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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.

Intrusion Detection Systems (IDSs) are crucial in protecting IoT networks from unauthorized access and security threats. The ability to detect anomalies and suspicious activities in real-time is vital for preventing cyber-attacks and minimizing the damage caused by them. Traditional IDSs have relied on signature-based approaches, which are limited in their ability to detect novel and unknown attacks. To overcome these limitations, this paper proposes a novel deep learning architecture named as Inverted Funnelized Multilayer Network (IFMN) for detecting intrusions in IoT networks. The proposed approach for intrusion detection employs a feature selection model that uses a Hybrid Yellow saddle goatfish algorithm and Particle Swarm Optimization algorithm for Feature Selection (HYFSPSO) to identify the optimal features. The effectiveness of the selected features is evaluated using a decision tree (DT) classification method, ensuring only the most informative features are used in the deep learning architecture for intrusion detection. For analyzing and proving the effectiveness of our scheme the current research have used three benchmark datasets i.e. KDD-CUP99, NSL-KDD and UNSW-NB15 datasets. The simulations of the proposed architecture are conducted in MATLAB and evaluated using performance matrices. While comparing the outcomes on 3 datasets results revealed that proposed HYSGPSO-DL based IDS approach is more effective on NSL-KDD and UNSW-NB15 datasets with an accuracy of 99.96% and 99.80%, while as it achieved an accuracy of 99.53% on KDD-CUP99 dataset. Additionally, comparative analysis with existing intrusion detection systems shows that our proposed scheme outperforms the state-of-the-art methods.

Type II diabetes mellitus (T2DM) accounts for approximately 90% of all diabetes mellitus cases in the world. Glucagon-like peptide-1 receptor (GLP-1R) agonists have established an increased capability to target directly or indirectly six core defects associated with T2DM, while, the underlying molecular mechanisms of these pharmacological effects are not fully known. This exploratory study was conducted to analyze the effect of treatment with GLP-1R agonists on urinary peptidome of T2DM patients. Urine samples of thirty-two T2DM patients from the PROVALID study (A Prospective Cohort Study in Patients with T2DM for Validation of Biomarkers) collected at pre- and post-treatment with GLP-1R agonist drugs were analyzed by CE-MS. In total, 70 urinary peptides were significantly affected by GLP-1R agonist treatment; generating from 26 different proteins. The downregulation of MMP proteases, based on the concordant downregulation of urinary collagen peptides was highlighted. Treatment also resulted in downregulation of peptides from SERPINA1, APOC3, CD99, CPSF6, CRNN, SERPINA6, HBA2, MB, VGF, PIGR and TTR, many of which were previously found to be associated with increased insulin resistance and inflammation. The findings indicate potential molecular mechanisms of GLP-1R agonists in the context of management of T2DM and prevention or delaying the progression of its associated diseases.

Individuals of a species cope with environmental variability through behavioral adjustments driven by individuals’ responsiveness to environmental stimuli. Three key empirical observations have been made for many animal species: The coexistence of different degrees of responsiveness within one species; the consistency of an individual’s degree of responsiveness across time; and the correlation of an individual’s degree of responsiveness across contexts. Taking up key elements of existing approaches, we provide one unifying explanation for all three observations, by identifying a unique evolutionarily stable strategy of an appropriately defined game within a stochastic environment that has all three features. Coexistence is explained by a form of negative frequency dependence. Consistency and correlation is explained through potentially small, individual, differences of states animals have and the resulting differential advantages they can get from it. Our results allow us to identify a variety of testable implications.

Adipose tissue is not only required for energy storage but is an essential endocrine organ with a central role in the pathology of obesity. The understanding of its role, both in human and equine medicine, is continually evolving. With obesity being an ever-growing problem in the equine population, gaining owner compliance is critical when implementing management plans. The aim of this review is to encourage the inclusion of the concept of adiposity in discussions with horse owners on obesity and metabolic syndrome. In doing this, we hope to improve clients understanding and therefore maximise the impact of diagnostic tests, monitoring tools and management.

Objectives: Previous observational studies have revealed a connection between sarcopenia and COVID-19. To evaluate their causal relationship, we utilized a bidirectional two-sample Mendelian randomization (MR) analysis to study the link of cause and effect between sarcopenia and COVID-19. Methods: Inverse variance weighting (IVW), MR-Egger, weighted, and weighted median were used in this research. Then we used the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and MR-Egger regression methods to estimate the pleiotropy of instrumental variables (IVs), while the outliers were excluded by MR-PRESSO. Moreover, we used Cochran’s Q statistic to evaluate the heterogeneity among the IVs. And we used leave-one-out sensitivity analysis to identify the SNPs that significantly affect the outcomes. Finally, the Bonferroni correction was used to correct each result. Results: The IVW results suggested that faster WP decreased the risk of all types of COVID-19 (COVID-19 infection: OR = 0.469, 95% CI: 0.326,0.676, P = 4.82E-05; COVID-19 hospitalization: OR = 0.247, 95% CI: 0.122,0.502, P = 1.11E-04; severe COVID-19: OR = 0.120, 95% CI: 0.046,0.314, P = 1.53E-05). However, there was no causal relationship between ASM, LH or RH and COVID-19, and WP adjusted for BMI had no significant connection with all types of COVID-19. Furthermore, no causal association of COVID-19 on sarcopenia was observed in the results of reverse MR analysis. Conclusion: Our bidirectional two-sample MR study suggests the causal relationship between WP and COVID-19 but it may be caused by the mediating role of BMI, thus there is no causal association between sarcopenia and COVID-19.

The seeds of ethanolic extract Aframomum pruinosum (EE) are popularly used in the management of cardiovascular conditions. This study was undertaken to evaluate the capacity of EE to prevent the development of cardiac hypertrophy in rats. Isoproterenol (0.3 mg/kg/day, sc) was injected to male rats alone or concomitantly with EE (37.5, 75, or 150 mg/kg, per os) or propranolol (20 mg/kg/day, per os) for 7 consecutive days and Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate measurements were performed. Cardiac homogenates were used to assay myeloperoxidase (MPO), superoxide dismutase (SOD), catalase, nitric oxide (NO) and reduced glutathione (GSH). Also, sections of heart tissue were stained with Hematoxylin-Eosin, Masson trichrome, or for immunohistological labelling of atrial natriuretic peptide (ANP). Chemical profiling of EE was done by gas chromatography-mass spectrometry (GC-MS). Isoproterenol administration caused a decline in SBP and DBP (p < 0.001). Heart rate, cardiac mass, cardiomyocyte surface, and MPO levels were significantly (p < 0.001) increased. All these alterations were significantly prevented (p < 0.01 and p < 0.001) by EE. EE inhibited immune cell infiltration and cardiac fibrosis elicited by isoproterenol injection. The overexpression of ANP in the atrium and ventricle induced by the isoproterenol was significantly (p < 0.001) prevented by EE. GC-MS analysis showed that EE possesses many compounds mainly nerolidol 2. EE possesses antihypertrophic effect against isoproterenol-induced cardiac hypertrophy that may result from its antifibrotic, anti-inflammatory properties, as well as its capacity to down regulate the expression of ANP.

Quantitative risk assessments of chemicals are routinely performed in rodents; however, there is growing recognition that non-animal approaches can be human-relevant alternatives. There is an urgent need to build confidence in non-animal alternatives given the international support to reduce the use of animals in toxicity testing where possible. In order for scientists and risk assessors to prepare for this paradigm shift in toxicity assessment, standardization and consensus on in vitro testing strategies and data interpretation will need to be established. To address this issue, an Expert Working Group (EWG) of the 8th International Workshop on Genotoxicity Testing (IWGT) evaluated the utility of quantitative in vitro genotoxicity concentration-response data for risk assessment. The EWG first evaluated available in vitro methodologies and then examined the variability and maximal response of in vitro tests to estimate biologically relevant values for the critical effect sizes considered adverse or unacceptable. Next, the EWG reviewed the approaches and computational models employed to provide human-relevant dose context to in vitro data. Lastly, the EWG evaluated risk assessment applications for which in vitro data are ready for use and applications where further work is required. The EWG concluded that in vitro genotoxicity concentration-response data can be interpreted in a risk assessment context. However, prior to routine use in regulatory settings, further research will be required to address the remaining uncertainties and limitations.

Pregnancy after atypical placental site nodule; a case-report

The use of hyperinsulinemia-euglycemia therapy in the treatment of amlodipine overdose in a dog.Authors: Connor Ellis, DVMa*, Adesola Odunayo, DVM, MS, DACVECCaa Department of Small Animal Clinical Sciences, University of Florida, Gainesville, FL, USA*Corresponding author: dr.connor.ellis@gmail.comCo-author: odunayoa@ufl.eduDeclarations of interest: None.No financial support was provided for the preparation of this manuscript.There are no conflicts of interest to declare for this manuscript.Consent statement:Written informed consent was obtained from the owner of this patient to publish this report in accordance with the journal’s patient consent policy.Manuscript type: case reportKeywords: amlodipine, calcium channel blockers, dog, hyperinsulinemiaKey Clinical Message: Hyperinsulinemia-euglycemia therapy (HIET) can be used for treatment of hypotension as well as other clinical signs associated with calcium channel blocker toxicosis. The use of HIET should be considered for amlodipine toxicosis in dogs.IntroductionAmlodipine is a frequently prescribed drug used to control hypertension in human and small animal patients1. This dihydropyridine calcium-channel blocker (CCB) inhibits the influx of calcium ion into the cell through the L-type calcium channel, causing peripheral vasodilation and afterload reduction1. Amlodipine is metabolized by the liver, widely distributed and highly protein bound, with a long half-life of approximately 30 hours in dogs2. While generally well tolerated, reported adverse reactions of amlodipine have been described at doses within the recommended range of 0.1-0.4 mg/kg PO q243–5.The minimum oral toxic dose of each CCB has not been well established in humans or animals, but signs of toxicity have been reported in CCBs at therapeutic doses6. Toxic doses of CCBs have been associated with significant morbidity and mortality6. Clinical signs in affected animals commonly include bradycardia, bradyarrhythmias, and hypotension, with other recognized adverse effects including pleural effusion, gingival hyperplasia, peripheral edema, gastrointestinal distress, hypothermia, central nervous system depression, and electrolyte abnormalities6. While there are currently no consensus guidelines for the treatment of CCB toxicosis in human or veterinary medicine, several retrospective studies and case series have been published in the offering best practice recommendations6–9. A recent veterinary review on CCB toxicosis highlighted decontamination and cardiovascular optimization using fluids and vasoactive medications as the most important interventions. Therapeutic recommendations also included the use of glucagon or intravenous lipid emulsion as secondary options for refractory toxicoses, and other supportive therapies as needed6.An important therapeutic intervention that has resulted in improved patient outcomes over the last 15 years in human patients is hyperinsulinemic-euglycemic therapy (HIET), with multiple publications outlining its efficacy in the human literature10–12. HIET utilizes supraphysiologic doses of insulin, with human doses ranging from 0.5-2.0 U/kg/hour, and concurrent dextrose supplementation to maintain euglycemia12. In brief, blockade of the L-type calcium channels that result in the antihypertensive effect of CCBs also decreases the release of insulin from pancreatic beta cells and reduces glucose uptake by tissues by decreasing sensitivity to insulin, with concurrent vasodilation and hypoperfusion leading to negative inotropy. Increasing insulin availability encourages glucose utilization by the myocardium and suppresses phosphodiesterase III activity, leading to intracellular calcium influx and a positive inotropic effect6. Treatment with HIET is considered a first-line intervention in CCB toxicity in human patients13. There are limited reports of the use of HIET in CCB toxicity in clinical patients in veterinary medicine. There is one case report of survival after HIET was utilized for diltiazem toxicosis in one dog, and another report of HIET therapy utilized for amlodipine toxicosis in a cat, although HIET was discontinued after 3 hours due to refractory hypoglycemia14,15. There are also two animal model studies outlining efficacy of HIET for CCB toxicosis in anesthetized dogs16,17. To the authors’ knowledge, this is the first report describing a protocol for HIET for the treatment of amlodipine toxicosis in the dog.Case descriptionA 1-year-old spayed female mixed breed dog, weighing 14.8 kg, presented to the emergency service for evaluation of ataxia and lethargy approximately 48 hours after ingestion of at least 10 mg of amlodipine (at least a 0.7 mg/kg dose). The ingestion was not witnessed by the owner, but the dog had access to a bottle containing 8 tablets of 10 mg standard release amlodipine, of which one was missing, and half of another tablet had been chewed, resulting in a maximum exposure dose of ~1 mg/kg. The dog reportedly displayed no adverse clinical signs for 24 hours after the potential ingestion, then developed lethargy, anorexia, vomiting, and ataxia in the next 24 hours. After consultation with a poison control center (Pet Poison Helpline, SafetyCall International, LLC), immediate veterinary care was recommended.At presentation, the dog was hypothermic with a rectal temperature of 37.2°C (98.9°F), bradycardic (80 beats/min), tachypneic (52 breaths/min), and dull. The dog was weakly ambulatory and the physical exam was otherwise normal. Systolic blood pressure using a Doppler ultrasonographic device (Parks Medical Electronics, Inc.) was 65 mm Hg. Venous blood was obtained when the peripheral catheter was placed for a PCV/total solids and blood gas with electrolytes. Pertinent findings included a PCV of 54% and a total solids of 66 g/L, a mixed acid-base status, hypocapnia, hyponatremia, hyperkalemia, ionized hypocalcemia, hyperglycemia, hyperlactatemia, decreased bicarbonate, and azotemia (Table 1).TABLE 1. Serial venous blood gas analysis.

The use or deployment of aerial seeding technology in forestry has shown to be efficient, rapid, and most suitable for restoration of large degraded and inaccessible areas. The technology is relatively cheaper compared to conventional methods of restoration. Although aerial seeding has been widely used globally in forestry, its application is comparatively new in Kenyan forestry. This paper reviews selected experiences from countries that pioneered the use of aerial seeding in restoring large degraded forestlands and highlights key requirements for successful aerial seeding programs. Literature shows that the use of aerial seeding in forestland restoration dates back in 1950s with reports showing moderate to high success rate in USA, Canada, Russia, Australia, New Zealand, China and India. Success of aerial seeding is largely determined by interaction of factors such as seed characteristics, timing of seeding, site conditions or micro-site environment. Competition from surrounding vegetation, and seed predation affect the efficiency of aerial seeding negatively. The paper concludes that aerial seeding technology is efficient, cost effective and therefore suitable for use in the restoration of the expansive degraded forests in Kenya.

Among many operating parameters that control cell culture environment, appropriate mixing and aeration are crucial for cells to meet oxygen demand in aerobic microbial and mammalian production processes. A model-based manufacturing facility fit approach was applied to define agitation and air flow rates during cell culture process scale-up from laboratory to manufacturing, of which computational fluid dynamics (CFD) was the core modeling tool. The realizable k-ε turbulent dispersed Eulerian two-fluid model was used to simulate gas-liquid flow in the bioreactor and predict volumetric oxygen transfer coefficients ( kLa), where the simulation was performed in the basal medium and the resulting kLa was adjusted using modification factors for surfactants such as Pluronic F68 and Antifoam C. The CFD prediction of kLa resulted in adequate agreement with the empirical values in 15,000-L and 25,000-L bioreactors. The model was then applied to define a range of agitation and bottom air flow rates for meeting cellular oxygen demand and mitigating risks of cell damage and safety hazards. The recommended operating conditions led to the completion of five manufacturing runs with a 100% success rate. The model-based approach reduced the required number of at scale development batches and hence enabled seamless scale-up, shortened timelines, and cost savings in cell culture process technology transfer.

Global warming rise has been observed as a result of ozone layer destruction, which makes it possible for UVB radiation to pass through atmosphere and kill people. It is believed that daily exposure to UVB radiation has biological effects on both humans and other living things. Concerning effect of UVB radiations, we examine the instinctive mechanism by which a specific amount of radiation induces oxidative stress and hyperthyroidism, which is further controlled by the antioxidant activity of Naringin (NG), due to the detrimental effects of UVB radiation on the biological system. For these examinations twenty-four adult male albino mice were divided into four equal groups; control group, UVB exposed group (2 hrs/day), UVB+NG treated group (80 mg/kg b.w), and NG-treated group. Doses were given orally, daily for 15 consecutive days. Specimens of the thyroid gland were processed for hormonal, biochemical, histological, immunohistochemical and immunofluorescence examinations. A morphometric study and statistical analysis of the findings were performed for different groups. Compared to the control group, the specimens of the UVB exposed mice showed alteration in mean height of the thyroid follicular epithelial cells and caspase-3, NOS-2 and THRβ-1 expression. In contrast, naringin prevent the changes caused due to repeated UVB radiations.