Dynamical analysis of spatial interaction models

We develop a novel dynamical method to examine spatial interaction models (SIMs). For each SIM, we use our dynamical framework to model emigration patterns. We look at the resulting population distributions to see if they are realistic or not. We use the US census data from 2010 and various spatial statistics to access the success or failure of each model. While we looked at over eighty different SIMs, we will focus here on two examples: the production constrained gravity model and the Radiation model. The results suggest that all these models fail to produce realistic population distributions and we identify the flaws within existing models. This leads us to suggest that we should define site attractiveness in terms of a second short range SIM leading to a new spatial interaction model - the Two-Trip model - which offers significant improvements when examined via our method. We also note that our Two-Trip adaptation can be used in any spatial modelling contexts, not just emigration

Using the Traditional Ex Vivo Whole Blood Model to Discriminate Bacteria by Their Inducible Host Responses

\ua9 2024 by the authors.Whole blood models are rapid and versatile for determining immune responses to inflammatory and infectious stimuli, but they have not been used for bacterial discrimination. Staphylococcus aureus, S. epidermidis and Escherichia coli are the most common causes of invasive disease, and rapid testing strategies utilising host responses remain elusive. Currently, immune responses can only discriminate between bacterial ‘domains’ (fungi, bacteria and viruses), and very few studies can use immune responses to discriminate bacteria at the species and strain level. Here, whole blood was used to investigate the relationship between host responses and bacterial strains. Results confirmed unique temporal profiles for the 10 parameters studied: IL-6, MIP-1α, MIP-3α, IL-10, resistin, phagocytosis, S100A8, S100A8/A9, C5a and TF3. Pairwise analysis confirmed that IL-6, resistin, phagocytosis, C5a and S100A8/A9 could be used in a discrimination scheme to identify to the strain level. Linear discriminant analysis (LDA) confirmed that (i) IL-6, MIP-3α and TF3 could predict genera with 95% accuracy; (ii) IL-6, phagocytosis, resistin and TF3 could predict species at 90% accuracy and (iii) phagocytosis, S100A8 and IL-10 predicted strain at 40% accuracy. These data are important because they confirm the proof of concept that host biomarker panels could be used to identify bacterial pathogens

Mesenteric panniculitis with pedal edema in a 33-year-old Pakistani man: a case report and literature review

<p>Abstract</p> <p>Introduction</p> <p>Mesenteric panniculitis is a rare pathology of unknown etiology characterized by inflammation and fibrosis in the mesentery. Its protean clinical and radiological manifestations make it a diagnostic challenge. There is no established treatment available for its management. The clinical outcome is inconsistent, with the prognosis ranging from complete resolution without any treatment to rapid progression culminating in death.</p> <p>Case presentation</p> <p>A 33-year-old Pakistani man presented with vague abdominal pain, an ill-defined epigastric mass and bilateral pedal edema. A detailed review of his history and laboratory investigations did not point to any diagnosis. The patient underwent an exploratory laparotomy based on the finding of mesenteric soft-tissue density on computed tomography. The laparotomy did not prove to be of any diagnostic or therapeutic value. Upon review of the pre-operative computed tomographic scan at our institution, a diagnosis of mesenteric panniculitis was made. An acceptable resolution of abdominal pain and pedal edema was attained after a 4-week trial of immunosuppressive therapy. This is the first reported case of mesenteric panniculitis with pedal edema as part of its presentation.</p> <p>Conclusion</p> <p>An increased awareness may lead to the development of a less invasive diagnostic approach and optimal treatment for this rarely recognized condition.</p

Protocol for faecal microbiota transplantation in ulcerative colitis (FMTUC): a randomised feasibility study

Background The interaction of the gut microbiota with the human host is implicated in the pathogenesis of inflammatory and immunological diseases including ulcerative colitis (UC). Faecal microbiota transplantation (FMT) as a method of restoring gut microbial diversity is of increasing interest as a therapeutic approach in the management of UC. The current literature lacks consensus about the dose of FMT, route of administration and duration of response. Methods and analysis This single-blinded randomised trial will explore the feasibility of FMT in 30 treatment-naïve patients with histologically confirmed distal UC limited to the recto-sigmoid region (up to 40 cm from the anal verge). This study aims to estimate the magnitude of treatment response to FMT under controlled conditions. The intervention (FMT) will be administered by rectal retention enema. It will test the feasibility of randomising patients to: (i) single FMT dose, (ii) five daily FMT doses or (iii) control (no FMT dose). All groups will receive standard antibiotic gut decontamination and bowel preparation before FMT. Recruitment will take place over a 24-month period with a 12-week patient follow-up. Trial objectives include evaluation of the magnitude of treatment response to FMT, investigation of the clinical value of metabolic phenotyping for predicting the clinical response to FMT and testing the recruitment rate of donors and patients for a study in FMT. This feasibility trial will enable an estimate of number of patients needed, help determine optimal study conditions and inform the choice of endpoints for a future definitive phase III study. Ethics and dissemination The trial is approved by the regional ethics committee and is sponsored by Abertawe Bro Morgannwg University’s Health Board. Written informed consent from all patients will be obtained. Serious adverse events will be reported to the sponsor. Trial results will be disseminated via peer review publication and shared with trial participants. Trial registration number ISRCTN58082603; Pre-results

Contribution of microscopy for understanding the mechanism of action against trypanosomatids

Transmission electron microscopy (TEM) has proved to be a useful tool to study the ultrastructural alterations and the target organelles of new antitrypanosomatid drugs. Thus, it has been observed that sesquiterpene lactones induce diverse ultrastructural alterations in both T. cruzi and Leishmania spp., such as cytoplasmic vacuolization, appearance of multilamellar structures, condensation of nuclear DNA, and, in some cases, an important accumulation of lipid vacuoles. This accumulation could be related to apoptotic events. Some of the sesquiterpene lactones (e.g., psilostachyin) have also been demonstrated to cause an intense mitochondrial swelling accompanied by a visible kinetoplast deformation as well as the appearance of multivesicular bodies. This mitochondrial swelling could be related to the generation of oxidative stress and associated to alterations in the ergosterol metabolism. The appearance of multilamellar structures and multiple kinetoplasts and flagella induced by the sesquiterpene lactone psilostachyin C indicates that this compound would act at the parasite cell cycle level, in an intermediate stage between kinetoplast segregation and nuclear division. In turn, the diterpene lactone icetexane has proved to induce the external membrane budding on T. cruzi together with an apparent disorganization of the pericellar cytoskeleton. Thus, ultrastructural TEM studies allow elucidating the possible mechanisms and the subsequent identification of molecular targets for the action of natural compounds on trypanosomatids.Fil: Lozano, Esteban Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Spina Zapata, Renata María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Barrera, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Tonn, Carlos Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Sosa Escudero, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Education, sense of mastery and mental health: results from a nation wide health monitoring study in Norway

<p>Abstract</p> <p>Background</p> <p>Earlier studies have shown that people with low level of education have increased rates of mental health problems. The aim of the present study is to investigate the association between level of education and psychological distress, and to explore to which extent the association is mediated by sense of mastery, and social variables like social support, negative life events, household income, employment and marital status.</p> <p>Methods</p> <p>The data for the study were obtained from the Level of Living Survey conducted by Statistics Norway in 2002. Data on psychological distress and psychosocial variables were gathered by a self-administered questionnaire, whereas socio-demographic data were based on register statistics. Psychological distress was measured by Hopkins Symptom Checklist 25 items.</p> <p>Results</p> <p>There was a significant association between low level of education and psychological distress in both genders, the association being strongest in women aged 55–67 years. Low level of education was also significantly associated with low sense of mastery, low social support, many negative life events (only in men), low household income and unemployment,. Sense of mastery emerged as a strong mediating variable between level of education and psychological distress, whereas the other variables played a minor role when adjusting for sense of mastery.</p> <p>Conclusion</p> <p>Low sense of mastery seems to account for much of the association between low educational level and psychological distress, and should be an important target in mental health promotion for groups with low level of education.</p

FOCUS4 biomarker laboratories: from the benefits to the practical and logistical issues faced during 6 years of centralised testing

Aims FOCUS4 was a phase II/III umbrella trial, recruiting patients with advanced or metastatic colorectal cancer, between 2014 and 2020. Molecular profiling of patients’ formalin-fixed, paraffin-embedded tumour blocks was undertaken at two centralised biomarker laboratories (Leeds and Cardiff), and the results fed directly to the Medical Research Council Clinical Trials Unit, and used for subsequent randomisation. Here the laboratories discuss their experiences. Methods Following successful tumour content assessment, blocks were sectioned for DNA extraction and immunohistochemistry (IHC). Pyrosequencing was initially used to determine tumour mutation status (KRAS, NRAS, BRAF and PIK3CA), then from 2018 onwards, next-generation sequencing was employed to allow the inclusion of TP53. Protein expression of MLH1, MSH2, MSH6, PMS2 and pTEN was determined by IHC. An interlaboratory comparison programme was initiated, allowing sample exchanges, to ensure continued assay robustness. Results 1291 tumour samples were successfully analysed. Assay failure rates were very low; 1.9%–3.3% for DNA sequencing and 0.9%–1.3% for IHC. Concordance rates of >98% were seen for the interlaboratory comparisons, where a result was obtained by both laboratories. Conclusions Practical and logistical problems were identified, including poor sample quality and difficulties with sample anonymisation. The often last-minute receipt of a sample for testing and a lack of integration with National Health Service mutation analysis services were challenging. The laboratories benefitted from both pretrial validations and interlaboratory comparisons, resulting in robust assay development and provided confidence during the implementation of new sequencing technologies. We conclude that our centralised approach to biomarker testing in FOCUS4 was effective and successful

Whole-Blood Flow-Cytometric Analysis of Antigen-Specific CD4 T-Cell Cytokine Profiles Distinguishes Active Tuberculosis from Non-Active States

T-cell based IFN-γ release assays do not permit distinction of active tuberculosis (TB) from successfully treated disease or latent M. tuberculosis infection. We postulated that IFN-γ and IL-2 cytokine profiles of antigen-specific T cells measured by flow-cytometry ex vivo might correlate with TB disease activity in vivo. Tuberculin (PPD), ESAT-6 and CFP-10 were used as stimuli to determine antigen-specific cytokine profiles in CD4 T cells from 24 patients with active TB and 28 patients with successfully treated TB using flow-cytometry. Moreover, 25 individuals with immunity consistent with latent M. tuberculosis infection and BCG-vaccination, respectively, were recruited. Although the frequency of cytokine secreting PPD reactive CD4 T cells was higher in patients with active TB compared to patients with treated TB (median 0.81% vs. 0.39% of CD4 T cells, p = 0.02), the overlap in frequencies precluded distinction between the groups on an individual basis. When assessing cytokine profiles, PPD specific CD4 T cells secreting both IFN-γ and IL-2 predominated in treated TB, latent infection and BCG-vaccination, whilst in active TB the cytokine profile was shifted towards cells secreting IFN-γ only (p<0.0001). Cytokine profiles of ESAT-6 or CFP-10 reactive CD4 T cells did not differ between the groups. Receiver operator characteristics (ROC) analysis revealed that frequencies of PPD specific IFN-γ/IL-2 dual-positive T cells below 56% were an accurate marker for active TB (specificity 100%, sensitivity 70%) enabling effective discrimination from non-active states. In conclusion, a frequency lower than 56% IFN-γ/IL-2 dual positive PPD-specific circulating CD4 T-cells is strongly indicative of active TB

Enumeration of Functional T-Cell Subsets by Fluorescence-Immunospot Defines Signatures of Pathogen Burden in Tuberculosis

IFN-γ and IL-2 cytokine-profiles define three functional T-cell subsets which may correlate with pathogen load in chronic intracellular infections. We therefore investigated the feasibility of the immunospot platform to rapidly enumerate T-cell subsets by single-cell IFN-γ/IL-2 cytokine-profiling and establish whether immunospot-based T-cell signatures distinguish different clinical stages of human tuberculosis infection.We used fluorophore-labelled anti-IFN-γ and anti-IL-2 antibodies with digital overlay of spatially-mapped colour-filtered images to enumerate dual and single cytokine-secreting M. tuberculosis antigen-specific T-cells in tuberculosis patients and in latent tuberculosis infection (LTBI). We validated results against established measures of cytokine-secreting T-cells.Fluorescence-immunospot correlated closely with single-cytokine enzyme-linked-immunospot for IFN-γ-secreting T-cells and IL-2-secreting T-cells and flow-cytometry-based detection of dual IFN-γ/IL-2-secreting T-cells. The untreated tuberculosis signature was dominated by IFN-γ-only-secreting T-cells which shifted consistently in longitudinally-followed patients during treatment to a signature dominated by dual IFN-γ/IL-2-secreting T-cells in treated patients. The LTBI signature differed from active tuberculosis, with higher proportions of IL-2-only and IFN-γ/IL-2-secreting T-cells and lower proportions of IFN-γ-only-secreting T-cells.Fluorescence-immunospot is a quantitative, accurate measure of functional T-cell subsets; identification of cytokine-signatures of pathogen burden, distinct clinical stages of M. tuberculosis infection and long-term immune containment suggests application for treatment monitoring and vaccine evaluation

An empirical Bayesian approach for model-based inference of cellular signaling networks

Background A common challenge in systems biology is to infer mechanistic descriptions of biological process given limited observations of a biological system. Mathematical models are frequently used to represent a belief about the causal relationships among proteins within a signaling network. Bayesian methods provide an attractive framework for inferring the validity of those beliefs in the context of the available data. However, efficient sampling of high-dimensional parameter space and appropriate convergence criteria provide barriers for implementing an empirical Bayesian approach. The objective of this study was to apply an Adaptive Markov chain Monte Carlo technique to a typical study of cellular signaling pathways. Results As an illustrative example, a kinetic model for the early signaling events associated with the epidermal growth factor (EGF) signaling network was calibrated against dynamic measurements observed in primary rat hepatocytes. A convergence criterion, based upon the Gelman-Rubin potential scale reduction factor, was applied to the model predictions. The posterior distributions of the parameters exhibited complicated structure, including significant covariance between specific parameters and a broad range of variance among the parameters. The model predictions, in contrast, were narrowly distributed and were used to identify areas of agreement among a collection of experimental studies. Conclusion In summary, an empirical Bayesian approach was developed for inferring the confidence that one can place in a particular model that describes signal transduction mechanisms and for inferring inconsistencies in experimental measurements