Stress and pore pressure histories in complex tectonic settings predicted with coupled geomechanical-fluid flow models

Most of the methods currently used for pore pressure prediction in sedimentary basins assume one dimensional compaction based on relationships between vertical effective stress and porosity. These methods may be inaccurate in complex tectonic regimes where stress tensors are variable. Modelling approaches for compaction adopted within the geotechnical field account for both the full three dimensional stress tensor and the stress history. In this paper a coupled geomechanical-fluid flow model is used, along with an advanced version of the Cam-Clay constitutive model, to investigate stress,pore pressure and porosity in a Gulf of Mexico style mini-basin bounded by salt subjected to lateral deformation. The modelled structure consists of two depocentres separated by a salt diapir. 20% of horizontal shortening synchronous to basin sedimentation is imposed. An additional model accounting solely for the overpressure generated due to 1D disequilibrium compaction is also defined. The predicted deformation regime in the two depocentres of the mini-basin is one of tectonic lateral compression, in which the horizontal effective stress is higher than the vertical effective stress. In contrast, sediments above the central salt diapir show lateral extension and tectonic vertical compaction due to the rise of the diapir. Compared to the 1D model, the horizontal shortening in the mini-basin increases the predicted present-day overpressure by 50%, from 20 MPa to 30 MPa. The porosities predicted by the mini-basin models are used to perform 1D, porosity-based pore pressure predictions. The 1D method underestimated overpressure by up to 6 MPa at 3400 m depth (26% of the total overpressure) in the well located at the basin depocentre and up to 3 MPa at 1900 m depth (34% of the total overpressure) in the well located above the salt diapir. The results show how 2D/3D methods are required to accurately predict overpressure in regions in which tectonic stresses are important

Alternative dosing guidelines to improve outcomes in childhood tuberculosis : a mathematical modelling study

Background Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden. Methods We used an integrated model that linked country-specific demographic data at the individual level from the 20 countries with the highest disease burden to pharmacokinetic, outcome, and epidemiological models. We estimated tuberculosis treatment outcomes in children younger than 5 years following WHO guidelines (children are dosed by weight bands corresponding to the number of fixed-dose combination tablets [75 mg rifampicin, 50 mg isoniazid, 150 mg pyrazinamide]) and two alternative dosing strategies: one based on a proposed algorithm that uses age, weight, and available formulations, in which underweight children would receive the same drug doses as would normal weight children of the same age; and another based on an individualised algorithm without dose limitations, in which derived doses results in target exposure attainment for the typical child. Findings We estimated that 57 234 (43%) of 133 302 children younger than 5 years who were treated for tuberculosis in 2017 were underdosed with WHO dosing and only 47% of children would reach the rifampicin exposure target. Underdosing and subtherapeutic exposures were more common among malnourished children than among age-matched healthy children. The proposed dosing approach improved estimated rifampicin target exposure attainment to 62% and equalised outcomes by nutritional status. An estimated third of unfavourable treatment outcomes might be resolved with this dosing strategy, saving the lives of a minimum of 2423 children in these countries annually. With individualised dosing approaches, almost all children could achieve adequate exposure for cure. Interpretation This work shows that a simple change in dosing procedure to include age and nutritional status, requiring no additional measurements or new drug formulations, is one approach to improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality

Biochar impacts on runoff and soil erosion by water: a systematic global scale meta-analysis

Biochar application to soil has the potential to affect soil and vegetation properties that are key for the processes of runoff and soil erosion. However, both field and pot experiments show a vast range of effects, from strong reductions to strong increases in runoff and/or soil erosion. Therefore, this study aimed to quantify and interpret the impacts of biochar on runoff and soil erosion through the first systematic meta-analysis on this topic. The developed dataset consists of 184 pairwise observations for runoff and soil erosion from 30 independent studies but 8 of which just focused on soil erosion. Overall, biochar application to soil significantly reduced runoff by 25 % and erosion by 16 %. Mitigation of soil erosion in the tropics was approximately three times stronger (30 %) than at temperate latitudes (9 %); erosion reduction in the subtropical zone was 14 %, but not significantly different from either the tropical or temperate zones. Fewer reported field observations for runoff resulted in larger confidence intervals and only the temperate latitudes showed a significant effect (i.e. a 28 % reduction). At topsoil gravimetric biochar concentrations between 0.6 % and 2.5 %, significant reductions occurred in soil erosion, with no effect at lower and higher concentrations. Biochar experiments that included a vegetation cover reduced soil erosion more than twice as much as bare soil experiments, i.e. 27 % vs 12 %, respectively. This suggests that soil infiltration, canopy interception, and soil cohesion mechanisms may have synergistic effects. Soil amended with biochar pyrolyzed at >500 °C was associated with roughly double the erosion reduction than soil amended with biochar produced at 300–500 °C, which potentially could be related to the enhancement of hydrophobicity in the latter case. Our results demonstrate substantial potential for biochar to improve ecosystem services that are affected by increased infiltration and reduced erosion, while mechanistic understanding needs to be improved

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

A diagenesis model for geomechanical simulations: formulation and implications for pore pressure and development of geological structures

Forward basin modelling is routinely used in many geological applications, with the critical limitation that chemical diagenetic reactions are often neglected or poorly represented. Here, a new, temperature‐dependent, kinetic diagenesis model is formulated and implemented within a hydromechanical framework. The model simulates the macroscopic effects of diagenesis on: 1) porosity loss, 2) sediment strength, 3) sediment stiffness and compressibility, 4) change in elastic properties, 5) increase in tensile strength due to cementation and 6) overpressure generation. A brief overview of the main diagenetic reactions relevant to basin modelling is presented and the model calibration procedure is demonstrated using published data for the Kimmeridge Clay Formation. The calibrated model is used to show the implications of diagenesis on prediction of overpressure development and structural deformation. The incorporation of diagenesis in a uniaxial burial model results in an increase in overpressure of up to 9 MPa due to both stress‐independent porosity loss and overpressure generated by disequilibrium compaction caused by a reduction in permeability. Finally, a compressional model is used to show that the incorporation of diagenesis within geomechanical models allows the transition from ductile to brittle behaviour to be captured due to the increase in strength that results in an over‐consolidated stress state. This is illustrated by comparison of the present day structures predicted by a geomechanical‐only model, where a ductile fold forms, and a geomechanical model accounting for diagenesis in which a brittle thrust structure is predicted

Assessing the implications of tectonic compaction on pore pressure using a coupled geomechanical approach

Overpressure prediction in tectonic environments is a challenging topic. The available pore pressure prediction methods are designed to work in environments where compaction is mostly one dimensional and driven by the vertical effective stress applied by the overburden. Furthermore, the impact of tectonic deformation on stresses, porosity and overpressure is still poorly understood. We use a novel methodology to capture the true compaction phenomena occurring in an evolving 3D stress regime by integrating a fully-coupled geomechanical approach with a critical state constitutive model. To this end, numerical models consisting of 2D plane strain clay columns are developed to account for compaction and overpressure generation during sedimentation and tectonic activity. We demonstrate that a high deviatoric stress is generated in compressional tectonic basins, resulting in a substantial decrease in porosity with continuing overpressure increase. The overpressure predictions from our numerical models are then compared to those estimated by the equivalent depth method (EDM) in order to quantify the error induced when using classical approaches, based on vertical effective stress, in tectonic environments. The stress paths presented here reveal that a deviation from the uniaxial burial trend can substantially reduce the accuracy of the EDM overpressure predictions

Current status of pharmacokinetic and safety studies of multidrug-resistant tuberculosis treatment in children

After decades of neglect, data are finally becoming available on the appropriate, safe dosing of key second-line anti-tuberculosis drugs used for treating multidrug-resistant tuberculosis (MDR-TB) in children, including levofloxacin (LVX), moxifloxacin (MFX), linezolid (LZD) and delamanid (DLM). Much needed data on some novel and repurposed drugs are still lacking, including for bedaquiline (BDQ), pretomanid (PTM) and clofazimine (CFZ). We review the status of pharmacokinetic (PK) and safety studies of key anti-tuberculosis medications in children with MDR-TB, identify priority knowledge gaps and note ongoing work to address those gaps, in the context of planning for an efficacy trial in children with MDR-TB. There is international consensus that an efficacy trial of a novel, all-oral, shortened MDR-TB treatment trial in children is both needed and feasible. Key novel and repurposed second-line anti-tuberculosis drugs include BDQ, DLM, PTM, MFX, LVX, CFZ and LZD. The rapidly emerging PK and safety data on these medications in children with MDR-TB from studies that are underway, completed or planned, will be critical in supporting such an efficacy trial. Commitment to addressing the remaining knowledge gaps, developing child-friendly formulations of key medications, improving the design of paediatric PK and safety studies, and development of international trial capacity in children with MDR-TB are important priorities

Integrating petrophysical, geological and geomechanical modelling to assess stress states, overpressure development and compartmentalisation adjacent to a salt wall, gulf of Mexico

Multi-well pressure data from the Magnolia Field, located on a flank of the salt-bounded Titan passive mini-basin in the Garden Banks area of the continental slope of the Gulf of Mexico, indicate remarkably high overpressures that vary, at similar depths, by up to 10 MPa between sand bodies 1 km apart. In the present paper, we integrate geological and geophysical analysis with 2D forward hydro-mechanical evolutionary modelling to assess the contribution of both disequilibrium compaction and diapir-related tectonic loading to the observed overpressure and to understand controls on pressure compartmentalisation. The 2D finite element evolutionary model captured the sedimentation of isolated sand channels bounded by mud-dominated sediments close to a rising salt wall which led to tectonic loading on sediments. Comparison of results from the 2D and 1D models shows that disequilibrium compaction can explain most of the overpressure as a result of very rapid deposition of mainly mud-rich, low permeability sediments; tectonic loading contributes around 7% of the observed overpressure. The models also show that linked to the high sedimentation rates, small variations in the permeability and connectivity of the mud-rich sections that bound the channel sands result in highly compartmentalised pressure distributions in adjacent sand bodies

Emerging data on rifampicin pharmacokinetics and approaches to optimal dosing in children with tuberculosis

INTRODUCTION: Despite its longstanding role in tuberculosis (TB) treatment, there continues to be emerging rifampicin research that has important implications for pediatric TB treatment and outstanding questions about its pharmacokinetics and optimal dose in children. AREAS COVERED: This review aims to summarize and discuss emerging data on the use of rifampicin for: 1) routine treatment of drug-susceptible TB; 2) special subpopulations such as children with malnutrition, HIV, or TB meningitis; 3) treatment shortening. We also highlight the implications of these new data for child-friendly rifampicin formulations and identify future research priorities. EXPERT OPINION: New data consistently show low rifampicin exposures across all pediatric populations with 10-20 mg/kg dosing. Although clinical outcomes in children are generally good, rifampicin dose optimization is needed, especially given a continued push to shorten treatment durations and for specific high-risk populations of children who have worse outcomes. A pooled analysis of existing data using applied pharmacometrics would answer many of the important questions remaining about rifampicin pharmacokinetics needed to optimize doses, especially in special populations. Targeted clinical studies in children with TB meningitis and treatment shortening with high-dose rifampicin are also priorities