Will more of the same achieve malaria elimination? Results from an integrated macroeconomic epidemiological demographic model

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordThe data underlying the model framework are available from the authors on request and selected parameters are also tabulated in the methods paper,22 and from the Malaria Atlas Project http:// www.map.ox.ac.uk/Historic levels of funding have reduced the global burden of malaria in recent years. Questions remain, however, as to whether scaling up interventions, in parallel with economic growth, has made malaria elimination more likely today than previously. The consequences of “trying but failing” to eliminate malaria are also uncertain. Reduced malaria exposure decreases the acquisition of semi-immunity during childhood, a necessary phase of the immunological transition that occurs on the pathway to malaria elimination. During this transitional period, the risk of malaria resurgence increases as proportionately more individuals across all age-groups are less able to manage infections by immune response alone. We developed a robust model that integrates the effects of malaria transmission, demography, and macroeconomics in the context of Plasmodium falciparum malaria within a hyperendemic environment. We analyzed the potential for existing interventions, alongside economic development, to achieve malaria elimination. Simulation results indicate that a 2% increase in future economic growth will increase the US$5.1 billion cumulative economic burden of malaria in Ghana to US$7.2 billion, although increasing regional insecticide-treated net coverage rates by 25% will lower malaria reproduction numbers by just 9%, reduce population-wide morbidity by −0.1%, and reduce prevalence from 54% to 46% by 2034. As scaling up current malaria control tools, combined with economic growth, will be insufficient to interrupt malaria transmission in Ghana, high levels of malaria control should be maintained and investment in research and development should be increased to maintain the gains of the past decade and to minimize the risk of resurgence, as transmission dropsMedical Research Council (MRC

Confluent Orthogonal Drawings of Syntax Diagrams

We provide a pipeline for generating syntax diagrams (also called railroad diagrams) from context free grammars. Syntax diagrams are a graphical representation of a context free language, which we formalize abstractly as a set of mutually recursive nondeterministic finite automata and draw by combining elements from the confluent drawing, layered drawing, and smooth orthogonal drawing styles. Within our pipeline we introduce several heuristics that modify the grammar but preserve the language, improving the aesthetics of the final drawing.Comment: GD 201

Systematic review of fatty acid composition of human milk from mothers of preterm compared to full-term infants

Background: Fatty acid composition of human milk serves as guidance for the composition of infant formulae. The aim of the study was to systematically review data on the fatty acid composition of human milk of mothers of preterm compared to full-term infants. Methods: An electronic literature search was performed in English (Medline and Medscape) and German (SpringerLink) databases and via the Google utility. Fatty acid compositional data for preterm and fullterm human milk were converted to differences between means and 95% confidence intervals. Results: We identified five relevant studies publishing direct comparison of fatty acid composition of preterm versus full-term human milk. There were no significant differences between the values of the principal saturated and monounsaturated fatty acids. In three independent studies covering three different time points of lactation, however, docosahexaenoic acid (DHA) values were significantly higher in milk of mothers of preterm as compared to those of full-term infants, with an extent of difference considered nutritionally relevant. Conclusion: Higher DHA values in preterm than in full-term human milk underlines the importance of using own mother's milk for feeding preterm babies and raises the question whether DHA contents in preterm formulae should be higher than in formulae for full-term infants. Copyright (c) 2008 S. Karger AG, Basel

Gut microbial activity as influenced by fiber digestion: dynamic metabolomics in an in vitro colon simulator

Understanding the interaction between the gut microbial activity and the host is essential, and in vitro models are being used to test and develop hypotheses regarding the impact of food components/drugs on the human gut ecosystem. However, while in vitro models provide excellent possibilities for dynamic investigations, studies have commonly been restricted to analyses of few, targeted metabolites. In the present study, we employed NMR-based metabolomics combined with multilevel data analysis as a tool to characterize the impact of polydextrose (PDX) fiber on the in vitro derived fecal metabolome. This approach enabled us to identify and quantify the fiber-induced response on several fecal metabolites; we observed higher levels of butyrate, acetate, propionate, succinate, N-acetyl compound and a lower level of amino acids (leucine, valine, isoleucine, phenylalanine, and lysine), valerate, formate, isovalerate and trimethylamine among the PDX-treated sample compared to the control samples. In addition, by the application of multilevel data analysis we were able to examine the specific inter-individual variations, and caprylic acid was identified to be the main marker of distinct microbial compositions among the subjects. Our work is expected to provide a useful approach to understand the metabolic impact of potential prebiotic compounds and get deeper insight into the molecular regulation of gut-microbe activities in the complex gut system

Antagomir-mediated suppression of microRNA-134 reduces kainic acid-induced seizures in immature mice

MicroRNAs are short non-coding RNAs that negatively regulate protein levels and perform important roles in establishing and maintaining neuronal network function. Previous studies in adult rodents have detected upregulation of microRNA-134 after prolonged seizures (status epilepticus) and demonstrated that silencing microRNA-134 using antisense oligonucleotides, termed antagomirs, has potent and long-lasting seizure-suppressive effects. Here we investigated whether targeting microRNA-134 can reduce or delay acute seizures in the immature brain. Status epilepticus was induced in 21 day-old (P21) male mice by systemic injection of 5 mg/kg kainic acid. This triggered prolonged electrographic seizures and select bilateral neuronal death within the CA3 subfield of the hippocampus. Expression of microRNA-134 and functional loading to Argonaute-2 was not significantly changed in the hippocampus after seizures in the model. Nevertheless, when levels of microRNA-134 were reduced by prior intracerebroventricular injection of an antagomir, kainic acid-induced seizures were delayed and less severe and mice displayed reduced neuronal death in the hippocampus. These studies demonstrate targeting microRNA-134 may have therapeutic applications for the treatment of seizures in children

Evolutionary dynamic optimisation of airport security lane schedules

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Reducing costs whilst maintaining passenger satisfaction is an important problem for airports. One area this can be applied is the security lane checks at the airport. However, reducing costs through reducing lane openings typically increases queue length and hence passenger dissatisfaction. This paper demonstrates that evolutionary methods can be used to optimise airport security lane schedules such that passenger dissatisfaction and staffing costs can be minimised. However, it is shown that these schedules typically over-fit the forecasts of passenger arrivals at security such that in actuality significant passenger delays can occur with deviations from the forecast. Consequently, this paper further demonstrates that dynamic evolutionary re-optimisation of these schedules can significantly mitigate this over-fitting problem with much reduced passenger delays

Do MRI findings identify patients with chronic low back pain and Modic changes who respond best to rest or exercise: A subgroup analysis of a randomised controlled trial

Background: No previous clinical trials have investigated MRI findings as effect modifiers for conservative treatment of low back pain. This hypothesis-setting study investigated if MRI findings modified response to rest compared with exercise in patients with chronic low back pain and Modic changes. Methods: This study is a secondary analysis of a randomised controlled trial comparing rest with exercise. Patients were recruited from a specialised outpatient spine clinic and included in a clinical trial if they had chronic low back pain and an MRI showing Modic changes. All patients received conservative treatment while participating in the trial. Five baseline MRI findings were investigated as effect modifiers: Modic changes Type 1 (any size), large Modic changes (any type), large Modic changes Type 1, severe disc degeneration and large disc herniation. The outcome measure was change in low back pain intensity measured on a 0-10 point numerical rating scale at 14-month follow-up (n = 96). An interaction = 1.0 point (0-10 scale) between treatment group and MRI findings in linear regression was considered clinically important. Results: The interactions for Modic Type 1, with large Modic changes or with large Modic changes Type 1 were all potentially important in size (-0.99 (95% CI -3.28 to 1.29), -1.49 (-3.73 to 0.75), -1.49 (-3.57 to 0.58), respectively) but the direction of the effect was the opposite to what we had hypothesized-that people with these findings would benefit more from rest than from exercise. The interactions for severe disc degeneration (0.74 (-1.40 to 2.88)) and large disc herniation (-0.92 (3.15 to 1.31)) were less than the 1.0-point threshold for clinical importance. As expected, because of the lack of statistical power, no interaction term for any of the MRI findings was statistically significant. Conclusions: Three of the five MRI predictors showed potentially important effect modification, although the direction of the effect was surprising and confidence intervals were wide so very cautious interpretation is required. Further studies with adequate power are warranted to study these and additional MRI findings as potential effect modifiers for common interventions

From biochemical markers to molecular endotypes of osteoarthritis: a review on validated biomarkers

\ua9 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.Introduction: Osteoarthritis (OA) affects over 500 million people worldwide. OA patients are symptomatically treated, and current therapies exhibit marginal efficacy and frequently carry safety-risks associated with chronic use. No disease-modifying therapies have been approved to date leaving surgical joint replacement as a last resort. To enable effective patient care and successful drug development there is an urgent need to uncover the pathobiological drivers of OA and how these translate into disease endotypes. Endotypes provide a more precise and mechanistic definition of disease subgroups than observable phenotypes, and a panel of tissue- and pathology-specific biochemical markers may uncover treatable endotypes of OA. Areas covered: We have searched PubMed for full-text articles written in English to provide an in-depth narrative review of a panel of validated biochemical markers utilized for endotyping of OA and their association to key OA pathologies. Expert opinion: As utilized in IMI-APPROACH and validated in OAI-FNIH, a panel of biochemical markers may uncover disease subgroups and facilitate the enrichment of treatable molecular endotypes for recruitment in therapeutic clinical trials. Understanding the link between biochemical markers and patient-reported outcomes and treatable endotypes that may respond to given therapies will pave the way for new drug development in OA

The Semi-Chiral Quotient, Hyperkahler Manifolds and T-duality

We study the construction of generalized Kahler manifolds, described purely in terms of N=(2,2) semichiral superfields, by a quotient using the semichiral vector multiplet. Despite the presence of a b-field in these models, we show that the quotient of a hyperkahler manifold is hyperkahler, as in the usual hyperkahler quotient. Thus, quotient manifolds with torsion cannot be constructed by this method. Nonetheless, this method does give a new description of hyperkahler manifolds in terms of two-dimensional N=(2,2) gauged non-linear sigma models involving semichiral superfields and the semichiral vector multiplet. We give two examples: Eguchi-Hanson and Taub-NUT. By T-duality, this gives new gauged linear sigma models describing the T-dual of Eguchi-Hanson and NS5-branes. We also clarify some aspects of T-duality relating these models to N=(4,4) models for chiral/twisted-chiral fields and comment briefly on more general quotients that can give rise to torsion and give an example.Comment: 31 page