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Materials with low stacking fault energies have been long sought for their many desirable mechanical attributes. Although there have been many successful reports of low stacking fault alloys (for example Cu-based and Mg-based), many have lacked sufficient strength to be relevant for structural applications. The recent discovery and development of multicomponent equiatomic alloys (or high-entropy alloys) that form as simple solid solutions on ideal lattices has opened the door to investigate changes in stacking fault energy in materials that naturally exhibit high mechanical strength. We report in this article our efforts to determine the stacking fault energies of two- to five-component alloys. A range of methods that include ball milling, arc melting, and casting, is used to synthesize the alloys. The resulting structure of the alloys is determined from x-ray diffraction measurements. First-principles electronic structure calculations are employed to determine elastic constants, lattice parameters, and Poisson’s ratios for the same alloys. These values are then used in conjunction with x-ray diffraction measurements to quantify stacking fault energies as a function of the number of components in the equiatomic alloys. We show that the stacking fault energies decrease with the number of components. Nonequiatomic alloys are also explored as a means to further reduce stacking fault energy. We show that this strategy leads to a means to further reduce the stacking fault energy in this class of alloys.

This article is a review of research on nanostructured high-entropy alloys with emphasis on those made by the severe plastic deformation methods of mechanical alloying and high-pressure torsion. An example of thin film refractory metal alloys made by magnetron sputtering is also presented. The article will begin with a discussion of the seminal research of B.S. Murty and co-workers who first produced nanocrystalline high-entropy alloys by mechanical alloying of powders. This will be followed by a listing of research, in mostly chronological order, of mainly 3d transition metal alloys made nanocrystalline by mechanical alloying. Research on the well-studied Cantor alloy, from the literature and the author’s laboratory will be presented. The author’s and co-worker’s research on a low-density high-entropy alloy with single-phase fcc or hcp structure and an extremely high strength (hardness)-to-weight ratio will be described.

This paper presents a brief overview of the field of structural nanocrystalline materials. These are materials in either bulk, coating, or thin film form whose function is for structural applications. The major processing methods for production of bulk nanocrystalline materials are reviewed. These methods include inert gas condensation, chemical reaction methods, electrodeposition, mechanical attrition, and severe plastic deformation. The stability of the nanocrystalline microstructure is discussed in terms of strategies for retardation of grain growth. Selected mechanical properties of nanocrystalline materials are described; specifically strength and ductility. Corrosion resistance is briefly addressed. Examples of present or potential applications for structural nanocrystalline materials are given.

This paper will review the grain growth in nanocrystalline materials with emphasis on the grain size stabilization that can result from solute additions. The grain growth in nominally pure nanocrystalline metals will be presented followed by descriptions of the stabilization of nanocrystalline grain sizes by kinetic approaches and thermodynamic strategies. The descriptions of nanocrystalline grain size by solute additions will be taken from the literature as well as from recent research in the authors’ laboratory. Examples of kinetic stabilization, which involves reduction of the grain boundary mobility, include second phase drag, solute drag, chemical ordering, and grain size stabilization. The thermodynamic stabilization, which is due to the lowering of the specific grain boundary energy by solute segregation to the grain boundaries, will be described for systems including Pd–Zr, Fe–Zr, Ni–W, Ni–P, and Co–P. Recrystallization during grain growth will be presented for the Ti–N system. Finally, a summary of alloys where nanocrystalline grain sizes can be maintained at annealing temperatures close to the melting point will be presented.

Feeding management of the postnatal and preweaning calf has an important impact on calf growth and development during this critical period and affects the health and well-being of the calves. After birth, an immediate and sufficient colostrum supply is a prerequisite for successful calf rearing. Colostrum provides high amounts of nutrient as well as non-nutrient factors that promote the immune system and intestinal maturation of the calf. The maturation and function of the neonatal intestine enable the calf to digest and absorb the nutrients provided by colostrum and milk. Therefore, colostrum intake supports the start of anabolic processes in several tissues, stimulating postnatal body growth and organ development. After the colostrum feeding period, an intensive milk feeding protocol, that is, at least 20% of BW milk intake/day, is required to realise the calf potential for growth and organ development during the preweaning period. Insufficient milk intake delays postnatal growth and may have detrimental effects on organ development, for example, the intestine and the mammary gland. The somatotropic axis as the main postnatal endocrine regulatory system for body growth is stimulated by the intake of high amounts of colostrum and milk and indicates the promotion of anabolic metabolism in calves. The development of the forestomach is an important issue during the preweaning period in calves, and forestomach maturation is best achieved by solid feed intake. Unfortunately, intensive milk-feeding programmes compromise solid feed intake during the first weeks of life. In the more natural situation for beef calves, when milk and solid feed intake occurs at the same time, calves benefit from the high milk intake as evidenced by enhanced body growth and organ maturation without impaired forestomach development during weaning. To realise an intensive milk-feeding programme, it is recommended that the weaning process should not start too early and that solid feed intake should be at a high extent despite intensive milk feeding. A feeding concept based on intensive milk feeding prevents hunger and abnormal behaviour of the calves and fits the principles of animal welfare during preweaning calf rearing. Studies on milk performance in dairy cows indicate that feeding management during early calf rearing influences lifetime performance. Therefore, an intensive milk-feeding programme affects immediate as well as long-term performance, probably by programming metabolic pathways during the preweaning period.

Background Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1–4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment. Methods This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MIC ECOFF and ƒT > 4×MIC ECOFF ) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes. Results A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MIC ECOFF and 36.7% achieved 100%ƒT > 4×MIC ECOFF . Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m 2 , and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MIC ECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival. Conclusions Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Trial registration Netherlands Trial Registry (EXPAT trial), NTR 5632 . Registered on 7 December 2015.

PurposeIndividualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.MethodsThis multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.ResultsIn total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55–71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96–1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.ConclusionsWe could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

Multijunction solar cells can overcome the fundamental efficiency limits of single-junction devices. The bandgap tunability of metal halide perovskite solar cells renders them attractive for multijunction architectures 1 . Combinations with silicon and copper indium gallium selenide (CIGS), as well as all-perovskite tandem cells, have been reported 2 – 5 . Meanwhile, narrow-gap non-fullerene acceptors have unlocked skyrocketing efficiencies for organic solar cells 6 , 7 . Organic and perovskite semiconductors are an attractive combination, sharing similar processing technologies. Currently, perovskite–organic tandems show subpar efficiencies and are limited by the low open-circuit voltage ( V oc ) of wide-gap perovskite cells 8 and losses introduced by the interconnect between the subcells 9 , 10 . Here we demonstrate perovskite–organic tandem cells with an efficiency of 24.0 per cent (certified 23.1 per cent) and a high V oc of 2.15 volts. Optimized charge extraction layers afford perovskite subcells with an outstanding combination of high V oc and fill factor. The organic subcells provide a high external quantum efficiency in the near-infrared and, in contrast to paradigmatic concerns about limited photostability of non-fullerene cells 11 , show an outstanding operational stability if excitons are predominantly generated on the non-fullerene acceptor, which is the case in our tandems. The subcells are connected by an ultrathin (approximately 1.5 nanometres) metal-like indium oxide layer with unprecedented low optical/electrical losses. This work sets a milestone for perovskite–organic tandems, which outperform the best p–i–n perovskite single junctions 12 and are on a par with perovskite–CIGS and all-perovskite multijunctions 13 . A thin low-loss indium oxide interconnect layer grown by atomic layer deposition enables perovskite–organic hybrid tandem solar cells with a high open-circuit voltage and a high power conversion efficiency.

Single-cell RNA sequencing data can unveil the molecular diversity of cell types. Cell type atlases of the mouse spinal cord have been published in recent years but have not been integrated together. Here, we generate an atlas of spinal cell types based on single-cell transcriptomic data, unifying the available datasets into a common reference framework. We report a hierarchical structure of postnatal cell type relationships, with location providing the highest level of organization, then neurotransmitter status, family, and finally, dozens of refined populations. We validate a combinatorial marker code for each neuronal cell type and map their spatial distributions in the adult spinal cord. We also show complex lineage relationships among postnatal cell types. Additionally, we develop an open-source cell type classifier, SeqSeek, to facilitate the standardization of cell type identification. This work provides an integrated view of spinal cell types, their gene expression signatures, and their molecular organization. Single-cell profiling has led to the identification of diverse cell types. Here, the authors generate a harmonized cell atlas of the mouse post-natal spinal cord. They also provide spatial analysis of the distribution of the identified cell types and an open-source cell type classifier.

Light mechanical stimulation of hairy skin can induce a form of itch known as mechanical itch. This itch sensation is normally suppressed by inputs from mechanoreceptors; however, in many forms of chronic itch, including alloknesis, this gating mechanism is lost. Here we demonstrate that a population of spinal inhibitory interneurons that are defined by the expression of neuropeptide Y::Cre (NPY::Cre) act to gate mechanical itch. Mice in which dorsal NPY::Cre-derived neurons are selectively ablated or silenced develop mechanical itch without an increase in sensitivity to chemical itch or pain. This chronic itch state is histamine-independent and is transmitted independently of neurons that express the gastrin-releasing peptide receptor. Thus, our studies reveal a dedicated spinal cord inhibitory pathway that gates the transmission of mechanical itch.