Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p> <p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p> <p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p&gt

Augmenting the 6-3-5 method with design information

This paper describes a comparative study between the 6-3-5 Method and the ICR Grid. The ICR Grid is an evolved variant of 6-3-5 intended to better integrate information into the concept generation process. Unlike a conventional 6-3-5 process where participants continually sketch concepts, using the ICR Grid (the name derived from its Inform, Create, Reflect activities and structured, grid-like output) participants are additionally required to undertake information search tasks, use specific information items for concept development, and reflect on the merit of concepts as the session progresses. The results indicate that although the quantity of concepts was lower, the use of information had a positive effect in a number of areas, principally the quality and variety of output. Although grounded in the area of product development, this research is applicable to any organisation undertaking idea generation and problem solving. As well as providing insights on the transference of information to concepts, it holds additional interest for studies on the composition and use of digital libraries

Primary care-based models of care for osteoarthritis: a scoping review protocol

Data availability: Underlying data: No underlying data are associated with this article.Background: The burden of osteoarthritis (OA) to individuals and health systems is substantial and is expected to increase due to population ageing and rising prevalence of obesity and multimorbidity. Primary care-based models of care (MoCs) are being increasingly developed in response to this growing burden. However, these MoCs have yet to be formally reviewed. A MoC can be defined as an ‘evidence-informed strategy, framework or pathway that outlines the optimal manner in which condition-specific care should be delivered to consumers within a local health system’. Objective: To identify and describe the available research regarding the extent, nature and characteristics of MoCs for OA that have been developed or evaluated in primary care. Methods: A scoping review will be conducted in accordance with the Arksey and O’Malley scoping review framework and the PRISMA-ScR guidelines. Systematic literature searches of MEDLINE, EMBASE, CINAHL, PsychINFO, Web of Science and LILACs will be conducted from 2010 to present, aligning with publication dates of recent clinical guidelines. A structured iterative search of grey literature will be conducted. Full-text original quantitative or mixed method studies which describe the development or evaluation of MoCs for OA in primary care will be considered. Data will be charted and synthesised and a narrative synthesis will be conducted. Conclusions: This scoping review will provide a broad overview regarding the extent, nature and characteristics of the available literature on primary care based MoCs for OA. Findings will be used to identify gaps in the current evidence to identify areas for future research.Health Research Board (HRB) Investigator-Led Project Award to HPF [LP-HSR 2019-012; BC is funded by Health Research Board (HRB) Emerging Investigator Award [EIA-2019-09]

Primary care-based models of care for osteoarthritis; a scoping review

Supplementary materials are available online at https://www.sciencedirect.com/science/article/pii/S004901722300063X?via%3Dihub#sec0028 .Copyright © 2023 The Authors Objective: To identify and describe the extent, nature, characteristics, and impact of primary care-based models of care (MoCs) for osteoarthritis (OA) that have been developed and/or evaluated. Design: Six electronic databases were searched from 2010 to May 2022. Relevant data were extracted and collated for narrative synthesis. Results: Sixty-three studies pertaining to 37 discrete MoCs from 13 countries were included, of which 23 (62%) could be classified as OA management programmes (OAMPs) comprising a self-management intervention to be delivered as a discrete package. Four models (11%) focussed on enhancing the initial consultation between a patient presenting with OA at the first point of contact into a local health system and the clinician. Emphasis was placed on educational training for general practitioners (GPs) and allied healthcare professionals delivering this initial consultation. The remaining 10 MoCs (27%) detailed integrated care pathways of onward referral to specialist secondary orthopaedic and rheumatology care within local healthcare systems. The majority (35/37; 95%) were developed in high-income countries and 32/37 (87%) targeted hip/and or knee OA. Frequently identified model components included GP-led care, referral to primary care services and multidisciplinary care. The models were predominantly ‘one-size fits all’ and lacked individualised care approaches. A minority of MoCs, 5/37 (14%) were developed using underlying frameworks, three (8%) of which incorporated behaviour change theories, while 13/37 (35%) incorporated provider training. Thirty-four of the 37 models (92%) were evaluated. Outcome domains most frequently reported included clinical outcomes, followed by system- and provider-level outcomes. While there was evidence of improved quality of OA care associated with the models, effects on clinical outcomes were mixed. Conclusion: There are emerging efforts internationally to develop evidence-based models focused on non-surgical primary care OA management. Notwithstanding variations in healthcare systems and resources, future research should focus on model development alignment with implementation science frameworks and theories, key stakeholder involvement including patient and public representation, provision of training and education for providers, treatment individualisation, integration and coordination of services across the care continuum and incorporation of behaviour change strategies to foster long-term adherence and self-management.Health Research Board Ireland Investigator-Led Project Award to HPF [ILP-HSR-2019-012]

Estimation of changes in the force of infection for intestinal and urogenital schistosomiasis in countries with Schistosomiasis Control Initiative-assisted programmes

The last decade has seen an expansion of national schistosomiasis control programmes in Africa based on large-scale preventative chemotherapy. In many areas this has resulted in considerable reductions in infection and morbidity levels in treated individuals. In this paper, we quantify changes in the force of infection (FOI), defined here as the per (human) host parasite establishment rate, to ascertain the impact on transmission of some of these programmes under the umbrella of the Schistosomiasis Control Initiative (SCI)

Logics of knowledge and action: critical analysis and challenges

International audienceWe overview the most prominent logics of knowledge and action that were proposed and studied in the multiagent systems literature. We classify them according to these two dimensions, knowledge and action, and moreover introduce a distinction between individual knowledge and group knowledge, and between a nonstrategic an a strategic interpretation of action operators. For each of the logics in our classification we highlight problematic properties. They indicate weaknesses in the design of these logics and call into question their suitability to represent knowledge and reason about it. This leads to a list of research challenges

Learning and Long-Term Retention of Large-Scale Artificial Languages

Recovering discrete words from continuous speech is one of the first challenges facing language learners. Infants and adults can make use of the statistical structure of utterances to learn the forms of words from unsegmented input, suggesting that this ability may be useful for bootstrapping language-specific cues to segmentation. It is unknown, however, whether performance shown in small-scale laboratory demonstrations of “statistical learning” can scale up to allow learning of the lexicons of natural languages, which are orders of magnitude larger. Artificial language experiments with adults can be used to test whether the mechanisms of statistical learning are in principle scalable to larger lexicons. We report data from a large-scale learning experiment that demonstrates that adults can learn words from unsegmented input in much larger languages than previously documented and that they retain the words they learn for years. These results suggest that statistical word segmentation could be scalable to the challenges of lexical acquisition in natural language learning.National Science Foundation (U.S.) (NSF DDRIG #0746251

Spatial Distribution of Calcium-Gated Chloride Channels in Olfactory Cilia

Background: In vertebrate olfactory receptor neurons, sensory cilia transduce odor stimuli into changes in neuronal membrane potential. The voltage changes are primarily caused by the sequential openings of two types of channel: a cyclic-nucleotide-gated (CNG) cationic channel and a calcium-gated chloride channel. In frog, the cilia are 25 to 200 mm in length, so the spatial distributions of the channels may be an important determinant of odor sensitivity. Principal Findings: To determine the spatial distribution of the chloride channels, we recorded from single cilia as calcium was allowed to diffuse down the length of the cilium and activate the channels. A computational model of this experiment allowed an estimate of the spatial distribution of the chloride channels. On average, the channels were concentrated in a narrow band centered at a distance of 29 % of the ciliary length, measured from the base of the cilium. This matches the location of the CNG channels determined previously. This non-uniform distribution of transduction proteins is consistent with similar findings in other cilia. Conclusions: On average, the two types of olfactory transduction channel are concentrated in the same region of the cilium

A Research Agenda for Helminth Diseases of Humans: Modelling for Control and Elimination

Mathematical modelling of helminth infections has the potential to inform policy and guide research for the control and elimination of human helminthiases. However, this potential, unlike in other parasitic and infectious diseases, has yet to be realised. To place contemporary efforts in a historical context, a summary of the development of mathematical models for helminthiases is presented. These efforts are discussed according to the role that models can play in furthering our understanding of parasite population biology and transmission dynamics, and the effect on such dynamics of control interventions, as well as in enabling estimation of directly unobservable parameters, exploration of transmission breakpoints, and investigation of evolutionary outcomes of control. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A research and development agenda for helminthiasis modelling is proposed based on identified gaps that need to be addressed for models to become useful decision tools that can support research and control operations effectively. This agenda includes the use of models to estimate the impact of large-scale interventions on infection incidence; the design of sampling protocols for the monitoring and evaluation of integrated control programmes; the modelling of co-infections; the investigation of the dynamical relationship between infection and morbidity indicators; the improvement of analytical methods for the quantification of anthelmintic efficacy and resistance; the determination of programme endpoints; the linking of dynamical helminth models with helminth geostatistical mapping; and the investigation of the impact of climate change on human helminthiases. It is concluded that modelling should be embedded in helminth research, and in the planning, evaluation, and surveillance of interventions from the outset. Modellers should be essential members of interdisciplinary teams, propitiating a continuous dialogue with end users and stakeholders to reflect public health needs in the terrain, discuss the scope and limitations of models, and update biological assumptions and model outputs regularly. It is highlighted that to reach these goals, a collaborative framework must be developed for the collation, annotation, and sharing of databases from large-scale anthelmintic control programmes, and that helminth modellers should join efforts to tackle key questions in helminth epidemiology and control through the sharing of such databases, and by using diverse, yet complementary, modelling approaches

Is it feasible and effective to provide osteopathy and acupuncture for patients with musculoskeletal problems in a GP setting? A service evaluation

<p>Abstract</p> <p>Background</p> <p>Spinal manipulation and acupuncture can be helpful in reducing the symptoms of musculoskeletal (MSK) pain. Both approaches are currently recommended by NICE as treatment options for patients with persistent low back pain. However, there has been no previous evaluation of a GP service using them together for MSK pain. The purpose of this study was to evaluate acceptability and outcomes for an osteopathy and acupuncture service (delivered by complementary therapy practitioners) for patients with MSK problems provided within a General Practice.</p> <p>Methods</p> <p>Patients were asked to complete a questionnaire before and after their course of treatment. Outcome measures included the Bournemouth Questionnaire (measuring MSK problems), EuroQoL-5D (measuring quality of life), medication use, physical activity and general well-being. Non-parametric tests were used to compare pre- and post- treatment variables. Qualitative data, regarding participants' views on the service, were collected from patients via a service survey and healthcare professionals via interviews. Qualitative data were analysed using thematic analysis.</p> <p>Results</p> <p>123 adults with MSK problems were referred into the service (79 female and 44 male, mean age 49 years). Complete patient questionnaire data sets (pre- and post- treatment) were available for 102 participants; 91 completed a service survey. All healthcare professionals involved in the service participated in interviews including all seven GPs and the administration manager at the practice, as well as the three acupuncture/osteopathy practitioners.</p> <p>Patient outcomes: comparisons between pre and post-treatment revealed a statistically significant improvement in MSK pain (p < 0.0001) and quality of life (p < 0.0001), and a statistically significant reduction in medication use (p < 0.0001). Qualitative analysis found that patients reported improvements in their MSK pain, mobility, other physical health conditions, well-being and self-management of their MSK problem.</p> <p>Acceptability of the service: overall patients and healthcare professionals were satisfied with the service and its provision within the Practice. Patients reported wanting increased appointment availability and flexibility, and more sessions. Complementary therapy practitioners reported finding the high number of referrals of chronic patients challenging, and wanting increased communication with GPs.</p> <p>Conclusions</p> <p>Provision of acupuncture and osteopathy for MSK pain is achievable in General Practice. A GP surgery can quickly adapt to incorporate complementary therapy provided key principles are followed.</p