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We introduce a novel co-design method for autonomous moving agents’ shape attributes and locomotion by combining deep reinforcement learning and evolution with user control. Our main inspiration comes from evolution, which has led to wide variability and adaptation in Nature and has significantly improved design and behavior simultaneously. Our method takes an input agent with optional user-defined constraints, such as leg parts that should not evolve or are only within the allowed ranges of changes. It uses physics-based simulation to determine its locomotion and finds a behavior policy for the input design that is used as a baseline for comparison. The agent is randomly modified within the allowed ranges, creating a new generation of several hundred agents. The generation is trained by transferring the previous policy, which significantly speeds up the training. The best-performing agents are selected, and a new generation is formed using their crossover and mutations. The next generations are then trained until satisfactory results are reached. We show a wide variety of evolved agents, and our results show that even with only 10% of allowed changes, the overall performance of the evolved agents improves by 50%. If more significant changes to the initial design are allowed, our experiments’ performance will improve even more to 150%. Our method significantly improved motion tasks without changing body structures, and it does not require considerable computation resources as it works on a single GPU and provides results by training thousands of agents within 30 minutes.

Besides many other uses, dried Cannabismay be used for “tea” preparation. This study focused on a comprehensive characterization of an aqueous infusion prepared according to a common practice from three fairly different Cannabiscultivars. The transfer of 42 phytocannabinoids and 12 major bioactive compounds (flavonoids) into the infusion was investigated using UHPLC-HRMS/MS. Phytocannabinoid acids were transferred generally in a higher extent compared to their counterparts; in the case of Δ9-THC, it was only in the range of 0.4–1.9% of content in the Cannabisused. A dramatic increase of phytocannabinoids, mainly of the neutral species, occurred when cream was added during steeping, and the transfer of Δ9-THC into “tea” achieved a range of 53–64%. Under such conditions, drinking a 250 mL cup of such tea by a 70 kg person might lead to multiple exceedance of the Acute Reference Dose (ARfD), 1 μg/kg b.w., even in the case when using hemp with a Δ9-THC content below 1% in dry weight for preparation.

Improving access to kidney transplants remains a priority for the transplant community. However, many medical, psychosocial, geographic, and socioeconomic barriers exist that prevent or delay transplantation for candidates with certain conditions. There is a lack of consensus regarding how to best approach many of these issues and barriers, leading to heterogeneity in transplant centers’ management and acceptance practices for a variety of pretransplant candidate issues. In this review, we address several of the more common contemporary patient medical and psychosocial barriers frequently encountered by transplant programs. The barriers discussed here include kidney transplant candidates with obesity, older age, prior malignancy, cardiovascular disease, history of nonadherence, and cannabis use. Improving understanding of how to best address these specific issues can empower referring providers, transplant programs, and patients to address these issues as necessary to progress toward eventual successful transplantation.

Two existing generic force fields have been augmented with partial charges and tuned in order to give intercompatible all-atom empirical potentials that can satisfactorily represent the known crystal phase structures of the organic phloroglucinol (Phg) (C6H6O3) and inorganic hexachlorocyclotriphosphazene (HCCP) (N3P3Cl6) molecules at several temperatures. It has been proposed that HCCP-Phg network polymers could act as efficient H2barrier layers in hydrogen storage tanks for cars. However, essential requirements for modeling such networks are adequate representations of both monomers in their pure dense phases using a common form of force field. Tests of their ability to maintain stable crystal structures have been made using classical molecular dynamics (MD) simulations on large 800-molecule supercells. The force fields have been optimized to match the densities calculated from the experimental unit cell dimensions at ambient conditions as well as the intermolecular potential energy, as estimated from experimental enthalpies of sublimation. For Phg, the crystal structure is stabilized by a network of hydrogen bonds and the Coulombic interactions contribute to over 55% of the total intermolecular potential energy. In contrast, the crystal structure of HCCP is intrinsically stabilized by the van der Waals terms. Both optimized force fields reproduce very well the orthorhombic symmetry of their respective crystals under constant-pressure NPTconditions. The model parameters tuned at ambient temperature also give reasonable agreement with crystallographic data at lower temperatures.

In this article, we propose DeepTree, a novel method for modeling trees based on learning developmental rules for branching structures instead of manually defining them. We call our deep neural model “situated latent” because its behavior is determined by the intrinsic state -encoded as a latent space of a deep neural model- and by the extrinsic (environmental) data that is “situated” as the location in the 3D space and on the tree structure. We use a neural network pipeline to train a situated latent space that allows us to locally predict branch growth only based on a single node in the branch graph of a tree model. We use this representation to progressively develop new branch nodes, thereby mimicking the growth process of trees. Starting from a root node, a tree is generated by iteratively querying the neural network on the newly added nodes resulting in the branching structure of the whole tree. Our method enables generating a wide variety of tree shapes without the need to define intricate parameters that control their growth and behavior. Furthermore, we show that the situated latents can also be used to encode the environmental response of tree models, e.g., when trees grow next to obstacles. We validate the effectiveness of our method by measuring the similarity of our tree models and by procedurally generated ones based on a number of established metrics for tree form.

Purpose: This study aims to evaluate the cost-utility of intraoperative tranexamic acid (TXA) in adult spinal deformity (ASD) patients undergoing long posterior (≥ 5 vertebral levels) spinal fusion. Methods: A decision-analysis model was built for a hypothetical 60-year-old adult patient with spinal deformity undergoing long posterior spinal fusion. A comprehensive review of the literature was performed to obtain event probabilities, costs and health utilities at each node. Health utilities were utilized to calculate Quality-Adjusted Life Years (QALYs). A base-case analysis was carried out to obtain the incremental cost and effectiveness of intraoperative TXA. Probabilistic sensitivity analysis was performed to evaluate uncertainty in our model and obtain mean incremental costs, effectiveness, and net monetary benefits. One-way sensitivity analyses were also performed to identify the variables with the most impact on our model. Results: Use of intraoperative TXA was the favored strategy in 88% of the iterations. The mean incremental utility ratio for using intraoperative TXA demonstrated higher benefit and lower cost while being lower than the willingness-to-pay threshold set at $50,000 per quality adjusted life years. Use of intraoperative TXA was associated with a mean incremental net monetary benefit (INMB) of $3743 (95% CI 3492–3995). One-way sensitivity analysis reported cost of blood transfusions due to post-operative anemia to be a major driver of cost–utility analysis. Conclusion: Use of intraoperative TXAs is a cost-effective strategy to reduce overall perioperative costs related to post-operative blood transfusions. Administration of intraoperative TXA should be considered for long fusions in ASD population when not explicitly contra-indicated due to patient factors.

The Extracorporeal Life Support Organization (ELSO) maintains the world’s largest extracorporeal membrane oxygenation (ECMO) registry by volume, center participation, and international scope. This 2022 ELSO Registry Report describes the program characteristics of ECMO centers, processes of ECMO care, and reported outcomes. Neonates (0–28 days), children (29 days–17 years), and adults (≥18 years) supported with ECMO from 2009 through 2022 and reported to the ELSO Registry were included. This report describes adjunctive therapies, support modes, treatments, complications, and survival outcomes. Data are presented descriptively as counts and percent or median and interquartile range (IQR) by year, group, or level. Missing values were excluded before calculating descriptive statistics. Complications are reported per 1,000 ECMO hours. From 2009 to 2022, 154,568 ECMO runs were entered into the ELSO Registry. Seven hundred and eighty centers submitted data during this time (557 in 2022). Since 2009, the median annual number of adult ECMO runs per center per year increased from 4 to 15, whereas for pediatric and neonatal runs, the rate decreased from 12 to 7. Over 50% of patients were transferred to the reporting ECMO center; 20% of these patients were transported with ECMO. The use of prone positioning before respiratory ECMO increased from 15% (2019) to 44% (2021) for adults during the coronavirus disease-2019 (COVID-19) pandemic. Survival to hospital discharge was greatest at 68.5% for neonatal respiratory support and lowest at 29.5% for ECPR delivered to adults. By 2022, the Registry had enrolled its 200,000th ECMO patient and 100,000th patient discharged alive. Since its inception, the ELSO Registry has helped centers measure and compare outcomes across its member centers and strategies of care. Continued growth and development of the Registry will aim to bolster its utility to patients and centers.

People suffering from chronic insomnia are at an increased risk of physical and mental illness. The absenteeism rate for people with sleep disorders in Germany is more than twice as high as for people without. Therefore, appropriate diagnosis and treatment of sleep disorders is a considerable medical and social necessity.

Menschen, die unter chronischer Insomnie leiden, haben ein erhöhtes Risiko für körperliche und psychische Erkrankungen. Die Fehlzeitenquote ist bei Personen mit Schlafstörungen in Deutschland mehr als doppelt so hoch wie bei Personen ohne. Daher ist eine angemessene Diagnose und Therapie von Schlafstörungen eine wesentliche medizinische und gesellschaftliche Notwendigkeit.

Histopathological examination is a crucial step in the diagnosis and treatment of many major diseases. Aiming to facilitate diagnostic decision making and improve the workload of pathologists, we developed an artificial intelligence (AI)-based prescreening tool that analyses whole-slide images (WSIs) of large-bowel biopsies to identify typical, non-neoplastic, and neoplastic biopsies.

This article investigates an unconventional approach to solving the control of lateral displacement for railway bogie wheelsets using recurrent higher order neural units (HONUs). Although studies addressing control of independently rotating wheelsets have shown promising results, they are rarely applied by railway manufacturers. Research and developments in modern bogie design are trending toward active yaw control design as an extension to conventional wheelsets mechanics, particularly for higher speeds. We investigate a model-reference architecture for active control via setpoint tracking of lateral displacement. Then, a new HONU sliding mode architecture is derived to solve convergence for zero lateral displacements in higher running speeds which is a more profoundly complex issue in maintaining minimal hunting motion. Starting from the property of nonlinear polynomial architecture of HONUs with in-parameter linearity, we derive a time-variant state-space representation via nonlinear identical decomposition. Then, an input-to-state stability (ISS) approach is applied to prove the local asymptotic convergence of the applied algorithm in each state point and the bounded-input-bounded-state stability of the entire nonlinear adaptive control loop. Using ISS theory, we also prove the global asymptotic stability of the HONU sliding mode controller for the actively controlled wheelset system. The techniques are validated by simulations and a real roller rig system.

Wire electrical discharge machining (WEDM) is an unconventional machining technology that is indispensable in many industries. Machining is performed using the thermoelectric principle, while it is possible to machine all at least minimally electrically conductive materials. Due to the wide range of applications of WEDM, it is necessary to ensure the appropriate quality of machined surfaces, regardless of the thickness of the machined materials, while maintaining an acceptable cutting speed. For this purpose, this study was performed to analyse the effect of material thickness on the cutting speed, morphology and topography of Ampcoloy 35 material. In this study, thicknesses from 5 to 160 mm were analysed in 5 mm increments with the same machine parameter settings. The surface topography and morphology were studied using electron and light microscopy, and cross-sections of the sample were created to examine the condition of the subsurface layer. It was found that the values of Ra at the edge ranged from 1.8 to 3.2 µm and in the middle of the sample from 1.7 to 3 µm, while the trend of increasing Ra with thickness is not visible. It is clear from the morphology analysis that a rugged surface with more craters was created at the edges than in the middle of the sample, while segregated lead needles were also formed at the edges of the samples.

Soil and water salinity are increasing problems worldwide, causing significantly reduced crop yields. Alfalfa (Medicago sativaL.) is often listed as salt‐sensitive, but field testing of improved cultivars is limited. Forage systems and improved high‐quality alfalfa varieties are needed to enable crop production under high salinity (HS) conditions. The objective of this study was to measure the yield and quality response of alfalfa to high saline conditions in the field and to document the relative saline tolerance of its varieties. HS irrigation water (electrical conductivity of water, or ECw8.0–11.0 dS m−1) was applied to 33 nondormant alfalfa cultivars and were compared with low salinity (LS) treatments (ECw0.5–1.2 dS m−1) over 4 years in a Mediterranean environment on a clay loam soil utilizing a split‐plot design. Crops were harvested seven to eight times per year, and the forage quality was measured on selected harvests utilizing near‐infrared spectroscopy. The average yield loss due to HS treatment was 23.9% compared with LS treatment, but yields averaged 23.4 Mg ha−1under HS over the 3 full years of production. This level of production is considered to be economically viable in this region. Differences in salinity tolerance between lines were identified in the field; individual cultivars lost 5%–35% of their LS yield when grown under HS conditions. Forage quality was significantly improved under HS versus LS conditions, but improvements were negatively correlated with biomass yield (R2> 0.81), similar to responses observed in drought‐stressed alfalfa. These yield results confirm greenhouse studies, indicating that alfalfa is highly salt tolerant once established in the field, with potential for further improvement with tolerant cultivars. Salinity tolerance should be chosen based on total biomass yield as well as on the salinity tolerance index (HS yield relative to LS yield). Agronomic practices to mitigate salinity and sodicity are critical, along with improved cultivars. Salinity tolerance index (STI) of alfalfa cultivars. Alfalfa cultivars respond differently to salinity, with some showing dramatic declines and others showing modest declines due to saline conditions. However, some cultivars with high STI, nevertheless, were low yielding, and some with a low STI performed well under high and low saline conditions.

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1–4, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.

This work compares eight classical H2molecular models in the gas phase taken from the existing literature. All models are based on Lennard-Jones (LJ) 12-6 terms for the van der Waals interactions and hence easier to transfer to multiphase molecular simulations than more sophisticated potentials. The H2potentials tested include one-site, two-site, three-site, and five-site models, with the sites being either the H atoms, the center-of-mass of the H2molecule, or massless sites. For the multisite models, high-frequency H–H stretching modes can lead to poor equipartition of the kinetic energy, and the timestep for molecular dynamics (MD) simulations should be reduced to maintain a stable numerical integration of the equations of motion. As such, only those models with rigid bonds are considered. In the present case, 600 MD simulations of H2gas were carried out over a large range of temperatures (−50 to +90 °C) and at densities corresponding to a pressure range of 50 to 2000 bar, which include the operating conditions of on-board storage tanks in hydrogen-fueled vehicles. Most of the models under study were found to reproduce reasonably well the experimental pVTphase diagram as well as the solubility. Discrepancies only became significant at the highest densities tested, and these could be used to rank the different models. All model diffusion coefficients were essentially indistinguishable from experimental results, and as such, kinetically dominated dynamic properties could not be used as a criterion for the choice of model. Among the eight models tested, two of them, i.e., the two-site model of Yang and Zhong and the one-site model derived from Buch performed very well over the range of conditions tested. They represent a good compromise between realism, simplicity, and computational efficiency.

This letter summarizes and proves the concept of bounded-input bounded-state (BIBS) stability for weight convergence of a broad family of in-parameter-linear nonlinear neural architectures (IPLNAs) as it generally applies to a broad family of incremental gradient learning algorithms. A practical BIBS convergence condition results from the derived proofs for every individual learning point or batches for real-time applications.

The Northern Refuge of Lake Michigan was established under the auspices of the Great Lakes Fishery Commission in 1985 as an additional step toward restoring a self‐sustaining Lake Trout Salvelinus namaycushpopulation to the lake. The overall goal of our study was to assess progress toward Lake Trout rehabilitation in the Northern Refuge through 2021. We conducted annual (1992–2021) gill‐net surveys in the fall to assess the adult population and beam trawl surveys in the spring to assess naturally reproduced age‐0 Lake Trout. Spawner abundance averaged 45 fish • 305 m of gill net−1• day−1during 1992–1999, just 4 fish • 305 m of gill net−1• day−1during 2000–2014, and then 67 fish • 305 m of gill net−1• day−1during 2018–2021. Sea Lamprey Petromyzon marinuswounding rate decreased by nearly 90% between the 2000–2014 and 2015–2021 periods. The average annual mortality rate of adult Lake Trout decreased from 43% during the 1990s and 2000s to 22% during 2015–2021. All of these population dynamics were partly driven by changes in Lake Trout stocking rates, which declined by roughly 50% during 1994–1996 but then increased roughly twofold during 2006–2010 and remained at this higher level during 2010–2018. In 2021, early signs of natural recruitment of Lake Trout became evident. Beam trawling during June 2021 yielded a wild age‐0 Lake Trout, the first ever caught since the surveys began in 1992. In addition, 15 (4% of total catch) of the Lake Trout caught in the fall 2021 gill‐net survey were unclipped (wild) fish. Estimated ages of these wild fish indicated that natural recruitment had begun sometime around 2015. With Alewife Alosa pseudoharengusabundance in Lake Michigan at record low levels, Sea Lamprey wounding rate greatly reduced, and Lake Trout spawner abundance at relatively high levels, the outlook for Lake Trout rehabilitation in the Northern Refuge holds promise. Impact statementWe documented significant progress toward the goal of establishing a self‐sustaining Lake Trout population in the Northern Refuge of Lake Michigan during 2009–2021. Accomplishing this goal is a key step in stabilizing the ecosystem, but additional effort is still needed to reach the goal. We documented significant progress toward the goal of establishing a self‐sustaining Lake Trout population in the Northern Refuge of Lake Michigan during 2009–2021. Accomplishing this goal is a key step in stabilizing the ecosystem, but additional effort is still needed to reach the goal.

ObjectiveTo develop an interpretable artificial intelligence algorithm to rule out normal large bowel endoscopic biopsies, saving pathologist resources and helping with early diagnosis.DesignA graph neural network was developed incorporating pathologist domain knowledge to classify 6591 whole-slides images (WSIs) of endoscopic large bowel biopsies from 3291 patients (approximately 54% female, 46% male) as normal or abnormal (non-neoplastic and neoplastic) using clinically driven interpretable features. One UK National Health Service (NHS) site was used for model training and internal validation. External validation was conducted on data from two other NHS sites and one Portuguese site.ResultsModel training and internal validation were performed on 5054 WSIs of 2080 patients resulting in an area under the curve-receiver operating characteristic (AUC-ROC) of 0.98 (SD=0.004) and AUC-precision-recall (PR) of 0.98 (SD=0.003). The performance of the model, named Interpretable Gland-Graphs using a Neural Aggregator (IGUANA), was consistent in testing over 1537 WSIs of 1211 patients from three independent external datasets with mean AUC-ROC=0.97 (SD=0.007) and AUC-PR=0.97 (SD=0.005). At a high sensitivity threshold of 99%, the proposed model can reduce the number of normal slides to be reviewed by a pathologist by approximately 55%. IGUANA also provides an explainable output highlighting potential abnormalities in a WSI in the form of a heatmap as well as numerical values associating the model prediction with various histological features.ConclusionThe model achieved consistently high accuracy showing its potential in optimising increasingly scarce pathologist resources. Explainable predictions can guide pathologists in their diagnostic decision-making and help boost their confidence in the algorithm, paving the way for its future clinical adoption.

ObjectivesThe comparison of treatment efficacy for cerebral cavernous malformations (CCMs) has not yet been well researched.DesignPubMed, Cochrane Library, Science Direct, ISI Web of Science, Embase and additional sources were searched to identify cohort studies about the treatment of CCMs published between 1990 and 2020. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed; the Newcastle-Ottawa Scale was used to assess the risk of bias and to evaluate limitations based on selection/outcome biases. The cumulative incidences with 95% CIs were calculated using the random effects model. The models of Poisson distribution were applied to evaluate risk factors of poorer treatment outcome by calculating rate ratios within 100 person-years with 95% CIs.ResultsA total of 100 cohorts yielding 8994 patients treated for CCMs within 41 098 person-years of follow-up were analysed. The efficacy of ensuring the prevention of haemorrhage was 97% in surgical, 86% in radiosurgical and 77% in the conservative treatment. The lowest mortality (1%) was after radiosurgery, and the highest persistent morbidity (22%) was in natural history series. Deep-seated and brainstem CCMs were associated with higher bleeding rates. Lobar localisation was a protective factor in all analyses. Patients with history of previous haemorrhage were exposed to higher risk of rebleeding. Male gender was a protective factor associated with lower risk of post-treatment haemorrhage.ConclusionsSurgical resection of CCM is effective in ensuring the prevention of haemorrhage with acceptable morbidity and mortality, but conservative and radiosurgical management is a justified treatment alternative. Brainstem and deep-seated CCMs are predominantly associated with higher haemorrhage rates.

The study presented focuses on material research of La Tène rivets and represents the very first study conducted into this class of archaeological finds from the Bohemian region. The rivets examined come from two significant archaeological sites situated in this geographical area—a hillfort Kolo near Týnec nad Labem and an oppidum in Stradonice. The sets of the rivets selected for the study were dated to the Late La Tène period (second–first century BC)—in the context of Western Europe, the term Celtic period can also be found. Thorough material research of the objects utilised a range of methods such as scanning electron microscopy with energy dispersive analyser, atomic absorption spectrometry, X-ray micro-tomography scanning, laser ablation-inductively coupled plasma-mass spectrometry, and Raman spectrometry. As a result, the research has identified and described three different technologies used to produce the rivets. The rivets uncovered there were mostly produced by casting from a bronze alloy or by putting wrought iron pins into the bronze melt of rivet heads. In addition, a minority of the rivets were produced using forged wrought iron with their heads plated with a very thin bronze plate. The results of the elemental analysis showed that several of the rivets and most of the rivet heads were made of bronze alloys with a tin content of 2–10 wt.%. The lead content of bronze alloy rivets from both sites varies from 0.2 to 10.1 wt.%. It can be assumed, that lead was intentionally added to the bronze melt used to produce the majority of the artefacts examined. Also, several bronze rivet heads were found to be decorated with enamel, which is a type of soda-lime-silica high lead glass coloured with crystals of Cu2O (the Colour of the enamel was predominantly red). In conclusion, two different groups of enamels were distinguished: (a) enamels with PbO up to 20% and (b) enamels with a higher content of PbO reaching up to 40%.

The National Judicial College (NJC) in Reno, Nevada is the only national college for judges in the United States. It offers courses to both new and experienced judges, teaching them how to do their job effectively. The NJC also offers specialty courses on topics such as writing opinions, understanding financial statements, and handling self-represented litigants. In addition, the NJC has outreach programs, a judicial academy for lawyers aspiring to become judges, and a civics education program for students. The college has also worked with international judicial systems and has its own sports teams. [Extracted from the article]

Fecal microbiota transplantation (FMT) is a therapeutic intervention for inflammatory diseases of the gastrointestinal tract, but its clinical mode of action and subsequent microbiome dynamics remain poorly understood. Here we analyzed metagenomes from 316 FMTs, sampled pre and post intervention, for the treatment of ten different disease indications. We quantified strain-level dynamics of 1,089 microbial species, complemented by 47,548 newly constructed metagenome-assembled genomes. Donor strain colonization and recipient strain resilience were mostly independent of clinical outcomes, but accurately predictable using LASSO-regularized regression models that accounted for host, microbiome and procedural variables. Recipient factors and donor–recipient complementarity, encompassing entire microbial communities to individual strains, were the main determinants of strain population dynamics, providing insights into the underlying processes that shape the post-FMT gut microbiome. Applying an ecology-based framework to our findings indicated parameters that may inform the development of more effective, targeted microbiome therapies in the future, and suggested how patient stratification can be used to enhance donor microbiota colonization or the displacement of recipient microbes in clinical practice.

Seroconversion after COVID-19 vaccination is impaired in kidney transplant recipients. Emerging variants of concern such as the B.1.617.2 (delta) and the B.1.1.529 (omicron) variants pose an increasing threat to these patients. In this observational cohort study, we measured anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies three weeks after a third mRNA vaccine dose in 49 kidney transplant recipients and compared results to 25 age-matched healthy controls. In addition, vaccine-induced neutralization of SARS-CoV-2 wild-type, the B.1.617.2 (delta), and the B.1.1.529 (omicron) variants was assessed using a live-virus assay. After a third vaccine dose, anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies were significantly lower in kidney transplant recipients compared to healthy controls. Only 29/49 (59%) sera of kidney transplant recipients contained neutralizing antibodies against the SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant and neutralization titers were significantly reduced compared to healthy controls (p< 0.001). Vaccine-induced cross-neutralization of the B.1.1.529 (omicron) variants was detectable in 15/35 (43%) kidney transplant recipients with seropositivity for anti-S1 IgG, surrogate neutralizing, and/or anti-RBD antibodies. Neutralization of the B.1.1.529 (omicron) variants was significantly reduced compared to neutralization of SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant for both, kidney transplant recipients and healthy controls (p< .001 for all).

Heat resistance, heat stableness and corrosion resistance are properties that predispose nickel superalloys such as Inconel 625, Mar-M247, Nimonic C 263 and B1914 to a very wide range of applications. Due to their mechanical properties, their machinability by conventional technologies is relatively difficult, so wire electrical discharge machining (WEDM) is widely used, where only one condition is placed on the material being machined, which is at least minimal electrical conductivity. Despite the fact that the main element of which these superalloys are always composed is nickel, their machinability by WEDM is quite different. For this reason, an extensive study comparing the machinability of the four above-mentioned nickel superalloys using WEDM was performed, examining the effect of setting the machine parameters on the cutting speed as well as on the quality of the surface and subsurface layer. It was found out that the cutting speed is different for individual materials with the same set of machine parameters and so that it is possible to significantly increase the quality of the machined surface for individual materials.

Graphical abstract:

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1–3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents—which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4–7—did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.

Combinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS–TP53double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.

Electrically charged particles can be created by the decay of strong enough electric fields, a phenomenon known as the Schwinger mechanism1. By electromagnetic duality, a sufficiently strong magnetic field would similarly produce magnetic monopoles, if they exist2. Magnetic monopoles are hypothetical fundamental particles that are predicted by several theories beyond the standard model3–7but have never been experimentally detected. Searching for the existence of magnetic monopoles via the Schwinger mechanism has not yet been attempted, but it is advantageous, owing to the possibility of calculating its rate through semi-classical techniques without perturbation theory, as well as that the production of the magnetic monopoles should be enhanced by their finite size8,9and strong coupling to photons2,10. Here we present a search for magnetic monopole production by the Schwinger mechanism in Pb–Pb heavy ion collisions at the Large Hadron Collider, producing the strongest known magnetic fields in the current Universe11. It was conducted by the MoEDAL experiment, whose trapping detectors were exposed to 0.235 per nanobarn, or approximately 1.8 × 109, of Pb–Pb collisions with 5.02-teraelectronvolt center-of-mass energy per collision in November 2018. A superconducting quantum interference device (SQUID) magnetometer scanned the trapping detectors of MoEDAL for the presence of magnetic charge, which would induce a persistent current in the SQUID. Magnetic monopoles with integer Dirac charges of 1, 2 and 3 and masses up to 75 gigaelectronvolts per speed of light squared were excluded by the analysis at the 95% confidence level. This provides a lower mass limit for finite-size magnetic monopoles from a collider search and greatly extends previous mass bounds.

Inefficient fertilizer use in agriculture causes nitrate runoff, polluting rivers and streams. This pollution can be mitigated by partially converting nitrate into ammonia – rebalancing the composition to ammonium nitrate, and allowing recycling of fertilizer. Here, we present efficient electrochemical conversion of nitrate (50 mM) to ammonia in acidic electrolyte using tubular porous Ti electrodes. A high faradaic efficiency (FE) of 58% and partial current density to ammonia of −33 mA cm−2at −1 V vs.RHE were achieved in the absence of inert gas purge. Additionally, we reveal that hydroxylamine is formed, as well as NO and N2O by spontaneous decomposition of nitrite, as has been determined by EC-MS analysis. The effective increase in local mass transport by introducing a flow of inert gas exiting the wall of the hollow fiber electrode results in an unprecedently high partial current density to ammonia of ∼−75 mA cm−2, while maintaining a faradaic efficiency to ammonia of up to 45%. This concept facilitates nitrate conversion at high FE even at low concentrations, and holds promise for development to practical scale if electrochemical potential and exiting gas flow rate are well controlled.

BackgroundRecent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression.ObjectiveTo explore the faecal and salivary microbiota as potential diagnostic biomarkers.MethodsWe applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case–control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case–control study (n=76), in the validation phase.ResultsFaecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19–9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation.ConclusionTaken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.

Single-cell genomics technology has transformed our understanding of complex cellular systems. However, excessive cost and a lack of strategies for the purification of newly identified cell types impede their functional characterization and large-scale profiling. Here, we have generated high-content single-cell proteo-genomic reference maps of human blood and bone marrow that quantitatively link the expression of up to 197 surface markers to cellular identities and biological processes across all main hematopoietic cell types in healthy aging and leukemia. These reference maps enable the automatic design of cost-effective high-throughput cytometry schemes that outperform state-of-the-art approaches, accurately reflect complex topologies of cellular systems and permit the purification of precisely defined cell states. The systematic integration of cytometry and proteo-genomic data enables the functional capacities of precisely mapped cell states to be measured at the single-cell level. Our study serves as an accessible resource and paves the way for a data-driven era in cytometry.

The unconventional technology of wire electrical discharge machining is a key engineering technology, designed primarily for machining of conventionally difficult machine materials. One of them is nickel alloys, which are majorly used in the aerospace and energy industries. The subject of research in this study was specifically the B1914 nickel-based superalloy, which was subjected to many analyses leading to an overall optimization of its machining using wire electrical discharge machining. In order to determine the effect of machine parameters setup (pulse off time, gap voltage, discharge current, pulse on time and wire feed) on cutting speed, topography, morphology, surface and subsurface layer quality, an extensive Box–Behnken design experiment consisting of 46 rounds was carried out. The analyses of the condition of the surface and subsurface layers were performed, including their chemical composition and changes caused by wire electrical discharge machining. It was found out that the factors like pulse off time, discharge current and pulse on time have the greatest effect on the cutting speed, although from the point of view of surface topography the parameter pulse off time is not significant. The remaining two parameters cause the cutting speed to act against the surface topography i.e. with the increasing cutting speed, the surface topography gets worse and vice versa.

Recirculation of chronic lymphocytic leukemia (CLL) cells between the peripheral blood and lymphoid niches plays a critical role in disease pathophysiology, and inhibiting this process is one of the major mechanisms of action for B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib. Migration is a complex process guided by chemokine receptors and integrins. However, it remains largely unknown how CLL cells integrate multiple migratory signals while balancing survival in the peripheral blood and the decision to return to immune niches. Our study provided evidence that CXCR4/CD5 intraclonal subpopulations can be used to study the regulation of migration of CLL cells. We performed RNA profiling of CXCR4dimCD5bright vs CXCR4brightCD5dim CLL cells and identified differential expression of dozens of molecules with a putative function in cell migration. GRB2–associated binding protein 1 (GAB1) positively regulated CLL cell homing capacity of CXCR4brightCD5dim cells. Gradual GAB1 accumulation in CLL cells outside immune niches was mediated by FoxO1-induced transcriptional GAB1 activation. Upregulation of GAB1 also played an important role in maintaining basal phosphatidylinositol 3-kinase (PI3K) activity and the “tonic” AKT phosphorylation required to sustain the survival of resting CLL B cells. This finding is important during ibrutinib therapy, because CLL cells induce the FoxO1-GAB1-pAKT axis, which represents an adaptation mechanism to the inability to home to immune niches. We have demonstrated that GAB1 can be targeted therapeutically by novel GAB1 inhibitors, alone or in combination with BTK inhibition. GAB1 inhibitors induce CLL cell apoptosis, impair cell migration, inhibit tonic or BCR-induced AKT phosphorylation, and block compensatory AKT activity during ibrutinib therapy.

Aims & Objectives The purpose of this study was to identify patient characteristics associated with engagement and completion of physical therapy (PT) following total knee arthroplasty (TKA) and examine the relationship between number of PT sessions attended and outcomes during the first 12 weeks after surgery.Methods Patients underwent unilateral primary TKA by a single surgeon and were advised to complete 17 PT sessions over 6 weeks at a hospital-affiliated facility. Analyses examined predictors of PT engagement (attendance of ≥2 sessions) and completion (attendance of 17 ± 1 sessions) within 6 weeks and associations between number of PT sessions attended and changes in range of motion (ROM) and Knee Injury and Osteoarthritis Outcome Score (KOOS) values.Results Patients living <40 km were more likely to be engaged in PT than those living ≥40 km from the clinic (P< .0001). Among patients who completed PT within 6 weeks, 95.0%, 85.1%, and 56.4% achieved flexion of, respectively, ≥90°, ≥100°, and ≥110°. Among engaged patients, the active flexion thresholds of ≥90°, ≥100°, and ≥110° were achieved by, respectively, 94.4%, 82.5%, and 58.1% by 6 weeks and by 96.7%, 92.1%, and 84.2% by 12 weeks. Improvement in KOOS Symptoms (P= .029), Function in daily living (P= .030) and quality of life (P= .031) linearly decreased as number of PT sessions increased.Conclusions These results raise the question of whether patients who meet satisfactory outcomes before completing 6 weeks of prescribed PT and those who attend more PT sessions than prescribed may be over-utilizing healthcare resources without additional benefit.

There is a need for gas separation membranes that can perform at high temperatures, for example, for CO2capture in industrial processes. Polyphosphazenes classify as interesting materials for use under these conditions because of their high thermal stability, hybrid nature, and postfunctionalization options. In this work, thin-film composite cyclomatrix polyphosphazene membranes are prepared via the interfacial polymerization reaction between polyhedral oligomeric silsesquioxane and hexachlorocyclotriphosphazene on top of a ceramic support. The prepared polyphosphazene networks are highly crosslinked and show excellent thermal stability until 340 °C. Single gas permeation experiments at temperatures ranging from 50 to 250 °C reveal a molecular sieving behavior, with permselectivities as high as 130 for H2/CH4at the low temperatures. The permselectivities of the membranes persist at the higher temperatures; at 250 °C H2/N2(40), H2/CH4(31) H2/CO2(7), and CO2/CH4(4), respectively, while maintaining permeances in the order of 10–7to 10–8mol m–2s–1Pa–1. Compared to other types of polymer-based membranes, especially the H2/N2and H2/CH4selectivities are high, with similar permeances. Consequently, the hybrid polyphosphazene membranes have great potential for use in high-temperature gas separation applications.

Sensor platforms can benefit from the incorporation of polymer brushes since brushes can concentrate the analyte near the sensor surface. Brushes that absorb acetone vapor are of particular interest since acetone is an important marker for biological processes. We present a simple procedure to synthesize acetone-responsive poly(methyl acrylate) brushes. Using spectroscopic ellipsometry, we show that these brushes respond within seconds and swell by more than 30% when exposed to acetone vapor. Moreover, quartz crystal microbalance measurements demonstrate that the brushes can be exploited to increase the acetone detection sensitivity of sensors by more than a factor 6. Surprisingly, we find that the swelling ratio of the brushes in acetone vapor is independent of the grafting density and the degree of polymerization of the polymers in the brush. This is qualitatively different from swelling of the same brushes in liquid environments, where the swelling ratio decreases for increasing grafting densities. Yet, it indicates that the brushes are robust and reproducible candidates for implementation in vapor sensor systems.

•Proposing the ANN-based prediction model to forecast future blood glucose level given CGM as the single input.•Utilizing time-domain features as additional attributes for proposed prediction model to improve the prediction accuracy.•By integrating time-domain features as additional attributes, it has improved majority of performance of models.•Proposed model outperformed other ML models and other models from previous studies, especially for short term forecasting.

Polycomb-group (PcG) proteins utilize epigenetic mechanisms to maintain the transcriptional silence of target genes. Recruitment of Drosophila PcG proteins to target genes requires the presence of a Polycomb Response Element (PRE). Some PcG target genes, including...Polycomb-group (PcG) proteins are evolutionarily conserved epigenetic regulators whose primary function is to maintain the transcriptional repression of target genes. Recruitment of Drosophila melanogasterPcG proteins to target genes requires the presence of one or more Polycomb Response Elements (PREs). The functions or necessity for more than one PRE at a gene are not clear and individual PREs at some loci may have distinct regulatory roles. Various combinations of sequence-specific DNA-binding proteins are present at a given PRE, but only Pleiohomeotic (Pho) is present at all strong PREs. The giant(gt) locus has two PREs, a proximal PRE1 and a distal PRE2. During early embryonic development, Pho binds to PRE1 ∼30-min prior to stable binding to PRE2. This observation indicated a possible dependence of PRE2 on PRE1 for PcG recruitment; however, we find here that PRE2 recruits PcG proteins and maintains transcriptional repression independently of Pho binding to PRE1. Pho-like (Phol) is partially redundant with Pho during larval development and binds to the same DNA sequences in vitro. Although binding of Pho to PRE1 is dependent on the presence of consensus Pho-Phol-binding sites, Phol binding is less so and appears to play a minimal role in recruiting other PcG proteins to gt. Another PRE-binding protein, Sp1/Kruppel-like factor, is dependent on the presence of Pho for PRE1 binding. Further, we show that, in addition to silencing gene expression, PcG proteins dampen transcription of an active gene.

Surface treatments are typical surface protection against corrosion or serve to create an attractive appearance for the end customer. However, the surface to which they are applied must be completely oxide-free, otherwise, defects occur which can cause subsequent corrosion or deterioration of the visual appearance of the product. The parts manufactured by wire electrical discharge machining, however, have a high tendency to oxidize. For this reason, this study was aimed at demonstrating the effect of machine setup parameters (gap voltage, pulse on and off time, wire feed and discharge current) on oxygen occurrence on the surface of two non-metallic (aluminium alloy 7475-T7351, chromium nickel superalloy Inconel 625) and four metallic materials (tool alloy steel X210Cr12, Hadfield steel, Creusabro 4800 and Hardox 400). Within this study, 18 samples were produced, where the chemical composition of energy-dispersive X-ray was analysed, on the basis of which the effect of these parameters on the surface oxidation was proved.