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Nick K. Jones1,2*, Lucy Rivett1,2*, Chris Workman3, Mark Ferris3, Ashley Shaw1, Cambridge COVID-19 Collaboration1,4, Paul J. Lehner1,4, Rob Howes5, Giles Wright3, Nicholas J. Matheson1,4,6¶, Michael P. Weekes1,7¶1 Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK2 Clinical Microbiology & Public Health Laboratory, Public Health England, Cambridge, UK3 Occupational Health and Wellbeing, Cambridge Biomedical Campus, Cambridge, UK4 Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK5 Cambridge COVID-19 Testing Centre and AstraZeneca, Anne Mclaren Building, Cambridge, UK6 NHS Blood and Transplant, Cambridge, UK7 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK*Joint first authorship¶Joint last authorshipCorrespondence: mpw1001@cam.ac.ukThe UK has initiated mass COVID-19 immunisation, with healthcare workers (HCWs) given early priority because of the potential for workplace exposure and risk of onward transmission to patients. The UK’s Joint Committee on Vaccination and Immunisation has recommended maximising the number of people vaccinated with first doses at the expense of early booster vaccinations, based on single dose efficacy against symptomatic COVID-19 disease.1-3At the time of writing, three COVID-19 vaccines have been granted emergency use authorisation in the UK, including the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech). A vital outstanding question is whether this vaccine prevents or promotes asymptomatic SARS-CoV-2 infection, rather than symptomatic COVID-19 disease, because sub-clinical infection following vaccination could continue to drive transmission. This is especially important because many UK HCWs have received this vaccine, and nosocomial COVID-19 infection has been a persistent problem.Through the implementation of a 24 h-turnaround PCR-based comprehensive HCW screening programme at Cambridge University Hospitals NHS Foundation Trust (CUHNFT), we previously demonstrated the frequent presence of pauci- and asymptomatic infection amongst HCWs during the UK’s first wave of the COVID-19 pandemic.4 Here, we evaluate the effect of first-dose BNT162b2 vaccination on test positivity rates and cycle threshold (Ct) values in the asymptomatic arm of our programme, which now offers weekly screening to all staff.Vaccination of HCWs at CUHNFT began on 8th December 2020, with mass vaccination from 8th January 2021. Here, we analyse data from the two weeks spanning 18thto 31st January 2021, during which: (a) the prevalence of COVID-19 amongst HCWs remained approximately constant; and (b) we screened comparable numbers of vaccinated and unvaccinated HCWs. Over this period, 4,408 (week 1) and 4,411 (week 2) PCR tests were performed from individuals reporting well to work. We stratified HCWs <12 days or > 12 days post-vaccination because this was the point at which protection against symptomatic infection began to appear in phase III clinical trial.226/3,252 (0·80%) tests from unvaccinated HCWs were positive (Ct<36), compared to 13/3,535 (0·37%) from HCWs <12 days post-vaccination and 4/1,989 (0·20%) tests from HCWs ≥12 days post-vaccination (p=0·023 and p=0·004, respectively; Fisher’s exact test, Figure). This suggests a four-fold decrease in the risk of asymptomatic SARS-CoV-2 infection amongst HCWs ≥12 days post-vaccination, compared to unvaccinated HCWs, with an intermediate effect amongst HCWs <12 days post-vaccination.A marked reduction in infections was also seen when analyses were repeated with: (a) inclusion of HCWs testing positive through both the symptomatic and asymptomatic arms of the programme (56/3,282 (1·71%) unvaccinated vs 8/1,997 (0·40%) ≥12 days post-vaccination, 4·3-fold reduction, p=0·00001); (b) inclusion of PCR tests which were positive at the limit of detection (Ct>36, 42/3,268 (1·29%) vs 15/2,000 (0·75%), 1·7-fold reduction, p=0·075); and (c) extension of the period of analysis to include six weeks from December 28th to February 7th 2021 (113/14,083 (0·80%) vs 5/4,872 (0·10%), 7·8-fold reduction, p=1x10-9). In addition, the median Ct value of positive tests showed a non-significant trend towards increase between unvaccinated HCWs and HCWs > 12 days post-vaccination (23·3 to 30·3, Figure), suggesting that samples from vaccinated individuals had lower viral loads.We therefore provide real-world evidence for a high level of protection against asymptomatic SARS-CoV-2 infection after a single dose of BNT162b2 vaccine, at a time of predominant transmission of the UK COVID-19 variant of concern 202012/01 (lineage B.1.1.7), and amongst a population with a relatively low frequency of prior infection (7.2% antibody positive).5This work was funded by a Wellcome Senior Clinical Research Fellowship to MPW (108070/Z/15/Z), a Wellcome Principal Research Fellowship to PJL (210688/Z/18/Z), and an MRC Clinician Scientist Fellowship (MR/P008801/1) and NHSBT workpackage (WPA15-02) to NJM. Funding was also received from Addenbrooke’s Charitable Trust and the Cambridge Biomedical Research Centre. We also acknowledge contributions from all staff at CUHNFT Occupational Health and Wellbeing and the Cambridge COVID-19 Testing Centre.

Scene flow tracks the three-dimensional (3D) motion of each point in adjacent point clouds. It provides fundamental 3D motion perception for autonomous driving and server robot. Although the Red Green Blue Depth (RGBD) camera or Light Detection and Ranging (LiDAR) capture discrete 3D points in space, the objects and motions usually are continuous in the macro world. That is, the objects keep themselves consistent as they flow from the current frame to the next frame. Based on this insight, the Generative Adversarial Networks (GAN) is utilized to self-learn 3D scene flow with no need for ground truth. The fake point cloud of the second frame is synthesized from the predicted scene flow and the point cloud of the first frame. The adversarial training of the generator and discriminator is realized through synthesizing indistinguishable fake point cloud and discriminating the real point cloud and the synthesized fake point cloud. The experiments on Karlsruhe Institute of Technology and Toyota Technological Institute (KITTI) scene flow dataset show that our method realizes promising results without ground truth. Just as human, the proposed method can identify the similar local structures of two adjacent frames even without knowing the ground truth scene flow. Then, the local correspondence can be correctly estimated, and further the scene flow is correctly estimated.   Corresponding author(s) Email: wanghesheng@sjtu.edu.cn

Leukocyte differential test is a widely performed clinical procedure for screening infectious diseases. Existing hematology analyzers require labor-intensive work and a panel of expensive reagents. Here we report an artificial-intelligence enabled reagent-free imaging hematology analyzer (AIRFIHA) modality that can accurately classify subpopulations of leukocytes with minimal sample preparation. AIRFIHA is realized through training a two-step residual neural network using label-free images of isolated leukocytes acquired from a custom-built quantitative phase microscope. By leveraging the rich information contained in quantitative phase images, we not only achieved high accuracy in differentiating B and T lymphocytes, but also classified CD4 and CD8 cells, therefore outperforming the classification accuracy of most current hematology analyzers. We validated the performance of AIRFIHA in a randomly selected test set and cross-validated it across all blood donors. Owing to its easy operation, low cost, and accurate discerning capability of complex leukocyte subpopulations, we envision AIRFIHA is clinically translatable and can also be deployed in resource-limited settings, e.g., during pandemic situations for the rapid screening of infectious diseases.  Corresponding author(s) Email:    rjzhou@cuhk.edu.hk,  rishikesh.pandey@uconn.edu

Tam Hunt [1], Jonathan SchoolerUniversity of California Santa Barbara Synchronization, harmonization, vibrations, or simply resonance in its most general sense seems to have an integral relationship with consciousness itself. One of the possible “neural correlates of consciousness” in mammalian brains is a combination of gamma, beta and theta synchrony. More broadly, we see similar kinds of resonance patterns in living and non-living structures of many types. What clues can resonance provide about the nature of consciousness more generally? This paper provides an overview of resonating structures in the fields of neuroscience, biology and physics and attempts to coalesce these data into a solution to what we see as the “easy part” of the Hard Problem, which is generally known as the “combination problem” or the “binding problem.” The combination problem asks: how do micro-conscious entities combine into a higher-level macro-consciousness? The proposed solution in the context of mammalian consciousness suggests that a shared resonance is what allows different parts of the brain to achieve a phase transition in the speed and bandwidth of information flows between the constituent parts. This phase transition allows for richer varieties of consciousness to arise, with the character and content of that consciousness in each moment determined by the particular set of constituent neurons. We also offer more general insights into the ontology of consciousness and suggest that consciousness manifests as a relatively smooth continuum of increasing richness in all physical processes, distinguishing our view from emergentist materialism. We refer to this approach as a (general) resonance theory of consciousness and offer some responses to Chalmers’ questions about the different kinds of “combination problem.”  At the heart of the universe is a steady, insistent beat: the sound of cycles in sync…. [T]hese feats of synchrony occur spontaneously, almost as if nature has an eerie yearning for order. Steven Strogatz, Sync: How Order Emerges From Chaos in the Universe, Nature and Daily Life (2003) If you want to find the secrets of the universe, think in terms of energy, frequency and vibration.Nikola Tesla (1942) I.               Introduction Is there an “easy part” and a “hard part” to the Hard Problem of consciousness? In this paper, we suggest that there is. The harder part is arriving at a philosophical position with respect to the relationship of matter and mind. This paper is about the “easy part” of the Hard Problem but we address the “hard part” briefly in this introduction.  We have both arrived, after much deliberation, at the position of panpsychism or panexperientialism (all matter has at least some associated mind/experience and vice versa). This is the view that all things and processes have both mental and physical aspects. Matter and mind are two sides of the same coin.  Panpsychism is one of many possible approaches that addresses the “hard part” of the Hard Problem. We adopt this position for all the reasons various authors have listed (Chalmers 1996, Griffin 1997, Hunt 2011, Goff 2017). This first step is particularly powerful if we adopt the Whiteheadian version of panpsychism (Whitehead 1929).  Reaching a position on this fundamental question of how mind relates to matter must be based on a “weight of plausibility” approach, rather than on definitive evidence, because establishing definitive evidence with respect to the presence of mind/experience is difficult. We must generally rely on examining various “behavioral correlates of consciousness” in judging whether entities other than ourselves are conscious – even with respect to other humans—since the only consciousness we can know with certainty is our own. Positing that matter and mind are two sides of the same coin explains the problem of consciousness insofar as it avoids the problems of emergence because under this approach consciousness doesn’t emerge. Consciousness is, rather, always present, at some level, even in the simplest of processes, but it “complexifies” as matter complexifies, and vice versa. Consciousness starts very simple and becomes more complex and rich under the right conditions, which in our proposed framework rely on resonance mechanisms. Matter and mind are two sides of the coin. Neither is primary; they are coequal.  We acknowledge the challenges of adopting this perspective, but encourage readers to consider the many compelling reasons to consider it that are reviewed elsewhere (Chalmers 1996, Griffin 1998, Hunt 2011, Goff 2017, Schooler, Schooler, & Hunt, 2011; Schooler, 2015).  Taking a position on the overarching ontology is the first step in addressing the Hard Problem. But this leads to the related questions: at what level of organization does consciousness reside in any particular process? Is a rock conscious? A chair? An ant? A bacterium? Or are only the smaller constituents, such as atoms or molecules, of these entities conscious? And if there is some degree of consciousness even in atoms and molecules, as panpsychism suggests (albeit of a very rudimentary nature, an important point to remember), how do these micro-conscious entities combine into the higher-level and obvious consciousness we witness in entities like humans and other mammals?  This set of questions is known as the “combination problem,” another now-classic problem in the philosophy of mind, and is what we describe here as the “easy part” of the Hard Problem. Our characterization of this part of the problem as “easy”[2] is, of course, more than a little tongue in cheek. The authors have discussed frequently with each other what part of the Hard Problem should be labeled the easier part and which the harder part. Regardless of the labels we choose, however, this paper focuses on our suggested solution to the combination problem.  Various solutions to the combination problem have been proposed but none have gained widespread acceptance. This paper further elaborates a proposed solution to the combination problem that we first described in Hunt 2011 and Schooler, Hunt, and Schooler 2011. The proposed solution rests on the idea of resonance, a shared vibratory frequency, which can also be called synchrony or field coherence. We will generally use resonance and “sync,” short for synchrony, interchangeably in this paper. We describe the approach as a general resonance theory of consciousness or just “general resonance theory” (GRT). GRT is a field theory of consciousness wherein the various specific fields associated with matter and energy are the seat of conscious awareness.  A summary of our approach appears in Appendix 1.  All things in our universe are constantly in motion, in process. Even objects that appear to be stationary are in fact vibrating, oscillating, resonating, at specific frequencies. So all things are actually processes. Resonance is a specific type of motion, characterized by synchronized oscillation between two states.  An interesting phenomenon occurs when different vibrating processes come into proximity: they will often start vibrating together at the same frequency. They “sync up,” sometimes in ways that can seem mysterious, and allow for richer and faster information and energy flows (Figure 1 offers a schematic). Examining this phenomenon leads to potentially deep insights about the nature of consciousness in both the human/mammalian context but also at a deeper ontological level.

Cannabis sativa is an extraordinarily versatile species. Hemp and its cousin marijuana, both C. sativa, have been used for millennia as a source of fibre, oil and for medicinal, spiritual and recreational purposes. Because the consumption of Cannabis can have psychoactive effects, the plant has been widely banned throughout the last century. In the past decade, evidence of its medicinal properties did lead to the relaxation of legislation in many countries around the world. Consequently, the genetics and development of Cannabis as well as Cannabis-derived products are the subject of renewed attention.Here, we review the biology of C. sativa, including recent insights from taxonomy, morphology and genomics, with an emphasis on the genetics of cannabinoid synthesis. Because the female Cannabis flower is of special interest as the site of cannabinoid synthesis, we explore flower development, flowering time well as the species’ unique sex determination system in detail. Furthermore, we outline the tremendous medicinal, engineering, and environmental opportunities that Cannabis bears. Together, the picture emerges that our understanding of Cannabis biology currently progresses at an unusual speed. A future challenge will be to preserve the multi-purpose nature of Cannabis, and to harness its medicinal properties and sustainability advantages simultaneously.

Quantum chemistry must evolve if it wants to fully leverage the benefits of the internet age, where the world wide web offers a vast tapestry of tools that enable users to communicate and interact with complex data at the speed and convenience of a button press. The Open Chemistry project has developed an open source framework that offers an end-to-end solution for producing, sharing, and visualizing quantum chemical data interactively on the web using an array of modern tools and approaches. These tools build on some of the best open source community projects such as Jupyter for interactive online notebooks, coupled with 3D accelerated visualization, state-of-the-art computational chemistry codes including NWChem and Psi4 and emerging machine learning and data mining tools such as ChemML and ANI. They offer flexible formats to import and export data, along with approaches to compare computational and experimental data.

This paper responds to one by Graham Martin and colleagues, who offered a critique of my previous publications on masks for the lay public in the Covid-19 pandemic. I address their charges that my co-authors and I had misapplied the precautionary principle; drawn conclusions that were not supported by empirical research; and failed to take account of potential harms. But before that, I remind Martin et al that the evidence on mask wearing goes beyond the contested trials and observational studies they place centre stage. I set out some key findings from basic science, epidemiology, mathematical modelling, case studies and natural experiments, and use this rich and diverse body of evidence as the backdrop for my rebuttal of their narrowly-framed objections. I challenge my critics’ apparent assumption that a particular kind of systematic review should be valorised over narrative and real-world evidence, since stories are crucial to both our scientific understanding and our moral imagination. I conclude by thanking my academic adversaries for the intellectual sparring match, but exhort them to remember our professional accountability to a society in crisis. It is time to lay straw men to rest and engage, scientifically and morally, with the dreadful tragedy that is unfolding across the world.

This Supporting information includes interactive plots, videos, and data captured while performing evaluation and validation experiments for our paper. 

The construct of wellbeing has been criticised as a neoliberal construction of western individualism that ignores wider systemic issues including increasing burden of chronic disease, widening inequality, concerns over environmental degradation and anthropogenic climate change. While these criticisms overlook recent developments, there remains a need for biopsychosocial models that extend theoretical grounding beyond individual wellbeing, incorporating overlapping contextual issues relating to community and environment. Our first GENIAL model \cite{Kemp_2017} provided a more expansive view of pathways to longevity in the context of individual health and wellbeing, emphasising bidirectional links to positive social ties and the impact of sociocultural factors. In this paper, we build on these ideas and propose GENIAL 2.0, focusing on intersecting individual-community-environmental contributions to health and wellbeing, and laying an evidence-based, theoretical framework on which future research and innovative therapeutic innovations could be based. We suggest that our transdisciplinary model of wellbeing - focusing on individual, community and environmental contributions to personal wellbeing - will help to move the research field forward. In reconceptualising wellbeing, GENIAL 2.0 bridges the gap between psychological science and population health health systems, and presents opportunities for enhancing the health and wellbeing of people living with chronic conditions. Implications for future generations including the very survival of our species are discussed.  

Floral plantings are promoted to foster ecological intensification of agriculture through provisioning of ecosystem services. However, a comprehensive assessment of the effectiveness of different floral plantings, their characteristics and consequences for crop yield across global regions is lacking. Here we quantified the impacts of flower strips and hedgerows on pest control and pollination services in adjacent crops using a global dataset of 529 sites. Flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average. However, effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively. These findings provide promising pathways to optimize floral plantings to more effectively contribute to ecosystem service delivery and ecological intensification of agriculture in the future.

Researchers' ability to accurately screen fossil and subfossil specimens for preservation of DNA and protein sequences remains limited. Thermal exposure and geologic age are usable proxies for sequence preservation on a broad scale but are of nominal use for specimens of similar depositional environments. Cell and tissue biomolecular histology is thus proposed as a novel proxy for determining sequence preservation potential of ancient specimens with improved accuracy. Biomolecular histology as a proxy is hypothesized to elucidate why fossils/subfossils of some depositional environments preserve sequences while others do not and to facilitate selection of ancient specimens for use in molecular studies.

IntroductionConsistent with World Health Organization (WHO) advice [1], UK Infection Protection Control guidance recommends that healthcare workers (HCWs) caring for patients with coronavirus disease 2019 (COVID-19) should use fluid resistant surgical masks type IIR (FRSMs) as respiratory protective equipment (RPE), unless aerosol generating procedures (AGPs) are being undertaken or are likely, when a filtering face piece 3 (FFP3) respirator should be used [2]. In a recent update, an FFP3 respirator is recommended if “an unacceptable risk of transmission remains following rigorous application of the hierarchy of control” [3]. Conversely, guidance from the Centers for Disease Control and Prevention (CDC) recommends that HCWs caring for patients with COVID-19 should use an N95 or higher level respirator [4]. WHO guidance suggests that a respirator, such as FFP3, may be used for HCWs in the absence of AGPs if availability or cost is not an issue [1].A recent systematic review undertaken for PHE concluded that: “patients with SARS-CoV-2 infection who are breathing, talking or coughing generate both respiratory droplets and aerosols, but FRSM (and where required, eye protection) are considered to provide adequate staff protection” [5]. Nevertheless, FFP3 respirators are more effective in preventing aerosol transmission than FRSMs, and observational data suggests that they may improve protection for HCWs [6]. It has therefore been suggested that respirators should be considered as a means of affording the best available protection [7], and some organisations have decided to provide FFP3 (or equivalent) respirators to HCWs caring for COVID-19 patients, despite a lack of mandate from local or national guidelines [8].Data from the HCW testing programme at Cambridge University Hospitals NHS Foundation Trust (CUHNFT) during the first wave of the UK severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic indicated a higher incidence of infection amongst HCWs caring for patients with COVID-19, compared with those who did not [9]. Subsequent studies have confirmed this observation [10, 11]. This disparity persisted at CUHNFT in December 2020, despite control measures consistent with PHE guidance and audits indicating good compliance. The CUHNFT infection control committee therefore implemented a change of RPE for staff on “red” (COVID-19) wards from FRSMs to FFP3 respirators. In this study, we analyse the incidence of SARS-CoV-2 infection in HCWs before and after this transition.

We present a case of synchronous dual hematological malignancies: multiple myeloma (MM) and masked essential Thrombocythemia (ET). Excessive thrombocytosis due to bone marrow recovery occurred during anti-myeloma therapy. Treatment for MM had no effect on ET; concomitant ET did not decrease the efficacy of anti-myeloma therapies in this frail patient.

Objectives: Despite its low sensitivity for the interstitial syndrome, chests X-Ray (XR) have been used on COVID-19 patients to exclude alternative diagnoses. Computed tomography (CT) scans can both exclude other pathological conditions and display a high level of sensitivity for the COVID-19 pneumonia. We therefore decided to compare the performance of lung ultrasonography (LUS) with that of lung CT scans in suspect or confirmed COVID-19 patients for the presence of interstitial pneumonia and the degree of lung injury. Methods: In a cross-sectional clinical study, LUS an CT were compared for the presence of interstitial pneumonia and the degree of lung injury in COVID-19 patients. Pearson’s and Spearman correlations analysis were performed to measure the degree of association between two methods. Bland–Altman plot was generated to provide a graphical visualization of the agreement between the two measurement methods. All statistical tests in this study were two-sided and p-values ≤ 0.05 were considered as statistically significant. Results: A good correlation between LUS and CT scan was obtained for estimates of lung injury in pneumonia in a group of COVID-19 suspect and diagnosed patients (R 2= 0.7613; p <0.01). Agreement between LUS and CT values is assessed by constructing Bland-Altman plot. Conclusions: LUS, as compared to CT scans, is an effective method to estimate degrees of lung injury in COVID-19 patients in the emergency department.

Understanding how bird species from white sand ecosystems (WSEs) have managed to inhabit and specialize in insular environment in the middle of the Amazon Rainforest is fundamental to understand the evolutionary processes in birds restricted to one type of habitat. We sought to evaluate the diversification processes of the specialist bird species of the white sand ecosystems of the Rio Negro basin by comparing them with the pool of bird species of riparian environments. Many WSEs may be ancient riverbeds, which may favor current riparian species to be potential colonizers and settle within the WSEs. For this, we used an extension of biogeographic evolutionary models to verify state-dependent speciation and extinction models that specifically explain the presence of unmeasured factors that can affect the estimated diversification rates for the states of any observed trait. Thus, it was possible to evaluate the evolutionary processes that most acted in the formation of bird communities of WSEs. The results showed that WSEs specialist bird species have different functional diversity to what was expected on a random basis and evolutionary models have higher extinction and speciation rates in WSEs specialist bird communities. This evidences that source-sink processes maintain WSEs over time, and that they receive generalist and specialist species from riparian ecosystems. According to the models analyzed, once the species have the high degree of adaptation required by an ecosystem with severe conditions, they cannot colonize other ecosystems. Extinction is an important process for the dynamics of biodiversity in the Amazon since, as many species are lost, there is also speciation and high adaptation. This work is one of the first to use local evolutionary analyses in Amazonian ecosystems and was effective in showing that extinction is recurrent, which is a cause for concern due to the severe and rapid ecological changes currently occurring.

Meglumine gadoterate induces immunoglobulin-independent human mast cell activation and MRGPRX2 internalizationTo the Editor,Gadolinium-based contrast agents (GBCA) are intravenous drugs used to enhance resolution in magnetic resonance imaging. They can induce immediate hypersensitivity reactions, yet their pathogenic mechanisms remain poorly characterized. This hampers the ability to predict which patients are at risk of developing them.1 In fact, affected patients usually show negative skin-tests and can react upon the first known GBCA exposure, which implies that IgE-independent mechanisms might be driving this inflammatory response.The Mas-related G protein-coupled receptor member X2 (MRGPRX2) has been recently associated with non-IgE mediated immediate hypersensitivity reactions.2 Some drugs, such as fluoroquinolones, vancomycin, neuromuscular blockade agents, icatibant, morphine, leuprolide and iodinated contrast media, have been reported to activate MRGPRX2, which is highly expressed in mast cells (MCs).3To assess the ability of GBCA to induce non-IgE-mediated hypersensitivity reactions, we stimulated the human MC line LAD2 with several commercial GBCA, namely, meglumine gadoterate, gadobutrol, gadoxetate disodium and gadoteridol. Then, we determined cell viability and degranulation by flow cytometry4 (see a detailed material and methods section in this article´s online supplementary ).Of the GBCA tested, only meglumine gadoterate was able to induce significant MC activation (Figure 1A ) without compromising cell viability (Figure 1B ), as compared to unstimulated MCs. We further assessed MRGPRX2 expression on LAD2 cells by flow cytometry, as well as changes in its expression following stimulations with either meglumine gadoterate or vancomycin (a known agonist of MRGPRX2).5 Under basal conditions, LAD2 cells expressed high levels of MRGPRX2 (Figure 1C ). Following incubation with vancomycin, the level of MRGPRX2 expression was reduced, as compared to untreated LAD2 cells. Interestingly, we observed a similar decrease in MRGPRX2 expression levels upon meglumine gadoterate and vancomycin challenges, as compared to controls, suggesting both the signaling and the internalization of this receptor (Figure 1D ).Meglumine gadoterate is an ionic macrocyclic paramagnetic contrast media. It is composed by gadolinium, which together with the chelating agent tetraxetan (also known as DOTA), yields gadoteric acid. The base meglumine and gadoteric acid form the salt meglumine gadoterate (Figure 2A ). Given that MRGPRX2 has affinity for cationic amphiphilic compounds,6 we ascertained the ability of meglumine to induce MC activation. Meglumine itself induced MC degranulation without affecting cell viability, as compared to untreated cells (Figure 2B ), although a reduction in MRGPX2 expression could not be confirmed (data not shown). Interestingly, meglumine caused MC activation at lower concentrations than meglumine gadoterate, according to the half maximal effective concentration (EC50) of both substances (Figure 2C ). The logarithmically transformed EC50 for meglumine gadoterate was 2.04 (R2= 0.75), and for meglumine was about one order of magnitude lower (1.06; R2= 0.71). Considering the EC50 for meglumine and its proportion in meglumine gadoterate (~26%), meglumine could be its main component responsible for MC degranulation.In conclusion, our study demonstrates the ability of meglumine gadoterate to induce MC activation, by an immunoglobulin-independent mechanism that is likely mediated by MRGPRX2. Furthermore, we have delved into the meglumine gadoterate components that are involved in MC activation, and identified meglumine as a potential causative of non-IgE mediated hypersensitivity reactions. These data raise the possibility that immediate hypersensitivity reactions following intravascular administration of ionic iodinated contrast media may be at least partly mediated by meglumine. Further studies should be performed to define clinically relevant interactions between diverse radiological contrast media and MRGPRX2.Authors: Paula H. Ruiz de Azcárate,1#Rodrigo Jiménez-Saiz,1-4 #* Celia López-Sanz,1 Azahara López-Raigada,5Francisco Vega,5 Carlos Blanco,5*# First authors* Corresponding authorsAffiliations: 1Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain.2Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid, Spain.3Faculty of Experimental Sciences, Universidad Francisco de Vitoria (UFV), Madrid, Spain.4Department of Medicine, McMaster Immunology Research Centre (MIRC), Schroeder Allergy and Immunology Research Institute (SAIRI), McMaster University, Hamilton, ON, Canada.5Department of Allergy, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain.*Co-correspondence to :1) Rodrigo Jiménez-Saiz, Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Diego de León 62, 28006, Madrid, Spain. Email address: rodrigo.jimenez@ufv.es2) Carlos Blanco, Department of Allergy, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Diego de León 62, 28006, Madrid, Spain. Email address: cblague@gmail.com Funding information: RJS reports grants by the FSE/FEDER through the Instituto de Salud Carlos III (CP20/00043; PI22/00236; Spain), The Nutricia Research Foundation (NRF-2021-13; The Netherlands), New Frontiers in Research Fund (NFRFE-2019-00083; Canada) and SEAIC (BECA20A9; Spain). PHR is supported by the INVESTIGO Program of the Community of Madrid (Spain), which is funded by “Plan de Recuperación, Transformación y Resiliencia” and “NextGenerationEU” of the European Union (09-PIN1-00015.6/2022).Conflict of interest : All the authors have no significant conflicts of interest to declare in relation to this manuscript.References1. Vega F, Lopez-Raigada A, Mugica MV, Blanco C. Fast challenge tests with gadolinium-based contrast agents to search for an alternative contrast media in allergic patients. Allergy.2022;77(10):3151-3153.2. Kolkhir P, Ali H, Babina M, et al. MRGPRX2 in drug allergy: What we know and what we do not know. J Allergy Clin Immunol. 2022.3. Foer D, Wien M, Karlson EW, Song W, Boyce JA, Brennan PJ. Patient Characteristics Associated With Reactions to Mrgprx2-Activating Drugs in an Electronic Health Record-Linked Biobank. J Allergy Clin Immunol Pract. 2022.4. López-Sanz C, Sánchez-Martínez E, Jiménez-Saiz R. Protocol to desensitize human and murine mast cells after polyclonal IgE sensitization. STAR Protocols. 2022;3(4):101755.5. Navines-Ferrer A, Serrano-Candelas E, Lafuente A, Munoz-Cano R, Martin M, Gastaminza G. MRGPRX2-mediated mast cell response to drugs used in perioperative procedures and anaesthesia. Sci Rep.2018;8(1):11628.6. Wolf K, Kühn H, Boehm F, et al. A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice. J Allergy Clin Immunol. 2021;148(2):506-522.e508.

In this paper, an enclosing control problem is investigated for nonholonomic mobile agents with a moving target of unknown velocity. An adaptive observer containing two internal variables is first designed for each agent to compensate for the lack of the target velocity information. One variable is designed to estimate the unknown target velocity and further its estimation error is assessed by the other internal variable to subsequently guarantee the control performance. Then using the estimated information from the adaptive observer, a dynamic control law for circular formation of nonholonomic agents around the moving target is designed by a backstepping process. The global asymptotical stability of the closed-loop system is achieved under the proposed dynamic control law with the adaptive observer. Finally, a simulation is conducted to demonstrate the effectiveness of the proposed approach.

Herein, we have developed a strategy of Rh(III)-catalyzed C–H activation of N-nitrosoanilines and iodonium ylides to construct novel tetralydrocarbzol-4-one scaffolds, which provided valuable templates for sequential C-H functionalization such as alkylation, alkenyla-tion, amidation and (hetero)arylation at C5-position of tetralydrocarbzol-4-one with different coupling partners. Gram-scale synthesis and further transformation of tetralydrocarbzol-4-one derivatives to Ondansetron and its analogues demonstrated the utility of this protocol, which enabled the concise and diverse construction of biologically active molecules.

Objective: To identify factors contributing to maternal mortality in Kazakhstan. Design: A retrospective study of the health and demography data set of Kazakhstan from 2000 to 2020. Setting and population: The data from the annual statistical report “Population health and healthcare organizations’ performance in the Republic of Kazakhstan from 2000 to 2020”. Kazakhstan and its 14 regions and 3 main cities for the period 2019-2020. Methods: We analyzed the MMR trend in Kazakhstan and in all 14 regions and 3 main cities for the period 2000-2020. We applied Univariate Linear Regression Models with Logarithmic Transformation of the outcome and predictors to detect determinants of MMR for 2019 and 2020 in Kazakhstan. Main Outcome Measures: Maternal mortality ratio and determinants. Results: Trends in MMR in many regions of Kazakhstan show a steady decline starting from 2000 until 2010-2015 with a subsequent increase by 2020. MMR was associated with factors such as socio-economic, health service-related, and population health indicators. An increase in most of these indicators leads to a decrease in maternal mortality, except obstetric beds per 1000 births, number of inpatient facilities, and population median age, which leads to an increase in MMR. Conclusions: Maternal mortality is a complex issue that is influenced by various socio-economic factors, healthcare system factors, and disease burden. Despite Kazakhstan’s alignment with the SDG goals, including reducing maternal mortality, the country’s middle-income status may have led to fluctuations in MMR.

Microbial infections are considered as one of the most important concerns of the world community. Developing drug delivery systems based on formulation of nanoparticles with antimicrobial agents have shown beneficial effectiveness against microbial infections and related antimicrobial resistance. In this study we prepared and characterized a chitosan based hydrogel loaded with zinc oxide nanoparticles for controlling the release of vancomycin and also improving its antibacterial effect. Characterization studies demonstrated that the developed biopolymeric hydrogel was able to sustained and controlled the release of vancomycin in response to acidic media for 96 hours. Furthermore, antimicrobial studies showed siginificant and efficient antibacterial activity of prepared hydrogel against S. aureus and P. aeruginosa. Based on obtained results, it can be concluded that the prepared chitosan hydrogel containing ZnO nanoparticles has a desirable activity for controlling the release of vancomycin and improving its antibacterial properties.

Proton exchange membrane (PEM) water electrolyzer has been regarded as a promising and versatile approach for practical H2 production. The oxygen evolution reaction (OER) possesses sluggish kinetics and a high reaction barrier, severely hindering the development of PEM water electrolyzers. Consequently, highly efficient and low-cost electrocatalysts are always essential to accelerate the reaction rate and lower the reaction barrier of OER. In this review paper, a detailed discussion towards fundamentally comprehending the reaction mechanisms of OER in acid media was conducted. Accordingly, we proposed the principles of designing advanced OER electrocatalysts for enhanced performance and lowered cost. After that, recent developments in designing various acidic OER electrocatalysts were summarized. Meanwhile, the available regulation strategies were presented, which can be used for tuning the electronic structures, boosting the electrocatalytic performances and reducing the costs of electrocatalysts. We also provided the existing challenges and perspectives of various OER electrocatalyst.

Approximatively 25 chemical elements are essential for the maintenance, growth and reproduction of all living organisms. Hence, the movement, distribution, and relative proportions of those elements on the landscape should have significant influence on the structure and functioning of biological communities. Yet our basic understanding for the spatial distribution of elements across landscapes and the drivers of those patterns are limited. Here, we propose a novel framework to apply tools from community and landscape ecology to study spatial patterns in elements. We illustrate this framework with an empirical proof of concept in the boreal forest and demonstrate how spatial grain and spatial dissimilarity of elements interact leading to predictable patterns in elemental distributions at various spatial scales. In particular, we observe that at finer spatial grains, sites with high contributions to elemental dissimilarity cluster together. As grain size increases, the landscape becomes more homogeneous with larger patches of sites with intermediate contributions to elemental dissimilarity emerging near aquatic-terrestrial boundaries. Meanwhile, an analysis revealed that the most important elemental contributors to spatial dissimilarity in this landscape are potassium and calcium, two infrequently studied elements in community ecology, raising new questions about their role in, or response to, distributions of biodiversity and ecosystem functions. Our novel framework demonstrates how we can use community metrics (e.g., dissimilarity) to investigate variability of individual elements, the building blocks of stoichiometric ratios, across landscapes. As a field, ecology is just beginning to fully acknowledge the contribution of biotic factors in shaping biogeochemical processes, but here we provide a framework for integrating abiotic and biotic processes. We conclude by hypothesizing that changes in the evenness or beta-diversity of elements should reflect the structure of biotic communities, providing a long-sought mechanistic link between community and ecosystem processes that can be measured directly in the field.

Opportunistic observation of Erabu sea snakes (Laticauda semifaciata) provide evidence that these species undertake a novel foraging tactic; coordinated communal hunting. Erabu sea snakes prey on cryptic fish species in highly complex reef habitats. Intra- and interspecific cooperative hunting strategies may increase chances for all members of the hunting party to encounter and capture prey in these complex habitats. Here we recorded 52 instances of communal hunting by Erabu sea snakes with conspecifics and other predatory fishes at recreational dive sites in Southern Lombok, Indonesia. These observations highlight the potential higher cognitive capacity of sea snakes to coordinate activities around communal hunting events.

Aim Prevalence of potentially suboptimal prescribing and associated risk factors were investigated among older patients attending primary care via Aboriginal Community Controlled Health Services (ACCHSs). Methods Prescription medications were audited for 420 systematically selected patients aged ≥50 years at three ACCHSs in urban, rural, and remote settings. Polypharmacy, potentially inappropriate medications (PIMs), and anticholinergic burden (ACB) were estimated and associated risk factors explored with logistic regression. Results The prevalence of polypharmacy, use of PIMs, and ACB score ≥3, was 43%, 18%, and 12%, respectively. In multivariable logistic regression analyses, polypharmacy was less likely in rural (OR=0.43, 95% CI=0.24-0.77) compared to urban health service patients, and more likely in those with heart disease (OR=2.62, 95% CI=1.62-4.25), atrial fibrillation (OR=4.25, 95% CI=1.08-16.81), hypertension (OR=2.14, 95% CI=1.34-3.44), diabetes (OR=2.72, 95% CI=1.69-4.39), or depression (OR=1.91, 95% CI=1.19-3.06). PIMs were more frequent in females (OR=1.88, 95% CI=1.03-3.42), and less frequent in rural (OR=0.41, 95% CI=0.19-0.85) and remote (OR=0.58, 95% CI=0.29-1.18) patients. Factors associated with PIMs were kidney disease (OR=2.60, 95% CI=1.37-4.92), urinary incontinence (OR=3.00, 95% CI=1.02-8.83), depression (OR=2.67, 95% CI=1.50-4.77), heavy alcohol use (OR=2.83, 95% CI 1.39-5.75) and subjective cognitive concerns (OR=2.69, 95% CI=1.31-5.52). High anticholinergic burden was less common in rural (OR=0.10, 95% CI 0.03-0.34) and remote (OR=0.51, 95% CI 0.25-1.04) patients, and more common in those with kidney disease (OR=3.07, 95% CI 1.50-6.30), or depression (OR=3.32, 95% CI 1.70-6.47). Conclusion Associations between potentially suboptimal prescribing and depression or cognitive concerns highlights the importance of considered medication review and deprescribing for these patients.