Uncertainty Analysis and Order-by-Order Optimization of Chiral Nuclear Interactions

Chiral effective field theory (chi EFT) provides a systematic approach to describe low-energy nuclear forces. Moreover, chi EFT is able to provide well-founded estimates of statistical and systematic uncertainties-although this unique advantage has not yet been fully exploited. We fill this gap by performing an optimization and statistical analysis of all the low-energy constants (LECs) up to next-to-next-to-leading order. Our optimization protocol corresponds to a simultaneous fit to scattering and bound-state observables in the pion-nucleon, nucleon-nucleon, and few-nucleon sectors, thereby utilizing the full model capabilities of chi EFT. Finally, we study the effect on other observables by demonstrating forward-error-propagation methods that can easily be adopted by future works. We employ mathematical optimization and implement automatic differentiation to attain efficient and machine-precise first-and second-order derivatives of the objective function with respect to the LECs. This is also vital for the regression analysis. We use power-counting arguments to estimate the systematic uncertainty that is inherent to chi EFT, and we construct chiral interactions at different orders with quantified uncertainties. Statistical error propagation is compared with Monte Carlo sampling, showing that statistical errors are, in general, small compared to systematic ones. In conclusion, we find that a simultaneous fit to different sets of data is critical to (i) identify the optimal set of LECs, (ii) capture all relevant correlations, (iii) reduce the statistical uncertainty, and (iv) attain order-by-order convergence in chi EFT. Furthermore, certain systematic uncertainties in the few-nucleon sector are shown to get substantially magnified in the many-body sector, in particular when varying the cutoff in the chiral potentials. The methodology and results presented in this paper open a new frontier for uncertainty quantification in ab initio nuclear theory

Construction and analysis of causally dynamic hybrid bond graphs

Engineering systems are frequently abstracted to models with discontinuous behaviour (such as a switch or contact), and a hybrid model is one which contains continuous and discontinuous behaviours. Bond graphs are an established physical modelling method, but there are several methods for constructing switched or ‘hybrid’ bond graphs, developed for either qualitative ‘structural’ analysis or efficient numerical simulation of engineering systems. This article proposes a general hybrid bond graph suitable for both. The controlled junction is adopted as an intuitive way of modelling a discontinuity in the model structure. This element gives rise to ‘dynamic causality’ that is facilitated by a new bond graph notation. From this model, the junction structure and state equations are derived and compared to those obtained by existing methods. The proposed model includes all possible modes of operation and can be represented by a single set of equations. The controlled junctions manifest as Boolean variables in the matrices of coefficients. The method is more compact and intuitive than existing methods and dispenses with the need to derive various modes of operation from a given reference representation. Hence, a method has been developed, which can reach common usage and form a platform for further study

S53P4 bioactive glass scaffolds induce BMP expression and integrative bone formation in a critical-sized diaphysis defect treated with a single-staged induced membrane technique

Surgical management of critical-sized diaphyseal defects involves multiple challenges, and up to 10% result in delayed or non-union. The two-staged induced membrane technique is successfully used to treat these defects, but it is limited by the need of several procedures and bone graft. Repeated procedures increase costs and morbidity, while grafts are subject to donor-site complications and scarce availability. To transform this two-staged technique into one graft-independent procedure, we developed amorphous porous scaffolds sintered from the clinically used bioactive glass S53P4. This work constitutes the first evaluation of such scaffolds in vivo in a critical-sized diaphyseal defect in the weight-bearing rabbit femur. We provide important knowledge and prospects for future development of sintered S53P4 scaffolds as a bone substitute. Critical-sized diaphysis defects are complicated by inherent sub-optimal healing conditions. The two staged induced membrane technique has been used to treat these challenging defects since the 1980 & rsquo;s. It involves temporary implantation of a membrane-inducing spacer and subsequent bone graft defect filling. A single-staged, graft-independent technique would reduce both socio-economic costs and patient morbidity. Our aim was to enable such single-staged approach through development of a strong bioactive glass scaffold that could replace both the spacer and the graft filling. We constructed amorphous porous scaffolds of the clinically used bioactive glass S53P4 and evaluated them in vivo using a critical sized defect model in the weight-bearing femur diaphysis of New Zealand White rabbits. S53P4 scaffolds and standard polymethylmethacrylate spacers were implanted for 2, 4, and 8 weeks. Induced membranes were confirmed histologically, and their osteostimulative activity was evaluated through RT-qPCR of bone morphogenic protein 2, 4, and 7 (BMPs). Bone formation and osseointegration were examined using histology, scanning electron microscopy, energy-dispersive X-ray analysis, and micro-computed tomography imaging. Scaffold integration, defect union and osteosynthesis were assessed manually and with X-ray projections. We demonstrated that S53P4 scaffolds induce osteostimulative membranes and produce osseointegrative new bone formation throughout the scaffolds. We also demonstrated successful stable scaffold integration with early defect union at 8 weeks postoperative in critical-sized segmental diaphyseal defects with implanted sintered amorphous S53P4 scaffolds. This study presents important considerations for future research and the potential of the S53P4 bioactive glass as a bone substitute in large diaphyseal defects. Statement of significance Surgical management of critical-sized diaphyseal defects involves multiple challenges, and up to 10% result in delayed or non-union. The two-staged induced membrane technique is successfully used to treat these defects, but it is limited by the need of several procedures and bone graft. Repeated procedures increase costs and morbidity, while grafts are subject to donor-site complications and scarce availability. To transform this two-staged technique into one graft-independent procedure, we developed amorphous porous scaffolds sintered from the clinically used bioactive glass S53P4. This work constitutes the first evaluation of such scaffolds in vivo in a critical-sized diaphyseal defect in the weight-bearing rabbit femur. We provide important knowledge and prospects for future development of sintered S53P4 scaffolds as a bone substitute. (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )Peer reviewe

The mixed problem in L^p for some two-dimensional Lipschitz domains

We consider the mixed problem for the Laplace operator in a class of Lipschitz graph domains in two dimensions with Lipschitz constant at most 1. The boundary of the domain is decomposed into two disjoint sets D and N. We suppose the Dirichlet data, f_D has one derivative in L^p(D) of the boundary and the Neumann data is in L^p(N). We find conditions on the domain and the sets D and N so that there is a p_0>1 so that for p in the interval (1,p_0), we may find a unique solution to the mixed problem and the gradient of the solution lies in L^p

S53P4 bioactive glass scaffolds induce BMP expression and integrative bone formation in a critical-sized diaphysis defect treated with a single-stage d induce d membrane technique

Surgical management of critical-sized diaphyseal defects involves multiple challenges, and up to 10% result in delayed or non-union. The two-staged induced membrane technique is successfully used to treat these defects, but it is limited by the need of several procedures and bone graft. Repeated procedures increase costs and morbidity, while grafts are subject to donor-site complications and scarce availability. To transform this two-staged technique into one graft-independent procedure, we developed amorphous porous scaffolds sintered from the clinically used bioactive glass S53P4. This work constitutes the first evaluation of such scaffolds in vivo in a critical-sized diaphyseal defect in the weight-bearing rabbit femur. We provide important knowledge and prospects for future development of sintered S53P4 scaffolds as a bone substitute. Critical-sized diaphysis defects are complicated by inherent sub-optimal healing conditions. The two staged induced membrane technique has been used to treat these challenging defects since the 1980 & rsquo;s. It involves temporary implantation of a membrane-inducing spacer and subsequent bone graft defect filling. A single-staged, graft-independent technique would reduce both socio-economic costs and patient morbidity. Our aim was to enable such single-staged approach through development of a strong bioactive glass scaffold that could replace both the spacer and the graft filling. We constructed amorphous porous scaffolds of the clinically used bioactive glass S53P4 and evaluated them in vivo using a critical sized defect model in the weight-bearing femur diaphysis of New Zealand White rabbits. S53P4 scaffolds and standard polymethylmethacrylate spacers were implanted for 2, 4, and 8 weeks. Induced membranes were confirmed histologically, and their osteostimulative activity was evaluated through RT-qPCR of bone morphogenic protein 2, 4, and 7 (BMPs). Bone formation and osseointegration were examined using histology, scanning electron microscopy, energy-dispersive X-ray analysis, and micro-computed tomography imaging. Scaffold integration, defect union and osteosynthesis were assessed manually and with X-ray projections. We demonstrated that S53P4 scaffolds induce osteostimulative membranes and produce osseointegrative new bone formation throughout the scaffolds. We also demonstrated successful stable scaffold integration with early defect union at 8 weeks postoperative in critical-sized segmental diaphyseal defects with implanted sintered amorphous S53P4 scaffolds. This study presents important considerations for future research and the potential of the S53P4 bioactive glass as a bone substitute in large diaphyseal defects. Statement of significance Surgical management of critical-sized diaphyseal defects involves multiple challenges, and up to 10% result in delayed or non-union. The two-staged induced membrane technique is successfully used to treat these defects, but it is limited by the need of several procedures and bone graft. Repeated procedures increase costs and morbidity, while grafts are subject to donor-site complications and scarce availability. To transform this two-staged technique into one graft-independent procedure, we developed amorphous porous scaffolds sintered from the clinically used bioactive glass S53P4. This work constitutes the first evaluation of such scaffolds in vivo in a critical-sized diaphyseal defect in the weight-bearing rabbit femur. We provide important knowledge and prospects for future development of sintered S53P4 scaffolds as a bone substitute. (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )Peer reviewe

Efficiency of two-phase methods with focus on a planned population-based case-control study on air pollution and stroke

<p>Abstract</p> <p>Background</p> <p>We plan to conduct a case-control study to investigate whether exposure to nitrogen dioxide (NO₂) increases the risk of stroke. In case-control studies, selective participation can lead to bias and loss of efficiency. A two-phase design can reduce bias and improve efficiency by combining information on the non-participating subjects with information from the participating subjects. In our planned study, we will have access to individual disease status and data on NO₂exposure on group (area) level for a large population sample of Scania, southern Sweden. A smaller sub-sample will be selected to the second phase for individual-level assessment on exposure and covariables. In this paper, we simulate a case-control study based on our planned study. We develop a two-phase method for this study and compare the performance of our method with the performance of other two-phase methods.</p> <p>Methods</p> <p>A two-phase case-control study was simulated with a varying number of first- and second-phase subjects. Estimation methods: <it>Method 1</it>: Effect estimation with second-phase data only. <it>Method 2</it>: Effect estimation by adjusting the first-phase estimate with the difference between the adjusted and unadjusted second-phase estimate. The first-phase estimate is based on individual disease status and residential address for all study subjects that are linked to register data on NO₂-exposure for each geographical area. <it>Method 3</it>: Effect estimation by using the expectation-maximization (EM) algorithm without taking area-level register data on exposure into account. <it>Method 4</it>: Effect estimation by using the EM algorithm and incorporating group-level register data on NO₂-exposure.</p> <p>Results</p> <p>The simulated scenarios were such that, unbiased or marginally biased (< 7%) odds ratio (OR) estimates were obtained with all methods. The efficiencies of method 4, are generally higher than those of methods 1 and 2. The standard errors in method 4 decreased further when the case/control ratio is above one in the second phase. For all methods, the standard errors do not become substantially reduced when the number of first-phase controls is increased.</p> <p>Conclusion</p> <p>In the setting described here, method 4 had the best performance in order to improve efficiency, while adjusting for varying participation rates across areas.</p

Tobacco use and caries risk among adolescents - a longitudinal study in Sweden

Background: Smoking and the use of smokeless tobacco have a detrimental impact on general and oral health. The relationship to dental caries is however still unclear. As caries is a multi-factorial disease with clear life-style, socio-economic and socio-demographic gradients, the tobacco use may be a co-variable in this complex rather than a direct etiological factor. Our aim was to analyze the impact of tobacco use on caries incidence among adolescents, with consideration to socio-economic variables by residency, using epidemiological data from a longitudinal study in the region of Halland, Sweden. Methods: The study population consisted of 10,068 adolescents between 16-19 years of age from whom yearly data on caries and tobacco use (cigarette smoking and use of smokeless tobacco) were obtained during the period 2006-2012. Reported DMFS increment between 16 and 19 years of age (Delta DMFS) for an individual was considered as the primary caries outcome. The outcome data were compared for self-reported never vs. ever users of tobacco, with consideration to neighborhood-level socio-economy (4 strata), baseline (i.e., 16 years of age) DMFS and sex. The region consists of 65 parishes with various socio-economic conditions and each study individual was geo-coded with respect to his/her residence parish. Neighborhood (parish-level) socio-economy was assessed by proportion of residing families with low household purchasing power. Results:Delta DMFS differed evidently between ever and never users of tobacco (mean values: 1.8 vs. 1.2; proportion with Delta DMFS > 0: 54.2% vs. 40.5%; p < 0.0001). Significant differences were observed in each neighborhood-level socio-economic stratum. Even after controlling for baseline DMFS and sex, Delta DMFS differed highly significantly between the ever and never users of tobacco (overall p < 0.0001). Conclusion: Tobacco use was clearly associated with increased caries increment during adolescence. Hence, this factor is relevant to consider in the clinical caries risk assessment of the individual patient as well as for community health plans dealing with oral health

LES and RANS of air and oxy-coal combustion in a pilot-scale facility: predictions of radiative heat transfer

The development of carbon capture and storage (CCS) technology is important to permit the use of fossil fuels while honouring commitments to curb greenhouse gas emissions. Coal is a valuable global resource, which is widely available around the world, however its detrimental e ect on climate change will limit its use in a future with strict controls over carbon emissions. Oxyfuel combustion is a promising CCS technology that is being actively pursued in the development of large scale demonstration projects. Under the oxyfuel process for CCS, the combustion gas is replaced with a mixture of recycled ue gas and enriched oxygen. The resulting combustion environment can vary signi cantly from traditional air- red combustion. The development of modelling capabilities will greatly improve the optimisation process to develop oxyfuel technology into an economically viable prospect. This study evaluates the use of large eddy simulation (LES) and Reynoldsaveraged Navier Stokes (RANS) models on the prediction of thermal radiation during coal combustion for both air- red and oxyfuel operation in a pilot-scale 250 kWth furnace. The furnace is part of the UKCCSRC Pilot-scale Advanced Capture Technology (PACT) facilities and was designed for detailed analysis of the combustion process. Two radiation models were evaluated during the RANS calculations, the widely used weighted sum of grey gases (WSGG) andthe full-spectrum correlated k (FSCK) model, while the LES case was calculated using the FSCK radiation model. The results show that the LES solutions are in better agreement with measured values than the RANS predictions for both air- red and oxyfuel coal combustion, however LES demands considerably more computational resources

Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia

Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis