The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia

Introduction: Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network ( www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and 270/1140 well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination. The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT03208725

Determination of representative loading conditions for effective semitrailer design

Obtaining a representative loading spectrum that corresponds well to the reality is still one of the greatest challenges for fatigue life calculations and optimal design of the trailer body. A good qualitative and quantitative knowledge of the spectrum leads to more efficient usage of material, a better design of connection points and an overall decrease of the weight of the trailer, which finally results in a significant decrease in the price of a ton of cargo per km. Despite that, the approach is nowadays mostly based on the experience and rules of thumb. It typically results in over-dimensioning of some parts while other parts remain vulnerable to failure due to unknown loading patterns. This paper describes a generic approach to solve the problems mentioned above applied in a research project named FORWARD (Fuel Optimized trailer Referring to Well Assessed Realistic Design loads). The project lasted two years and was carried out in cooperation with several different trailer manufacturers and 1st tier suppliers. The loading history of more than 1000 hours for five trailer types were captured in the shape of strains, accelerations and velocities of various elements of the trailers, enabling reconstruction of the loading in terms of forces and moments acting on the wheels and kingpin. Parallel to this extensive test-campaign, a novel generic physics-based computational approach was developed to predict selected loads encountered during common manoeuvres to all trailer types. The computational approach was validated against test-data and resulted in creating a generic multi-body library applicable for all trailer types, and an automated post-processing routine for the large amount of test-data

Implementation of a heterogeneous, variable-fidelity framework for flight mechanics analysis in preliminary aircraft design

This paper presents the implementation of a framework for flight mechanical analysis with adaptable aerodynamics methods in the preliminary stage of aircraft design. Basis to the framework are software modules for the disciplines conceptual design, flight mechanics and aerodynamics which have been developed within different design frameworks and which contain heterogeneous interfaces. The focus is placed on the technique for the integration of the different analysis components and the realization of the variable-fidelity capability. Backbone of the framework is the XML-based 'Common Parametric Aircraft Configuration Schema' (CPACS) which was extended in course of this study. The paper introduces the utilized analysis codes and software modules, presents their integration into the framework and discusses the faced challenges and developed solutions. Exemplary results are shown as illustrative use cases. Analogies of linked design systems lead to a standardized integration process. In a next step the homogenization of different design systems by a unified parameterization appears to be feasible

Minimally invasive postmortem intestinal tissue sampling in malnourished and acutely ill children is feasible and informative

BACKGROUND:Intestinal disorders such as environmental enteric dysfunction (EED) are prevalent in low- and middle-income countries (LMICs) and important contributors to childhood undernutrition and mortality. Autopsies are rarely performed in LMICs but minimally invasive tissue sampling is increasingly deployed as a more feasible and acceptable procedure, although protocols have been devoid of intestinal sampling to date. We sought to determine (1) the feasibility of postmortem intestinal sampling, (2) whether autolysis precludes enteric biopsies' utility, and (3) histopathologic features among children who died during hospitalization with acute illness or undernutrition. METHODS:Transabdominal needle and endoscopic forceps upper and lower intestinal sampling were conducted among children aged 1 week to 59 months who died while hospitalized in Blantyre, Malawi. Autolysis ratings were determined for each hematoxylin and eosin slide, and upper and lower intestinal scoring systems were adapted to assess histopathologic features and their severity. RESULTS:Endoscopic and transabdominal sampling procedures were attempted in 28 and 14 cases, respectively, with >90% success obtaining targeted tissue. Varying degrees of autolysis were present in all samples and precluded histopathologic scoring of 6% of 122 biopsies. Greater autolysis in duodenal samples was seen with longer postmortem interval (Beta = 0.06, 95% confidence interval, 0.02-0.11). Histopathologic features identified included duodenal Paneth and goblet cell depletion. Acute inflammation was absent but chronic inflammation was prevalent in both upper and lower enteric samples. Severe chronic rectal inflammation was identified in children as young as 5.5 weeks. CONCLUSIONS:Minimally invasive postmortem intestinal sampling is feasible and identifies histopathology that can inform mortality contributors