a substantial contributor to these, with awareness raising campaigns a key strategy for encouraging earlier presentation. However, research has identified a number of barriers to help-seeking beyond awareness, such as fear, concerns about wasting the doctor’s time, personal commitments and access.
This research sought to explore social context and help-seeking for people with symptoms of lung or colorectal cancer, comparing the experiences of prompt consulters with those who prolonged presentation. 164 people with symptoms of lung or colorectal cancer completed a questionnaire on symptom experience and social context and 26 of these took part in follow-up semi-structured interviews.
People with symptoms of bleeding or pain had shorter patient intervals than those experiencing other symptoms. Those with symptoms which were perceived of as severe body state deviations decided to seek help much quicker than those with general or systemic symptoms, who instead reappraised symptoms over time. Symptom appraisal and help-seeking processes were informed by numerous contributory elements, which were drawn from four contextual domains of a person's life; individual experience, interpersonal relationships, health care system interactions and social and temporal context. They included micro-level elements, such as exposure to carcinogens as well as macro-level factors, like social discourses on morality, calling into question the centrality of awareness-raising campaigns to encourage earlier presentation among the symptomatic population. A novel model The Contextual Model of the Patient Interval, is presented to illustrate this part of the diagnostic pathway.
The concept of risk is used to explain how people assess the necessity of help-seeking and the threshold of tolerability is introduced as a means of explaining the timing of help-seeking decision making, based on contextual contributory elements and symptom burden. The assessment of cancer risk is one contributory element which is explored in detail and its incorporation into calculations of the threshold of tolerability is considered. The idea of 'critical incidents' is used to explain the assessment of cancer risk among people who consulted quickly about symptoms, with 'cancer candidacy' being used to explain the cancer risk assessments undertaken by those with prolonged patient intervals.
In line with a societal focus on risk generally, public health developments have now resulted in a shift away from contagion and treatment, towards prediction and prevention, under the 'new public health' approach. The focus on risk and prevention has created an environment in which discourses of 'early presentation' and the 'good patient' have emerged. These discourses place moral obligations on people in relation to acceptable responses to symptoms and the need to present oneself as a 'good patient', which are explored through the examples of 'time wasting', the Be Clear on Cancer campaign, and discrepant reports of patient interval length from this study
Risk and the importance of absent symptoms in constructions of the ‘cancer candidate’
Cancer is a disease that is imbued with notions of risk, with individuals expected to avoid ‘risky’ behaviours and act swiftly when symptoms indicating a risk of cancer emerge. Cancer symptoms, however, are often ambiguous and indicative of a number of other conditions, making it difficult for people to assess when symptoms may, or may not, be the result of cancer. Here, we discuss interview data from a study examining the symptom appraisal and help-seeking experiences of patients referred for assessment of symptoms suspicious of a lung or colorectal cancer in the North-East of England. We explore how individuals draw upon ideas about cancer risks to assess whether cancer may be a possible explanation for their symptoms and to inform their decisions about help-seeking. In our analysis, we applied the concept of candidacy to the data, to highlight how lay epidemiology shapes people’s perceptions of cancer risk, and their subsequent responses to it. We found that participants appraised their symptoms, and the likelihood that they may have cancer, in light of relevant information on risk. These sources of information related to lifestyle factors, family history of cancer, environmental factors, and importantly, the symptomatic experience itself, including the absence of symptoms that participants associated with cancer. The importance of experienced, and absent, symptoms was a core element of participants’ everyday constructions of the ‘cancer candidate’, which informed symptom appraisal and subsequent help-seeking decision-making
Barriers to Early Presentation amongst Rural Residents Experiencing Symptoms of Colorectal Cancer : A Qualitative Interview Study
Peer reviewedPublisher PD
Reconceptualising Rural Cancer Inequalities : Time for a New Research Agenda
Peer reviewedPublisher PD
Scaling analysis reveals the mechanism and rates of prion replication in vivo.
Prions consist of pathological aggregates of cellular prion protein and have the ability to replicate, causing neurodegenerative diseases, a phenomenon mirrored in many other diseases connected to protein aggregation, including Alzheimer's and Parkinson's diseases. However, despite their key importance in disease, the individual processes governing this formation of pathogenic aggregates, as well as their rates, have remained challenging to elucidate in vivo. Here we bring together a mathematical framework with kinetics of the accumulation of prions in mice and microfluidic measurements of aggregate size to dissect the overall aggregation reaction into its constituent processes and quantify the reaction rates in mice. Taken together, the data show that multiplication of prions in vivo is slower than in in vitro experiments, but efficient when compared with other amyloid systems, and displays scaling behavior characteristic of aggregate fragmentation. These results provide a framework for the determination of the mechanisms of disease-associated aggregation processes within living organisms
Backbone 1H, 13C, and 15N resonance assignments for lysozyme from bacteriophage lambda
Lysozyme from lambda bacteriophage (λ lysozyme) is an 18 kDa globular protein displaying some of the structural features common to all lysozymes; in particular, λ lysozyme consists of two structural domains connected by a helix, and has its catalytic residues located at the interface between these two domains. An interesting feature of λ lysozyme, when compared to the well-characterised hen egg-white lysozyme, is its lack of disulfide bridges; this makes λ lysozyme an interesting system for studies of protein folding. A comparison of the folding properties of λ lysozyme and hen lysozyme will provide important insights into the role that disulfide bonds play in the refolding pathway of the latter protein. Here we report the 1H, 13C and 15N backbone resonance assignments for λ lysozyme by heteronuclear multidimensional NMR spectroscopy. These assignments provide the starting point for detailed investigation of the refolding pathway using pulse-labelling hydrogen/deuterium exchange experiments monitored by NMR
Factor X activating Atractaspis snake venoms and the relative coagulotoxicity neutralising efficacy of African antivenoms
Atractaspis snake species are enigmatic in their natural history, and venom effects are correspondingly poorly described. Bite reports are scarce but bites have been described as causing severe hypertension, profound local tissue damage leading to amputation, and deaths are on record. Clinical descriptions have largely concentrated upon tissue effects, and research efforts have focused upon the blood-pressure affecting sarafotoxins. However, coagulation disturbances suggestive of procoagulant functions have been reported in some clinical cases, yet this aspect has been uninvestigated. We used a suite of assays to investigate the coagulotoxic effects of venoms from six different Atractaspis specimens from central Africa. The procoagulant function of factor X activation was revealed, as was the pseudo-procoagulant function of direct cleavage of fibrinogen into weak clots. The relative neutralization efficacy of South African Antivenom Producer's antivenoms on Atractaspis venoms were boomslang>polyvalent>saw-scaled viper. While the boomslang antivenom was the most effective on Atractaspis venoms, the ability to neutralize the most potent Atractaspis species in this study was up to 4-6 times less effective than boomslang antivenom neutralizes boomslang venom. Therefore, while these results suggest cross-reactivity of boomslang antivenom with the unexpectedly potent coagulotoxic effects of Atractaspis venoms, a considerable amount of this rare antivenom may be needed. This report thus reveals potent venom actions upon blood coagulation that may lead to severe clinical effects with limited management strategies
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
Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset
Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline
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