International research and guidelines on post-tuberculosis chronic lung disorders: a systematic scoping review.

Introduction: Pulmonary tuberculosis (TB) is an important risk factor for chronic respiratory disease due to residual lung damage. Yet, the WHO End TB strategy does not mention post-TB chronic lung disorders (PTBLDs) and programmatic interventions to address PTBLD are lacking. This study assessed the scope of current guidelines and evidence on PTBLD to inform policy and research action. Methods: A systematic literature search was conducted following Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Eight databases (TRIP, International Guideline Library, MEDLINE/PubMed, EMBASE, Web of Science, Global Health, Cochrane Library) were searched for records on PTBLD published between 1 January 1990 and 1 December 2017. Non-English records, case series, conference abstracts and letters to editors were excluded. Data were extracted and charted on publication year, location, PTBLD condition(s) and main study outcome. Results: A total of 212 guidelines and 3661 articles were retrieved. After screening, only three international TB guidelines mentioned TB sequelae, but none described how to identify or manage the condition. A total of 156 articles addressed PTBLD: 54 (35%) mentioned unspecified TB sequelae; 47 (30%) specific post-TB conditions including aspergillosis, bronchial stenosis or bronchiectasis; 52 (33%) post-TB obstructive disorders or lung function impairment; and 20 (13%) post-TB respiratory symptoms or chest X-ray abnormalities. The first two groups mostly assessed surgery or ventilation techniques for patient management, while the last two groups typically assessed prevalence or predictors of disease. Conclusion: This is the first review to provide a comprehensive overview of the current literature on PTBLD. The scope of evidence around the burden of PTBLD warrants inclusion and recognition of the problem in international TB guidelines. Research is now needed on early detection of PTBLD and patient management options that are suitable for high-burden TB countries

Comparison of Xpert MTB/RIF with Other Nucleic Acid Technologies for Diagnosing Pulmonary Tuberculosis in a High HIV Prevalence Setting: A Prospective Study

In this prospective, real-world cohort study nested within a national screening program for tuberculosis, Lesley Scott and colleagues compare the performance of Xpert MTB/RIF on a single sputum sample with different TB sputum detection technologies

Investigating the robustness of the classical enzyme kinetic equations in small intracellular compartments

<p>Abstract</p> <p>Background</p> <p>Classical descriptions of enzyme kinetics ignore the physical nature of the intracellular environment. Main implicit assumptions behind such approaches are that reactions occur in compartment volumes which are large enough so that molecular discreteness can be ignored and that molecular transport occurs via diffusion. Though these conditions are frequently met in laboratory conditions, they are not characteristic of the intracellular environment, which is compartmentalized at the micron and submicron scales and in which active means of transport play a significant role.</p> <p>Results</p> <p>Starting from a master equation description of enzyme reaction kinetics and assuming metabolic steady-state conditions, we derive novel mesoscopic rate equations which take into account (i) the intrinsic molecular noise due to the low copy number of molecules in intracellular compartments (ii) the physical nature of the substrate transport process, i.e. diffusion or vesicle-mediated transport. These equations replace the conventional macroscopic and deterministic equations in the context of intracellular kinetics. The latter are recovered in the limit of infinite compartment volumes. We find that deviations from the predictions of classical kinetics are pronounced (hundreds of percent in the estimate for the reaction velocity) for enzyme reactions occurring in compartments which are smaller than approximately 200 nm, for the case of substrate transport to the compartment being mediated principally by vesicle or granule transport and in the presence of competitive enzyme inhibitors.</p> <p>Conclusion</p> <p>The derived mesoscopic rate equations describe subcellular enzyme reaction kinetics, taking into account, for the first time, the simultaneous influence of both intrinsic noise and the mode of transport. They clearly show the range of applicability of the conventional deterministic equation models, namely intracellular conditions compatible with diffusive transport and simple enzyme mechanisms in several hundred nanometre-sized compartments. An active transport mechanism coupled with large intrinsic noise in enzyme concentrations is shown to lead to huge deviations from the predictions of deterministic models. This has implications for the common approach of modeling large intracellular reaction networks using ordinary differential equations and also for the calculation of the effective dosage of competitive inhibitor drugs.</p

Bone refilling in cortical bone multicellular units: Insights into tetracycline double labelling from a computational model

Bone remodelling is carried out by `bone multicellular units' (BMUs) in which active osteoclasts and active osteoblasts are spatially and temporally coupled. The refilling of new bone by osteoblasts towards the back of the BMU occurs at a rate that depends both on the number of osteoblasts and on their secretory activity. In cortical bone, a linear phenomenological relationship between matrix apposition rate (MAR) and BMU cavity radius is found experimentally. How this relationship emerges from the combination of complex, nonlinear regulations of osteoblast number and secretory activity is unknown. Here, we extend our previous mathematical model of cell development within a single BMU to investigate how osteoblast number and osteoblast secretory activity vary along the BMU's closing cone. MARs predicted by the model are compared with data from tetracycline double labelling experiments. We find that the linear phenomenological relationship observed in these experiments between MAR and BMU cavity radius holds for most of the refilling phase simulated by our model, but not near the start and end of refilling. This suggests that at a particular bone site undergoing remodelling, bone formation starts and ends rapidly. Our model also suggests that part of the observed cross-sectional variability in tetracycline data may be due to different bone sites being refilled by BMUs at different stages of their lifetime. The different stages of a BMU's lifetime depend on whether the cell populations within the BMU are still developing or have reached a quasi-steady state while travelling through bone. We find that due to their longer lifespan, active osteoblasts reach a quasi-steady distribution more slowly than active osteoclasts. We suggest that this fact may locally enlarge the Haversian canal diameter (due to a local lack of osteoblasts compared to osteoclasts) near the BMU's point of origin.Comment: 16 pages, 6 figures, 3 tables. V3: minor changes: added 2 paragraphs (BMU cavity in Section 2 and Model Robustness in Section 4), references [52,54

Understanding the (non-)Use of Societal Wellbeing Indicators in National Policy Development : What Can We Learn from Civil Servants? A UK Case Study

Gross Domestic Product is often used as a proxy for societal well-being in the context of policy development. Its shortcomings in this context are, however, well documented, and numerous alternative indicator sets have been developed. Despite this, there is limited evidence of widespread use of these alternative indicator sets by people working in policy areas relevant to societal wellbeing. Civil servants are an important group of indicator end-users. Better understanding their views concerning measuring societal wellbeing can support wider discussions about what factors determine indicator use and influence in policy decision-making. Taking the UK as a case study, we ask what views exist among civil servants in the UK about measuring societal well-being? To answer this question, we used a bootstrapped Q methodology, interviewing 20 civil servants to elicit their views about measuring societal well-being. Three distinct discourses emerged from our analysis: one that was concerned about the consequences of ignoring natural, social and human capital in decision making; one that emphasised opportunity and autonomy as key determinants of well-being; and one that focused on the technical aspects of measuring societal well-being. Each of these discourses has direct implications for the way that we integrate societal wellbeing into policy making and highlights the potential benefits of including end-users in indicator development and strategy

Deep Sequencing Whole Transcriptome Exploration of the σE Regulon in Neisseria meningitidis

Bacteria live in an ever-changing environment and must alter protein expression promptly to adapt to these changes and survive. Specific response genes that are regulated by a subset of alternative σ70-like transcription factors have evolved in order to respond to this changing environment. Recently, we have described the existence of a σE regulon including the anti-σ-factor MseR in the obligate human bacterial pathogen Neisseria meningitidis. To unravel the complete σE regulon in N. meningitidis, we sequenced total RNA transcriptional content of wild type meningococci and compared it with that of mseR mutant cells (ΔmseR) in which σE is highly expressed. Eleven coding genes and one non-coding gene were found to be differentially expressed between H44/76 wildtype and H44/76ΔmseR cells. Five of the 6 genes of the σE operon, msrA/msrB, and the gene encoding a pepSY-associated TM helix family protein showed enhanced transcription, whilst aniA encoding a nitrite reductase and nspA encoding the vaccine candidate Neisserial surface protein A showed decreased transcription. Analysis of differential expression in IGRs showed enhanced transcription of a non-coding RNA molecule, identifying a σE dependent small non-coding RNA. Together this constitutes the first complete exploration of an alternative σ-factor regulon in N. meningitidis. The results direct to a relatively small regulon indicative for a strictly defined response consistent with a relatively stable niche, the human throat, where N. meningitidis resides

Energy allocation and behaviour in the growing broiler chicken

Broiler chickens are increasingly at the forefront of global meat production but the consequences of fast growth and selection for an increase in body mass on bird health are an ongoing concern for industry and consumers. To better understand the implications of selection we evaluated energetics and behaviour over the 6-week hatch-to-slaughter developmental period in a commercial broiler. The effect of posture on resting metabolic rate becomes increasingly significant as broilers grow, as standing became more energetically expensive than sitting. The proportion of overall metabolic rate accounted for by locomotor behaviour decreased over development, corresponding to declining activity levels, mean and peak walking speeds. These data are consistent with the inference that broilers allocate energy to activity within a constrained metabolic budget and that there is a reducing metabolic scope for exercise throughout their development. Comparison with similarly sized galliforms reveals that locomotion is relatively energetically expensive in broilers

A niche remedy for the dynamical problems of neutral theory

We demonstrate how niche theory and Hubbell's original formulation of neutral theory can be blended together into a general framework modeling the combined effects of selection, drift, speciation, and dispersal on community dynamics. This framework connects many seemingly unrelated ecological population models, and allows for quantitative predictions to be made about the impact of niche stabilizing and destabilizing forces on population extinction times and abundance distributions. In particular, the existence of niche stabilizing forces in our blended framework can simultaneously resolve two major problems with the dynamics of neutral theory, namely predictions of species lifetimes that are too short and species ages that are too long.Comment: 47 pages, 4 figures, Accepted to Theoretical Ecolog