Discover and publish cutting edge, open research.

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: [email protected] 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: [email protected]

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:    [email protected],  [email protected]

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.

Urbanization is one the main threats to biodiversity and its effects are projected to increase in magnitude, hence stressing the importance to better understand how urbanization may affect vital ecosystem services, such as pollination. Studies on the impact of urbanization have largely focused on only one aspect of the pollination process (e.g. pollinator visitation, pollen deposition), potentially misrepresenting the full complexity of urbanization effects on pollination services. Evaluating impacts across multiple components of pollination can also help pinpoint the underlying mechanisms driving urbanization effects. This study evaluates how urbanization affects multiple aspects of the pollination process in common milkweed populations, including pollinator community composition and visitation rate, pollen removal and deposition on stigmas. Urbanization altered floral visitor composition, with small bees having a larger presence in urbanized areas. Insect visitation rate and pollen removal were also higher in more urbanized areas, perhaps suggesting a positive impact of urbanization as predicted by the intermediate disturbance hypothesis. However, pollen deposition on stigmas, which is a key component of fertilization success, was not different between natural and urbanized sites. Our findings highlight the complexity evaluating urbanization effects on pollination, as these likely depend on the specific aspect of pollination evaluated and on the of the intensity of disturbance. Our study thus stresses the importance of evaluating multiple components of the pollination process in order to fully understand overall effects and the mechanisms underlying urbanization effects on this vital ecosystem service

Background: The recovery of acid-base and hydro electrolytic balance at medical discharge after Raid races and its association with comfort index is unknown. Objetives: To determine hydroelectrolytic and acid base variations before, after and at the time of clinical discharge in 276 horses that completed 90 km Raid competitions. Study design: Cross sectional study Methods: Hematocrit, total protein, sodium, potassium, chloride, calcium, and serum pH were determined in samples before and after the race and after hydration and analyzed using a mixed procedure, including the moment regarding the race, comfort index, and their interaction. Results: Comfort index did not affect any variable; An interaction with comfort index and blood sample was only found in potassium concentrations, as concentrations were lower after hydration than before the race only in worse climate conditions (p<0.05). The pH values after the race were greater (p<0.01) than before the race and after hydration. The hematocrit and total protein values after hydration showed a correction to normal values, however, for total protein no differences were observed between this sample and before the race, while the hematocrit at medical discharge was still greater than the sample before the race (p<0.05). Sodium concentrations before and after the race were greater than those after hydration (p<0.05), for chloride, the concentrations before the race were greater than those after the race and hydration (p<0.05). Calcium concentrations after the race and hydration were lower than before the race (p<0.05). Main limitations: The medical treatment after races (hydration therapy) in each horse is not known. Conclusion: Most hydroelectrolytic and acid-base variables at the medical discharge did not reach the values before the race, but they were within the normal values. The comfort indicator was not explanatory in most of the variables.

Drug discovery and testing is a lengthy process that is essential before human clinical trials. Animal models are vital in preclinical drug assessment, yet ethical concerns and species variations persist. Although cell-based models are used, they struggle to precisely predict drug efficacy, toxicity, and organ interactions due to cultured cells’ inability to maintain original functions and structures in typical in vitro systems. To overcome these limitations, the emerging technology of organ-on-a-chip is being developed as an alternative to traditional preclinical drug testing models. The implementation of organ-on-a-chip technology holds great potential in significantly enhancing the accuracy and efficacy of preclinical testing, thereby enabling more precise prediction of a drug’s performance in clinical trials. Moreover, the development of multi-organ-on-a-chip (MOC) systems enables the replication of various organs in vitro, making the study of drug-body interactions possible. In this review, we first introduce the design of organ-on-a-chip devices. Subsequently, we describe the applications of different tissue co-culture configurations in organ-on-a-chip for drug testing. Finally, we summarize the challenges and prospects associated with organ-on-a-chip technology. In conclusion, this review provides a comprehensive overview of organ-on-a-chip technology, multi-organ-on-a-chip for drug testing, and the challenges and prospects for the future.

Regularity for strongly elliptic equations with ϵ-periodic highly oscillatory coefficients in two-dimensional space is concerned. In each ϵ-cell, the diffusion coefficients of the elliptic equations are ω 2 ∈ ( 1 , ∞ ) in a small disk with radius ϵµ 4 ( < 1 4 ) and 1 outside the disk of the cell. Two cases are considered. Case one is that ϵ,µ,ω are independent in the elliptic equations. So the diffusion coefficients of the elliptic equations are ϵ-periodic and discontinuous. L p -gradient estimate uniform in ϵ,µ,ω for the elliptic solutions is derived. However, the integrability p ( >2) of the solutions is not a large number. Case two is that ϵ , µ ( = ω − 1 ) are independent in the elliptic equations. The diffusion coefficients of the elliptic equations are ϵ-periodic, discontinuous, and L 1 -bounded. Lipschitz estimate uniform in ϵ , µ ( = ω − 1 ) for the elliptic solutions is obtained.

Objective: To evaluate respiratory functions in children with cat sensitization using impulse oscillometry (IOS) and spirometry and to compare these with those of healthy controls. Methods: This prospective case-control study included 130 children aged 3-17 years with cat sensitization (CS group) accompanying respiratory allergic diseases (Group I: asthma, Group II: allergic rhinitis, and Group III: co-existent asthma and allergic rhinitis), and 70 age- and sex-matched healthy controls (HC group). The cases’ demographic parameters were recorded, and respiratory functions were analyzed using IOS and spirometry. The association between IOS and spirometric parameters was also evaluated. Results: At IOS evaluation, zR5, R5-20, Fres, and AX values were higher in children in the CS group compared to the HC group (p=0.029, p=0.008, p=0.001, and p<0.001, respectively), while zX5 and zX20 values were lower (p=0.001 and p<0.001). R5-20 and AX were higher in asthma compared to allergic rhinitis (p=0.008, 0=0.015), but were insignificant compared to both together. R5-20, Fres, and AX were higher, and zX20 was lower in the pre-school age group (p<0.001). No correlation was found between zFEV1, zFVC, zFEV1/FVC, zFEF25-75 and zR5 values in the CS group (p>0.05). Conclusions: Pulmonary resistance was higher and reactance was lower in the entire and peripheral airways in children with cat sensitization accompanying respiratory allergic diseases compared to the healthy controls. Peripheral airway resistance and reactance were more impared in asthma group compared to allergic rhinitis. However, peripheral airway resistance and main airway reactance were more impaired in the pre-school age group than in the older age group.

The mountains in the Atlantic Forest domain are environments that harbor a high biodiversity, including species adapted to colder climates that were probably influenced by the climatic variations of the Pleistocene. To understand the phylogeographic pattern and assess the taxonomic boundaries between two sister montane species, a genomic study of the butterflies Actinote mantiqueira and A. alalia (Nymphalidae: Acraeini) was conducted. Analyses based on the COI barcode region failed to recover any phylogenetic or genetic structure discriminating the two species or sampling localities. However, SNPs gathered using GBS provided a strong isolation pattern in all analyses (genetic distance, phylogenetic hypothesis, clustering analyses, and FST statistics) that is consistent with morphology, separating all individuals of A. alalia from all populations of A. mantiqueira. The three sampled mountain ranges where A. mantiqueira populations occur — Serra do Mar, Serra da Mantiqueira, and Poços de Caldas Plateau — were identified as three isolated clusters. Paleoclimate simulations indicate that both species’ distributions changed according to climatic oscillations in the Pleistocene period, with the two species potentially occurring in areas of lower altitude during glacial periods when compared to the interglacial periods (as the present). Besides, a potential path between their distribution through the Serra do Mar Mountain range was inferred. Therefore, the Pleistocene climatic fluctuation had a significant impact on the speciation process between A. alalia and A. mantiqueira, which was brought on by isolation at different mountain summits during interglacial periods, as shown by the modeled historical distribution and the observed genetic structure.

Cold-water corals form vast reefs that are highly valuable habitats for diverse deep-sea communities. The deep ocean is, however, getting warmer, and models predict that the temperature of the Atlantic Ocean will further increase by up to 3°C by the end of the century. Understanding the response of cold-water corals to ocean warming is therefore essential to assess their resilience to future water temperatures. Here, we investigate at the holobiont level, the coral host and its associated microbiome, the effects of elevated temperatures on the reef-forming cold-water coral Lophelia pertusa (now named Desmophyllum pertusum) from the north east Atlantic Ocean. We show that at temperature increases of +3 and +5°C, L. pertusa exhibits significant mortality concomitant with changes in its microbiome. A metagenomic approach revealed the presence of genes markers for bacterial virulence factors suggesting that coral death was due to infection by pathogenic bacteria. Differences in survival were observed between L. pertusa colonies, as well as colony-specific microbiome signatures, indicating strong colony variability between colonies in response to warming waters. We hypothesize that L. pertusa, regardless of their ocean of origin, can only survive a temperature increase of < 3°C over a long period of time. Regional variations in deep-sea temperature increase should therefore be taken into account in future estimates of the global distribution of cold-water corals.

Objectives: Nearly 80% of children within the U.S. live with a sibling, and siblings exert a unique and typically lifelong influence on one another. Past research supports an influence between psychopathology of one individual and the psychological functioning of their siblings. Recently this relationship has been examined in the context of borderline personality disorder (BPD), such that siblings of individuals with BPD are at heightened risk of developing psychiatric disorders and engaging in problematic behaviors. Beyond the influence siblings have on one another, there is growing work demonstrating that many siblings of individuals with mental health difficulties face unique challenges in terms of balancing care for themselves and care for their siblings, and yet don’t have resources available for these specific challenges. Methods: The current study utilizes written statements from applications submitted to the Family Connections TM program by siblings of those with emotion regulation (ER) difficulties or BPD. A qualitative analysis is utilized to examine statements written by these sibling applicants, and salient themes are discussed. Results/Conclusion: We hope to clarify the experiences of siblings within these dyads and make a case for increased opportunities for these siblings to access care and support, in order to improve outcomes and support for both siblings.

The regulation of the central metabolism and fermentation pathways and its effect on antimicrobial susceptibility in the anaerobic pathogen Bacteroides fragilis is not completely understood. In this study, we show that B. fragilis encodes for two iron-dependent redox-sensitive regulatory pirin protein genes, pir1 and pir2, whose mRNA expression is upregulated following oxygen exposure and growth in iron-limiting conditions. Pir1 and Pir2 modulate short-chain fatty acids production and alter susceptibility to metronidazole (MTZ), and to amixicile (AMIX), a novel inhibitor of pyruvate:ferredoxin oxidoreductase (PFOR) in anaerobes. Consistent with this, we showed that Pir1 forms direct protein-protein interactions with PFOR as determined by two-hybrid system assays. In addition, AlphaFold2-based structural analysis predicts that Pir1 and Pir2 form stable interactions with several enzymes of the central metabolism including the 2-ketoglutarate:ferredoxin oxidoreductases Kor1AB and Kor2CDAEBG. A series of metabolic mutants and electron transport chain inhibitors were used to show a wide-ranging effect of bacterial metabolism on MTZ and AMIX susceptibility. Furthermore, we show that AMIX is an effective antimicrobial against B. fragilis in an experimental model of intra-abdominal infection. This investigation led to the discovery that the kor2AEBG genes are essential for growth, and we present evidence that kor2AEBG genes have dual functions including the reductive synthesis of 2-ketoglutarate via reverse TCA cycle. However, the metabolic activity that bypasses KorAEBG function remains to be defined. Collectively our investigation reveals new information on B. fragilis central metabolism and its modulatory control by pirin proteins which may be leveraged for the future development of new narrow-spectrum antimicrobials

Non-conventional renewable energy sources integration into distribution systems, data science, and enabling technological infrastructures present formidable challenges in transforming distribution systems, particularly in accommodating active demand. With escalating energy demand emphasizing the need for dependable tracking and predictive methodologies. These methodologies are essential for managing Distributed Energy Resources (DERs) and digital infrastructure. Effectively monitoring active demand requires a comprehensive understanding of the transactional system concept, encompassing digital infrastructure, and decentralized demand. Despite the increasing prominence of metaheuristic techniques in demand response integration, existing literature predominantly focuses on specific techniques rather than providing a characterization of dynamic transaction integration for active demand. Technological advancements, such as smart meters and communication systems, propel the evolution of the demand concept from rudimentary consumption measurement to active consumer involvement. This paper reviews the evolutionary trajectories of essential concepts in the energy sector, namely active demand, DERs, and transactive systems. Through in-depth analysis, Simultaneously, the paper systematically examines prevalent metaheuristic techniques in the literature, specifically focusing on their role in integrating and predicting the behaviors of active demand and DERs. The paper presents a methodology that, if utilized as a roadmap, would facilitate the evidence of stages required for the integration of DERs .

Custom-made 3D printed subperiosteal implant for restoration ofsevere atrophic jaw: a case reportIn the last decades, considerable progress has been made in the field of oral implantology, regarding endosseous implants, especially through the changes brought by the digital revolution. Although their versatility and predictability has been proven over time through clinical studies and follow-ups, endosseous implants have certain limitations, mainly given by the patients’ perspectives: the general state of health, bone supply, long osseointegration time, etc. Well-designed subperiosteal implants have been reported to function successfully for many years and came as an alternative to endoseous implants. The analog method of inserting subperiosteal implants has been widely discussed and used over time, and represents a well-defined protocol. However, the first surgical time, that of taking impression of the residual bone field, caused problems for the clinicians as follows: the trauma inflicted to the patient was greater as he was subjected to two surgical interventions instead of one(first for the impression of the bone and second for the insertion of the implant), the grip contraction of the impression material creates the possibility that the implant doesn’t fit to the bone. Digital technology comes into our hands in order to solve this unpleasant situations, offering the possibility to design the future implant on the CBCT scan of the patient long before the surgery itself.This case report reviews the design characteristics of 3D printed superiosteal implants, step by step procedure and its particularities compared with the analog method, the anatomy of the areas upon which the implants rest in the maxillae, based on recent research perfomed in Romania, in collaboration with AB Dental International (1).IntroductionThe use of endosseous dental implants to replace missing teeth has been a very predictable solution for many years and is now one of the most common techniques in dental rehabilitation. However, sufficient bone quantity and quality is required for implantation. In cases of severe bone resorption, bone regeneration techniques, zygomathic implants, nerve lateralization and sinus lift surgeries were proposed, but unfortunatelly these methods require more advanced surgical procedures, which may result in higher complication rates, morbidity, and longer treatment times.Subperiosteal implants were first developed in Sweden at the beginning of 1940’s and have been used ever since, with a decrease in popularity with the invention of the first endoseous implants by Branemark. Subperiosteal implants were custom-made based on an impression obtained in the stage I surgery and inserted below the periosteum and stabilised to the bone with mini-screws, then covered by the mucosa in the stage II surgery. Thus, the pacient was subject to two surgeries at an interval of 21 days. The subperiosteal implants were made of cobalt-chrome or titanium alloys and were connected to the prosthesis using transmucosal abutments that emerged into the oral cavity. Their replacement or decrease in use was due to the complexity of the production process, the imperfect fit of the implant caused by relative instability of the impression material, the wide range of complications (2).Different protocols have been proposed lately for subperiosteal implants, especially the ones 3D printed, but infortunately romanian clinicians need to collaborate with abroad factories or laboratories in order to treat these cases. Here, the authors present their experience with an innovative design of a customized subperiosteal implant manufactured by AB Dental International based on the CBCT scan of the patient.Case history/examinationA 58 years old male patient with severe maxillary athrophy was referred to the clinic due to complaints of inappropriate masticatory and aesthetic function. He reported a mixed tooth-implant supported maxillary rehabilitation with five implants and two teeth which failed 3 years ago after more that 15 years of use due to peri-implantitis and mobility. Ever since, our patient has been wearing a removable acrylic denture. The pacient denied smoking habits or relevant systemic diseases. In order to decide whether he is a valid candidate for a subperiosteal implant or not, the patient was passed through the entire selection process which included: general examination, clinical local examination of the oral mouth, laboratory analysis and radiographs. The pre-operative laboratory analysis were slightly modified with a high value of the PDW (Platelet Distribution Width) which can indicate anemia or an infection in the body. Clinical examination [Fig. 1(a)](12) and orthopatomography [Fig. 1(b)](12) indicated a combined horizontal and vertical severe osseous atrophy, confirmed through cone-beam computed tomography (CBCT) [Fig. 2](12).Note : In some areas, due to the severe bone atrophy, oro-sinusal communications covered only by the mucosa were evident on the CBCT scan, in which case the patient’s removable denture functioned as a protective „shield”.The cone-beam computed tomography has confirmed an inflamtion of the sinus mucosa due to odontal causes (infections associated with the previous teeth) and the severe lack of alveolar bone in all the maxillary regions that could be seen in the preliminary radiographs. The highest points of the residual bone were found, firstly, as it can be observed on the CBCT, in the third molars region both sides [Fig. 2(a) and 2(b)](12) with dimensions ranging between 2.4 and 7.2 mm in height and 6.6 and 10.2 mm in width in the first quadran and between 4.8 and 10.2 mm in height and 5.4 and 9.6 mm in width in the second quadran.Implant placement in the posterior region of the maxilla, the distal area of the maxillary alveolar process, which corresponds most frequently to the position of the third molar, has been suggested by many authors as an alternative to bone grafting. The posterior maxillary region typically has type III or IV bone quality, consisting of thin cortical bone and low-density trabecular bone. Primary stability is adversely affected by this. Due to inadequate primary locking, as well as short implants having unfavourable biomechanics, this region tends to have low success rates. Therefore, clinicians face a challenge in rehabilitating this area (3).The second area where we could measure some significant alveolar bone is the second molars region both sides [Fig. 3(a) and 3(b)](12) with dimensions ranging between 2.1 and 2.7 mm in height and 10.8 mm width in the first quadran and between 3.0 and 3.9 mm in height and 9.3 and 9.9 mm in width in the second quadran.As it can be observed in the CBCT scan, in the first molars region both sides, the residual alveolar bone height is either less that 3.0 mm or unsignificant [Fig. 3(a), Fig. 4(a)](12), making implant placement without lateral window sinus lift impossible. In the first quadran, it is important to notice the abcence of the cortical vestibular bone and the oral comunication with the maxillary sinus, closed only by the mucosa (an where we previously mentioned that patient’s removable denture functioned as a protective “shield”).As it can be observed in the figures above [Fig 4, Fig. 5 and Fig. 6](12), the other areas of alveolar bone have no significant dimensions that could be useful for a complete implant-prosthetic rehabilitation. Thus, the possible initial treatment plan proposed was bilateral window sinus lifting with delayed implant placement after 8 – 10 months from the initial surgery and guided bone regeneration for vertical and horizontal deficiency in the frontal area. During these 8 – 10 months of healing, the patient was to be only aesthetically rehabilitated with a removable prosthesis and the prognosis was reserved. Because he has high functional and aesthetic requests, and due to the fact that he has already been edentulous for 3 years by now, we had to find a more appropriate treatment solution.

A document by Jennifer Cai. Click on the document to view its contents.