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Constraint-based reconstruction and analysis (COBRA) provides a molecular mechanistic framework for integrative analysis of experimental molecular systems biology data and quantitative prediction of physicochemically and biochemically feasible phenotypic states. The COBRA Toolbox is a comprehensive desktop software suite of interoperable COBRA methods. It has found widespread application in biology, biomedicine, and biotechnology because its functions can be flexibly combined to implement tailored COBRA protocols for any biochemical network. This protocol is an update to the COBRA Toolbox v.1.0 and v.2.0. Version 3.0 includes new methods for quality-controlled reconstruction, modeling, topological analysis, strain and experimental design, and network visualization, as well as network integration of chemoinformatic, metabolomic, transcriptomic, proteomic, and thermochemical data. New multi-lingual code integration also enables an expansion in COBRA application scope via high-precision, high-performance, and nonlinear numerical optimization solvers for multi-scale, multi-cellular, and reaction kinetic modeling, respectively. This protocol provides an overview of all these new features and can be adapted to generate and analyze constraint-based models in a wide variety of scenarios. The COBRA Toolbox v.3.0 provides an unparalleled depth of COBRA methods.

ABSTRACT: Objectives: We evaluated the association of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) rectal colonisation with crude mortality and whether this association is independent of the risk of KPC-Kp infection. Methods: This was a prospective cohort study of patients followed-up 90 days after a study of rectal colonisation. Cox regression was used to study the variables associated with crude mortality. Sensitivity analyses for 90-day crude mortality in different subcohorts were performed. Results: A total of 1244 patients (1078 non-colonised and 166 colonised) were included. None of the non-colonised patients and 78 (47.0%) of the colonised patients developed KPC-Kp infection. The 90-day crude mortality was 18.0% (194/1078) in non-colonised patients and 41.6% (69/166) in colonised patients. Rectal colonisation was not associated with crude mortality [hazard ratio (HR) = 1.03, 95% confidence interval (CI) 0.69–1.54; P = 0.85] when the model was adjusted for severe KPC-Kp infection [INCREMENT-CPE score (ICS) > 7]. KPC-Kp infection with ICS > 7 was associated with an increased risk of all-cause mortality (HR = 2.21, 95% CI 1.35–3.63; P = 0.002). In the sensitivity analyses, KPC-Kp colonisation was not associated with mortality in any of the analysed subcohorts, including patients who did not develop KPC-Kp infection (HR = 0.93, 95% CI 0.60–1.43; P = 0.74). Conclusion: KPC-Kp rectal colonisation was not associated with crude mortality. Mortality increased when colonised patients developed severe KPC-Kp infection (ICS > 7). Rectal colonisation was a necessary although insufficient condition to die from a KPC-Kp infection.

We present a code modularization approach to design efficient and massively parallel cubic- and linear-scaling solvers for electronic structure calculations using atomic orbitals. The modular implementation of the orbital minimization method, in which linear algebra and parallelization issues are handled via external libraries, is demonstrated in the SIESTA code. The distributed block compressed sparse row (DBCSR) and scalable linear algebra package (ScaLAPACK) libraries are used for algebraic operations with sparse and dense matrices, respectively. The MatrixSwitch and libOMM libraries, recently developed within the Electronic Structure Library, facilitate switching between different matrix formats and implement the energy minimization. We show results comparing the performance of several cubic-scaling algorithms, and also demonstrate the parallel performance of the linear-scaling solvers, and their supremacy over the cubic-scaling solvers for insulating systems with sizes of several hundreds of atoms.

Municipal solid waste (MSW) management is vital in achieving sustainable development goals. It is a complex activity embracing collection, transport, recycling, and disposal; and whose management depends on proper strategic decision-making. The use of decision support methods such as multi-criteria decision-making (MCDM) is widespread in MSW management. However, their application mainly focuses on selecting plant locations and the best technologies for waste treatment. Despite the critical role played by transport in promoting sustainability, MCDM has seldom been applied for the selection of sustainable transport alternatives in the field of MSW management. There are a few MCDM studies about choosing waste collection vehicles, but none that include the most recent green vehicles among the options or consider feasible future scenarios. In this article, different engine technologies for collection trucks (diesel, compressed natural gas (CNG), hybrid CNG-electric, electric, and hydrogen) are evaluated under sustainability criteria in a Spanish city by applying the stratified best and worst method (SBWM). This method enables considering the uncertainty associated with future events to establish various feasible scenarios. The results show that the best-valued options are electric and diesel trucks, in that order, followed by CNG and hybrid CNG-electric, and with hydrogen-powered trucks coming last. The SBWM has proven helpful in defining a comprehensive framework for selecting the most suitable engine technology to support long-term MSW collection. Considering sustainability among the criteria and feasible future scenarios in waste management collection decision-making provides more comprehensive and conclusive results that help managers and policymakers make better informed and more reliable decisions.

We present a method for human brain fixation based on simultaneous perfusion of 4% paraformaldehyde through carotids after a flush with saline. The left carotid cannula is used to perfuse the body with 10% formalin, to allow further use of the body for anatomical research or teaching. The aim of our method is to develop a vascular fixation protocol for the human brain, by adapting protocols that are commonly used in experimental animal studies. We show that a variety of histological procedures can be carried out (cyto- and myeloarchitectonics, histochemistry, immunohistochemistry, intracellular cell injection, and electron microscopy). In addition, ex vivo, ex situ high-resolution MRI (9.4T) can be obtained in the same specimens. This procedure resulted in similar morphological features to those obtained by intravascular perfusion in experimental animals, provided that the postmortem interval was under 10 h for several of the techniques used and under 4 h in the case of intracellular injections and electron microscopy. The use of intravascular fixation of the brain inside the skull provides a fixed whole human brain, perfectly fitted to the skull, with negligible deformation compared to conventional techniques. Given this characteristic of ex vivo, in situ fixation, this procedure can probably be considered the most suitable one available for ex vivo MRI scans of the brain. We describe the compatibility of the method proposed for intravascular fixation of the human brain and fixation of the donor’s body for anatomical purposes. Thus, body donor programs can provide human brain tissue, while the remainder of the body can also be fixed for anatomical studies. Therefore, this method of human brain fixation through the carotid system optimizes the procurement of human brain tissue, allowing a greater understanding of human neurological diseases, while benefiting anatomy departments by making the remainder of the body available for teaching purposes.

Spain has an aging population; 19.93% of the Spanish population is over 65. Aging is accompanied by several health issues, including mental health disorders and changes in the gut microbiota. The gut-brain axis is a bidirectional network linking the central nervous system with gastrointestinal tract functions, and therefore, the gut microbiota can influence an individual’s mental health. Furthermore, aging-related physiological changes affect the gut microbiota, with differences in taxa and their associated metabolic functions between younger and older people. Here, we took a case–control approach to study the interplay between gut microbiota and mental health of elderly people. Fecal and saliva samples from 101 healthy volunteers over 65 were collected, of which 28 (EE|MH group) reported using antidepressants or medication for anxiety or insomnia at the time of sampling. The rest of the volunteers (EE|NOMH group) were the control group. 16S rRNA gene sequencing and metagenomic sequencing were applied to determine the differences between intestinal and oral microbiota. Significant differences in genera were found, specifically eight in the gut microbiota, and five in the oral microbiota. Functional analysis of fecal samples showed differences in five orthologous genes related to tryptophan metabolism, the precursor of serotonin and melatonin, and in six categories related to serine metabolism, a precursor of tryptophan. Moreover, we found 29 metabolic pathways with significant inter-group differences, including pathways regulating longevity, the dopaminergic synapse, the serotoninergic synapse, and two amino acids.

Abstract In potentially severe diseases in general and COVID-19 in particular, it is vital to early identify those patients who are going to progress to severe disease. A recent living systematic review dedicated to predictive models in COVID-19, critically appraises 145 models, 8 of them focused on prediction of severe disease and 23 on mortality. Unfortunately, in all 145 models, they found a risk of bias significant enough to finally "not recommend any for clinical use". Authors suggest concentrating on avoiding biases in sampling and prioritising the study of already identified predictive factors, rather than the identification of new ones that are often dependent on the database. Our objective is to develop a model to predict which patients with COVID-19 pneumonia are at high risk of developing severe illness or dying, using basic and validated clinical tools. We studied a prospective cohort of consecutive patients admitted in a teaching hospital during the “first wave” of the COVID-19 pandemic. Follow-up to discharge from hospital. Multiple logistic regression selecting variables according to clinical and statistical criteria. 404 consecutive patients were evaluated, 392 (97%) completed follow-up. Mean age was 61 years; 59% were men. The median burden of comorbidity was 2 points in the Age-adjusted Charlson Comorbidity Index, CRB was abnormal in 18% of patients and basal oxygen saturation on admission lower than 90% in 18%. A model composed of Age-adjusted Charlson Comorbidity Index, CRB score and basal oxygen saturation can predict unfavorable evolution or death with an area under the ROC curve of 0.85 (95% CI 0.80–0.89), and 0.90 (95% CI 0.86 to 0.94), respectively. Prognosis of COVID-19 pneumonia can be predicted without laboratory tests using two classic clinical tools and a pocket pulse oximeter.

Annual top-dressing application of agricultural lime is a common practice in fruit orchards on acidic soils in southern Chile, which could result in surface over-liming and base imbalances. A trial was performed in a cherry orchard with an 8-year history of surface liming to evaluate the effectiveness of lime materials in neutralizing acidity in the soil profile and the effect on the tree nutritional status. No-lime (NL), calcitic (AgL), hydrated (HL), and liquid (LL) lime treatments were applied on soil surface at commercial rates, and soil acidity variables were measured at depths of 0–5, 5–10, and 10–20 cm in samples collected at 0, 15, 30, 60, and 225 days after application. Tree nutritional status was evaluated through foliar analysis. Top-dressing application of AgL was ineffective in ameliorating subsoil acidity at depths >5 cm, even in high-rainfall conditions. HL did not exhibit greater alkalinity mobility compared to AgL, although it had a faster but shorter-lived reaction. At the manufacturer-recommended rates, LL application was ineffective. After 8 years of top-dressing liming with AgL, a significant stratification of soil pH, Al, and Ca was observed. However, foliar concentration of bases did not reflect the surface Ca accumulation in soil, discarding an antagonistic cation competition for tree uptake. [ABSTRACT FROM AUTHOR]

Although gut dysbiosis is associated with cow's milk allergy (CMA), causality remains uncertain. This study aimed to identify specific bacterial signatures that influence the development and outcome of the disease. We also investigated the effect of hypoallergenic formula (HF) consumption on the gut microbiome of milk-allergic children. 16S rRNA amplicon sequencing was applied to characterize the gut microbiome of 32 milk-allergic children aged 5–12 years and 36 age-matched healthy controls. We showed that the gut microbiome of children with CMA differed significantly from that of healthy children, regardless of whether they consumed cow's milk. Compared to that of healthy cow's milk consumers, it was depleted in Bifidobacterium, Coprococcus catus, Monoglobus, and Lachnospiraceae GCA-900066575, while being enriched in Oscillibacter valericigenes, Negativibacillus massiliensis, and three genera of the Ruminococcaceae family. Of these, only the Ruminococcaceae taxa were also enriched in healthy children not consuming cow's milk. Furthermore, the gut microbiome of children who developed tolerance and had received an HF was similar to that of healthy children, whereas that of children who had not received an HF was significantly different. Our results demonstrate that specific gut microbiome signatures are associated with CMA, which differ from those of dietary milk elimination. Moreover, HF consumption affects the gut microbiome of children who develop tolerance. [ABSTRACT FROM AUTHOR]

IntroductionPain is one of the most persistent symptoms after cancer treatment. The central nervous system can erroneously stay in its alarm phase, altering the pain experience of patients who have cancer. Pain neuroscience education (PNE) with multimodal approaches may benefit these patients.ObjectiveThis protocol aims to determine the effectiveness of a PNE tool on pain, physical function and quality of life, as a supplement to a multimodal rehabilitation (MR) program in patients who had breast cancer (BC).MethodsAn 8-week double-blinded randomized controlled trial will be conducted, including 72 participants who had BC and who have persistent pain, randomized into three groups: PNE program + MR program, traditional biomedical information + MR program and control group. The PNE program will include educational content that participants will learn through a mobile app and the MR program will include a concurrent exercise program and manual therapy. The primary outcome will be the perceived pain assessed using the Visual Analogue Scale and secondary outcomes are others related to pain, physical function and quality of life. All outcomes will be evaluated at baseline, at the end of the intervention and 6 months after the end of intervention.DiscussionThe proposed study may help BC patients with persistent pain improve their pain experience, quality of life and provide for more adaptive pain-coping strategies. This protocol could propose an action guide to implement different integral approaches for the treatment of sequelae. This treatment option could be offered to this patient profile and it could be easily implemented in the healthcare systems due to its low costs.Trial registrationClinicalTrials.gov, NCT04877860. (February18, 2022).