Cotrimoxazole for childhood febrile illness in Malaria-endemic regions

The efficacy of co-trimoxozole for the treatment of Plasmodium falciparum parasitaemia in children younger than 5 years of age was evaluated in Malawi. 46 children with P. falciparum parasitaemia, 37% of whom also met clinical criteria for a diagnosis of acute lower respiratory tract infection, were treated with 20 mglkg co-trimoxazole twice daily for five days. Parasitaemia (mean clearance time 2.7 days) and symptoms were rapidly abolished and improvement was maintained during follow-up for 14 days. Co-trimoxazole may be an effective single treatment for febrile illness in young children in areas where malaria is endemic, resources are few, and diagnosis must rely on clinical findings alone

Potential impact of a maternal vaccine for RSV: a mathematical modelling study

Respiratory syncytial virus (RSV) is a major cause of respiratory morbidity and one of the main causes of hospitalisation in young children. While there is currently no licensed vaccine for RSV, a vaccine candidate for pregnant women is undergoing phase 3 trials. We developed a compartmental age-structured model for RSV transmission, validated using linked laboratory-confirmed RSV hospitalisation records for metropolitan Western Australia. We adapted the model to incorporate a maternal RSV vaccine, and estimated the expected reduction in RSV hospitalisations arising from such a program. The introduction of a vaccine was estimated to reduce RSV hospitalisations in Western Australia by 6-37% for 0-2month old children, and 30-46% for 3-5month old children, for a range of vaccine effectiveness levels. Our model shows that, provided a vaccine is demonstrated to extend protection against RSV disease beyond the first three months of life, a policy using a maternal RSV vaccine could be effective in reducing RSV hospitalisations in children up to six months of age, meeting the objective of a maternal vaccine in delaying an infant's first RSV infection to an age at which severe disease is less likely

Epithelial cell shedding and barrier function: a matter of life and death at the small intestinal villus tip

The intestinal epithelium is a critical component of the gut barrier. Composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, this delicate structure prevents the transfer of harmful microorganisms, antigens, and toxins from the gut lumen into the circulation. The equilibrium between the rate of apoptosis and shedding of senescent epithelial cells at the villus tip, and the generation of new cells in the crypt, is key to maintaining tissue homeostasis. However, in both localized and systemic inflammation, this balance may be disturbed as a result of pathological IEC shedding. Shedding of IECs from the epithelial monolayer may cause transient gaps or microerosions in the epithelial barrier, resulting in increased intestinal permeability. Although pathological IEC shedding has been observed in mouse models of inflammation and human intestinal conditions such as inflammatory bowel disease, understanding of the underlying mechanisms remains limited. This process may also be an important contributor to systemic and intestinal inflammatory diseases and gut barrier dysfunction in domestic animal species. This review aims to summarize current knowledge about intestinal epithelial cell shedding, its significance in gut barrier dysfunction and host-microbial interactions, and where research in this field is directed

Building an international network for a primary care research program: reflections on challenges and solutions in the set-up and delivery of a prospective observational study of acute cough in 13 European countries

BACKGROUND: Implementing a primary care clinical research study in several countries can make it possible to recruit sufficient patients in a short period of time that allows important clinical questions to be answered. Large multi-country studies in primary care are unusual and are typically associated with challenges requiring innovative solutions. We conducted a multi-country study and through this paper, we share reflections on the challenges we faced and some of the solutions we developed with a special focus on the study set up, structure and development of Primary Care Networks (PCNs).METHOD: GRACE-01 was a multi-European country, investigator-driven prospective observational study implemented by 14 Primary Care Networks (PCNs) within 13 European Countries. General Practitioners (GPs) recruited consecutive patients with an acute cough. GPs completed a case report form (CRF) and the patient completed a daily symptom diary. After study completion, the coordinating team discussed the phases of the study and identified challenges and solutions that they considered might be interesting and helpful to researchers setting up a comparable study.RESULTS: The main challenges fell within three domains as follows:i) selecting, setting up and maintaining PCNs;ii) designing local context-appropriate data collection tools and efficient data management systems; andiii) gaining commitment and trust from all involved and maintaining enthusiasm.The main solutions for each domain were:i) appointing key individuals (National Network Facilitator and Coordinator) with clearly defined tasks, involving PCNs early in the development of study materials and procedures.ii) rigorous back translations of all study materials and the use of information systems to closely monitor each PCNs progress;iii) providing strong central leadership with high level commitment to the value of the study, frequent multi-method communication, establishing a coherent ethos, celebrating achievements, incorporating social events and prizes within meetings, and providing a framework for exploitation of local data.CONCLUSIONS: Many challenges associated with multi-country primary care research can be overcome by engendering strong, effective communication, commitment and involvement of all local researchers. The practical solutions identified and the lessons learned in implementing the GRACE-01 study may assist in establishing other international primary care clinical research platforms

Creation of a multiple-use recombinant inbred line population for the development of molecular markers in soft white winter wheat

Tese de doutoramento em Física (Pré-Bolonha), especialidade de Física Experimental, apresentada à Faculdade de Ciências e Tecnologia da Universidade de CoimbraPositron emission tomography based on resistive plate chambers (RPC-PET) has been proposed for both preclinical and clinical applications. We firstly present imaging results of needle-like and planar 22Na sources obtained with a prototype of a high-acceptance small-animal RPC-PET. The two detector modules utilized in this experiment had an effective front face of 6.4 x 6.4 cm^2 and consisted of 5 gas gaps and 6 glass electrodes with a total thickness of 5 mm. The data included lines of response (LORs) inclined up to 58º, and the depth of interaction (DOI) was accurately measured, demonstrating the parallax-free property inherent to RPC-PET. The maximum likelihood expectation-maximization (MLEM) reconstruction of the acquired data yielded an excellent and stable resolution of 0.4 mm full width at half maximum (FWHM). Concurrently, we pursued studies of a suggested whole-body single-bed RPC-PET. It has been shown by simulation that RPC-PET with an axial field-of-view (AFOV) of 2.4 m is feasible and yields an absolute sensitivity at least one order of magnitude superior to that of typical crystal-based PET scanners. In addition, RPC-PET offers an important time-of-flight (TOF) advantage and provides a potentially very-high spatial resolution at the detector level. In the second part of this work, a fully three-dimensional reconstruction algorithm capable of processing the very inclined LORs from large AFOV systems such as RPC-PET is demonstrated. It relies on the application of a TOF-based-kernel into the MLEM algorithm. With the 300 ps FWHM time resolution, already experimentally demonstrated, a rejection of 63% of the body-scattered events is obtained. We present reconstructed results from blind simulations corresponding to the anthropomorphic phantom, NCAT, with oncological lesions introduced into different locations within the human body. A comparison between 300 and 600 ps FWHM TOF reconstructed images is performed, with an increasing detectability being observed for a better TOF resolution. We finally compare issues related to image convergence speed. An alternative new approach, which consists in dividing the full-body data into nine different image regions that are reconstructed independently with graphical processing unit (GPU) assistance, provides a six times faster reconstruction compared with a GPU-based whole-body reconstruction. For a 300 ps FWHM RPC-PET scanner, this allows reaching a reconstructed image, that results from 1.6 x 10^10 annihilations within 7 minutes and upon injection of 2 mCi, just 4 minutes after the end of data acquisition. We conclude that RPC-PET is well oriented to compete with other commercial PET scanners in the global market.A tomografia por emissão de positrões baseada em detectores do tipo câmaras de placas resistivas (RPC-PET) foi proposta para aplicação em ensaios com pequenos animais e na prática clínica. Neste trabalho, apresentamos primeiramente resultados experimentais obtidos a partir de um protótipo RPC-PET de alta aceitação para pequenos animais. Foram obtidas imagens de fontes do radioisótopo 22Na, uma quase pontual e outra planar. Usámos dois módulos de detectores RPC com uma área activa de 6.4 x 6.4 cm^2 e uma espessura de 5 mm, constituída por 6 vidros empilhados e 5 espaços gasosos definidos entre eles. Os dados adquiridos incluíram linhas de coincidência (LORs) inclinadas até um ângulo de 58º, tornando essencial a medida precisa da profundidade de interacção. A identificação dos espaços gasosos onde ocorreram as avalanches permitiu demonstrar a ausência de erro de paralaxe nas medidas realizadas com o RPC-PET para pequenos animais. A partir da reconstrução dos dados processados com o algoritmo maximum likelihood expectation-maximization (MLEM), obtivemos uma resolução espacial com largura a meia altura (FWHM) de 0.4 mm, excelente e estável. Em paralelo, continuámos a estudar as potencialidades de um protótipo RPC-PET de corpo inteiro e cama única, orientado para pessoas. Já foi anteriormente demonstrado por simulação que um scanner RPC-PET com 2.4 m de campo de visão axial (AFOV) é viável e permitirá o aumento de sensibilidade de pelo menos uma ordem de grandeza em relação aos scanners PET com cristais. Duas outras virtudes do RPC-PET são a sua capacidade de medição do tempo de voo (TOF) dos fotões e a elevada resolução espacial ao nível do detector. Na segunda parte deste trabalho apresentamos um algoritmo de reconstrução, totalmente tridimensional, capaz de processar LORs muito inclinadas em sistemas com um AFOV longo, como é o caso do RPC-PET. Este algoritmo acrescenta um kernel ao algoritmo MLEM, baseado na informação de TOF. Com uma resolução temporal de 300 ps FWHM, já experimentalmente comprovada, é possível rejeitar 63% dos eventos dispersados no corpo humano. Exibimos imagens reconstruídas obtidas a partir de simulações do fantoma antropomórfico, NCAT, com lesões oncológicas situadas em diferentes locais do corpo humano. A comparação entre imagens conseguidas com resoluções temporais de 300 ps e 600 ps FWHM, permite observar uma detectabilidade acrescida associada à melhor resolução de TOF. Por último, são estudados os tempos de convergência da reconstrução. Um método inovador e alternativo, que consiste na divisão dos dados do corpo humano em nove regiões e na reconstrução independente desses dados com recurso a unidades de processamento gráfico (GPUs), permite uma reconstrução seis vezes mais rápida do que a reconstrução de corpo inteiro também com o auxílio de GPUs. A partir de dados de 1.6 x 10^10 aniquilações ocorridas durante uma aquisição de 7 minutos e para uma actividade injectada de 2 mCi, um scanner RPC-PET com uma resolução temporal de 300 ps FWHM permitirá obter uma imagem reconstruída apenas 4 minutos após o fim da aquisição. Podemos assim concluir que o RPC-PET está bem colocado para competir no mercado dos scanners PET comerciais

Development of an intervention to support the implementation of evidence-based strategies for optimising antibiotic prescribing in general practice.

BACKGROUND: Trials show that antimicrobial stewardship (AMS) strategies, including communication skills training, point-of-care C-reactive protein testing (POC-CRPT) and delayed prescriptions, help optimise antibiotic prescribing and use in primary care. However, the use of these strategies in general practice is limited and inconsistent. We aimed to develop an intervention to enhance uptake and implementation of these strategies in primary care. METHODS: We drew on the Person-Based Approach to develop an implementation intervention in two stages. (1) Planning and design: We defined the problem in behavioural terms drawing on existing literature and conducting primary qualitative research (nine focus groups) in high-prescribing general practices. We identified 'guiding principles' with intervention objectives and key features and developed logic models representing intended mechanisms of action. (2) Developing the intervention: We created prototype intervention materials and discussed and refined these with input from 13 health professionals and 14 citizens in two sets of design workshops. We further refined the intervention materials following think-aloud interviews with 22 health professionals. RESULTS: Focus groups highlighted uncertainties about how strategies could be used. Health professionals in the workshops suggested having practice champions, brief summaries of each AMS strategy and evidence supporting the AMS strategies, and they and citizens gave examples of helpful communication strategies/phrases. Think-aloud interviews helped clarify and shorten the text and user journey of the intervention materials. The intervention comprised components to support practice-level implementation: antibiotic champions, practice meetings with slides provided, and an 'implementation support' website section, and components to support individual-level uptake: website sections on each AMS strategy (with evidence, instructions, links to electronic resources) and material resources (patient leaflets, POC-CRPT equipment, clinician handouts). CONCLUSIONS: We used a systematic, user-focussed process of developing a behavioural intervention, illustrating how it can be used in an implementation context. This resulted in a multicomponent intervention to facilitate practice-wide implementation of evidence-based strategies which now requires implementing and evaluating. Focusing on supporting the uptake and implementation of evidence-based strategies to optimise antibiotic use in general practice is critical to further support appropriate antibiotic use and mitigate antimicrobial resistance

Stem cell differentiation increases membrane-actin adhesion regulating cell blebability, migration and mechanics

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/K. S. is funded by an EPSRC PhD studentship. S.T. is funded by an EU Marie Curie Intra European Fellowship (GENOMICDIFF)

Privacy in crowdsourcing:a systematic review

The advent of crowdsourcing has brought with it multiple privacy challenges. For example, essential monitoring activities, while necessary and unavoidable, also potentially compromise contributor privacy. We conducted an extensive literature review of the research related to the privacy aspects of crowdsourcing. Our investigation revealed interesting gender differences and also differences in terms of individual perceptions. We conclude by suggesting a number of future research directions.</p

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor