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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: [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.

The utility of eDNA for fish species and community monitoring is well-established using targeted amplification (i.e., qPCR and ddPCR) and passive sequencing approaches (i.e., metabarcoding). However, the lack of optimized and standardized methods reduces the sensitivity of this approach and precludes the reliable comparison of findings across studies, respectively. DNA extraction is a prime target for optimization efforts because the extraction method is highly variable across eDNA studies despite being the most influential factor in detection efficiency across the entire post-collection workflow. Sequence analysis is arguably the least standardized step in the workflow, with new bioinformatics pipelines frequently emerging in the literature and being implemented with innumerable unique combinations of parameter values. The current study aimed to support the optimization and standardization of eDNA methods for fish detection by assessing two commercial DNA extraction kits manufactured by Qiagen and Macherey-Nagel on cost, time, and performance specifications and comparing the success of brook trout detection by metabarcoding across three bioinformatics pipelines, qPCR, and ddPCR. Our protocols were effective in detecting brook trout in all 20 samples analyzed. Brook trout eDNA was detected by ddPCR in nine (90%) Qiagen extracts but only seven (70%) Macherey-Nagel extracts. In comparison, detection success was equal across the two extraction kits using qPCR (70%) and metabarcoding (100%). The metabarcoding pipelines performed equally well in detecting brook trout with no significant differences in read numbers associated with the target species. Under our experimental conditions, the Qiagen kit was selected as the preferred kit due to its overall good performance and considerably lower cost despite a slightly longer extraction time.

One major goal of immunological research is to understand fundamental mechanisms of immune system function and translate these discoveries into innovative approaches for diagnosing, treating, and ideally, preventing disease. Recent years have seen dramatic progress in our appreciation of basic immunologic principles and the pace of taking discoveries to patients is often breath-taking. This is an amazing time for immunologists and the future for the next generation of scientists is bright, indeed. An international meeting held in August 2023 on the Lofoten Islands in Norway provided a forum for discussing promising pathways for future research in our field. This 4th Lofoten workshop was also an opportunity to address another issue, just as important as the future of immunologic research. The recent COVID-19 pandemic highlighted the international phenomenon of a communication gulf between scientists and the public. This manifested itself with both misinformation and deliberate disinformation campaigns around the pandemic, potential treatments for COVID-19, and tragically, the importance of vaccination for individual and community health. The August workshop was an ideal opportunity for scientists from around the world to discuss their experiences in efforts at disseminating non-partisan, trustworthy information that would be useful for their communities. This report summarizes views on future directions in immunologic research presented at round-table discussions at the workshop and subsequent responses to surveys sent to meeting participants. It also summarizes some of the conversation around the responsibility of scientists to communicate with the non-science community and approaches we may use to meet this obligation.

The Gastroenterology Immunology Neuroscience (GIN) Discovery Program represents a new model for research that overcomes the limitations imposed by traditional ‘research silos’ in medical science. By adopting a cross-disciplinary, highly-integrated approach, the GIN Program unites the fields of gastroenterology, immunology, and neuroscience to comprehensively address chronic health challenges. This initiative not only bridges the gaps between basic science, clinical research, and patient care but also emphasises the importance of diversity in ideas, perspectives, and approaches when fostering innovation. The program’s organic, bottom-up growth strategy has facilitated the formation of a vibrant, interdisciplinary community, captivating attention from both national and international institutions. With a vision to create effective therapeutic solutions and pioneer advancements in gut-immune-brain axis research, the GIN Program exemplifies the power of interdisciplinary collaboration. This innovative commitment to change the landscape of medical research aims to inspire similar models that prioritise open communication, mutual respect, and a commitment to groundbreaking science.

Gastrodin is one of the foremost effective components of traditional Chinese medicine Gastrodia elata Bl., which has been widely used for anti-hypertension in China. However, the protection from myocardial apoptosis in hypertension of gastrodin has not been systematic studied. Our current study investigated the therapeutic effects and underlying mechanisms of gastrodin on cardiac protection in hypertensive mice. Treatment of gastrodin in Ang II-infused C57BL/6 mice significantly alleviated the increase of blood pressure, cardiac dysfunction, heart tibial ratio, and cardiac pathological changes. Kyoto Encyclopedia of Genes and Genomes pathway analyses applied in the data of RNA-sequencing by gastrodin treatment identified 697 up-regulated transcripts and 714 down-regulated transcripts, as well as 1105 enriched signaling pathways, which also revealed that apoptosis and PRDX2/p53 pathway were involved in the cardiac protection role of gastrodin. Consistently, gastrodin treatment significantly reduced the cell apoptosis in cardiac tissues of Ang II-infused mice and Ang II-stimulated H9c2 cells. In addition, gastrodin treatment significantly also decreased the Bax/Bcl-2 ratio on protein level, and down-regulated the protein levels of cleaved-caspase3, cleaved-caspase9, PRDX2 and p53 in both cardiac tissues and H9c2 cells stimulated with Ang II. In conclusion, gastrodin treatment exhibits cardiac protection by reducing myocardial apoptosis and suppressing PRDX2/p53 pathway activation in vitro and in vivo.

Objectives: Research indicates that low doses of interleukin-2 (IL-2) can effectively mitigate RA symptoms by promoting Treg cells, while high doses may enhance immune responses. Consequently, this study employed mutated IL-2 to minimize its impact on CD8 + T and NK cell activation while preserving its influence on Treg cells. Methods: We constructed IL-2 mutants by overlap PCR and assessed its impact on the proliferation and functionality of Treg cells by flow cytometry and PCR. Furthermore, the synergistic effects of mutated IL-2 and MSC on collagen-induced arthritis (CIA) in mice were evaluated through the infusion of lentiviral-transfected mesenchymal stromal cell (MSC) for CIA treatment and through pathological section staining to assess inflammatory joint injury, cartilage destruction, and osteoclast infiltration. Results: Mutant IL-2 demonstrated targeted enhancement of both the proportion and proliferative activity of Treg cells with a diminished capacity to stimulate the proliferation of CD8 + T cells and NK cells relative to wild-type IL-2. Moreover, MSC-mutant IL-2 significantly augmented the proportion of Treg cells compared to either MSC or mutant IL-2 in isolation. Treatment with MSC-mutant IL-2 infusion in CIA mice ameliorated arthritis symptoms and reduced inflammatory infiltration and cartilage damage in their joints. Conclusion: Mutant IL-2 enhances Treg function and proliferation while exerting reduced effects on CD8 + and NK cell activation. MSC expressing mutant IL-2 demonstrates therapeutic benefits in CIA by increasing the proportion of Treg cells and reducing the proportion of CD8 + T cells.

Zn alloy stent has become a promising implantable cardiac patch stent. However, traditional Zn alloy stents not only easily induce neointimal hyperplasia, but also cannot improve reperfusion ischemia after myocardial infarction. Here, the Yb/Er/CeO 2 coating grow on the surface of Zn substrate, which inhibits the release of Zn 2+ and enhances the proliferation of vascular endothelial cells. This layer improves re-endothelialization and avoiding restenosis. Yb/Er/CeO 2 coating generates the transition from the valence band to conduction band under 980 nm excitation, which forms transfer energy of photo-induced electron-hole pairs. This transfer energy can catalyze H 2O and O 2 to generate a chemical link group, which accelerate the deposition rate of drug-eluting coating PLGA and increase the corrosion resistance of Zn stents. Particularly, the Yb/Er/CeO 2 coating exhibits good catalytic ability for active oxygen species (ROS), which can effectively scavenge myocardial cells damage. Yb/Er/CeO 2 nanoparticles layer (Nps) improve mitochondrial function and increases oxidative phosphorylation, which achieves anti-damage effects. Zn@Yb/Er/CeO 2/PLGA can serve as an excellent myocardial patch scaffold for repairing damaged myocardial cells, which has promising applications in the treatment of cardiovascular diseases.

The processing stage (i.e., the early semantic representation stage, the late response-selection stage, or both) at which the spatial-numerical association of response codes (SNARC) effect occurs is still controversial. The two-stage processing model hypothesizes that the SNARC effect involves both stages and that different interference factors acting at the two stages might be the core reason for the observed stage flexibility of the SNARC effect. To test this hypothesis, the present study was designed to elicit the SNARC, Stroop (semantic-representation stage related), and Simon (response-selection stage related) effects together in one magnitude comparison task and used the event-related potentials (ERPs) to observe the temporal dynamics of these effects. The behavioral results showed no interaction between the Stroop and Simon effects, while these two effects both interacted with the SNARC effect. Furthermore, the ERP results showed an interaction of the Stroop effect with the SNARC effect for the early sensory P1 component, while the interaction of the Simon effect with the SNARC effect was evident for the late N2 and P300 components. The current study repeatedly verified the independence of Stroop and Simon effects. Most importantly, the temporal-specific interactions among the SNARC effect and the other two stage-related factors provided further evidence to support the two-stage processing model that the SNARC effect involves both the representation and response-selection stages.

Familial hypercholesterolemia (FH) is the most common metabolic disorder and is inherited in an autosomal dominant fashion. FH presents with xanthomas and early coronary artery disease, owing to relatively high levels of low-density lipid-cholesterol (LDL-C) compared to hypercholesterolemia without a genetic predisposition. The first clinical manifestation of this condition could be an acute coronary syndrome in undiagnosed and unsuspecting patient. Various clinical criteria are available to make a diagnosis of FH and a clinician should use the one which he is familiar with. Owing to very high LDL-C levels patients often need multiple oral lipid lowering agents to achieve the desired LDL-C goal. There are multiple novel parenteral lipid lowering agents in offing and some are in pipeline with advantage of high potency and weekly or monthly dosing. This case report emphasizes the importance of FH screening and aggressive treatment to decrease morbidity and mortality in the general population.

Title PageYELLOW NAIL SYNDROME: a case reportIntroductionYellow Nail Syndrome (YNS) is a rare disorder characterised by the triad of yellow and thickened nails, respiratory manifestations and lower limbs lymphedema. Two out of three clinical characteristics are required to diagnosis [1]. Less than 400 cases are described in literature with a prevalence of < 1/1.000.000. The diagnosis is clinical, particularly based on nail abnormalities, pulmonary manifestations, lymphedema and sinusitis. YNS is a condition of unknown aetiology, usually sporadic or presenting as a paraneoplastic syndrome, associated with cancer. To date there is not a specific treatment for YNS [1]. Resolution has been observed in up to 30% of patients, either spontaneously, or after cancer treatments in case of a paraneoplastic condition [1]. Herein we present a paraneoplastic case of YNS in a 67-years old never-smoker female, complaining chronic productive purulent cough for the last two years, after diagnosis of breast cancer.Key Clinical MessageYellow nail syndrome is a rare disorder affecting multiple districts. The diagnosis is clinical, based on nail abnormalities, pulmonary manifestations and lymphedema.The aetiology is unknown, usually presenting spontaneously or as a paraneoplastic syndrome.There is not an established treatment, while resolution is scarce.Case ReportCase History . A 67-years old never-smoker female was referred to a Respiratory outpatient clinic complaining productive purulent cough for the last two years despite treatments with mucolytic and antitussive. Two years before, following a diagnosis of left ductal mucinous breast cancer (G2 pT1No), she underwent quadrant surgery and local radiotherapy. Since then in remission and currently receiving hormonal therapy with anastrozole. She has a history of atrial fibrillation treated with warfarin and she refers otitis and sinusitis of recent onset (3 months). The high resolution thoracic CT scan highlighted bronchiectasis in the lower right inferior bronchus with mucus plugs. Spirometry was performed in stable conditions showing mild obstruction. A short course of oral clarithromycin was not effective in reducing respiratory symptoms. The thoracic CT scan performed after 6 months showed a parenchymal consolidation (organising pneumonia) in the lower right lobe (Fig 1A). She was then referred to our Outpatient clinic.Methods . She reported that during the last year her nails turned yellow, thicker and frail with slowed growth of both finger and toenails (Fig. 1B). Onychomycosis was excluded by a Dermatologic evaluation and Wood’s lamp test. No history of lower limb lymphedema was reported. Due to persistent respiratory symptoms resistant to antibiotic therapy a bronchoscopy was performed showing purulent material dripping from the nasal districts and mucous-purulent secretions in the lower right bronchus, in the absence of sign of malignancy. Based on xantonychia, bronchiectasis and sinusitis a diagnosis of yellow nail syndrome was performed.Conclusion and Results . A short course of azithromycin was started although the bronchoscopy culture resulted negative, with partial remission of the productive cough. The patient was subsequently chronically treated with low dose azithromycin (500 mg twice/week), a cycling combination of N-Acetyl-L-Cysteine + Lactoferrin + Resveratrol; cycling oral Vitamin E and inhaled umeclidinium. After six-months the patients referred remission of the chronic productive cough, otitis and sinusitis; the yellow nails condition remained unchanged. She is continuing the regular oncologist follow up, still in remission.DiscussionYellow Nail Syndrome (YNS) - OMIM 153300; ORPHA662 - is a rare disorder characterised by the triad of yellow and thickened nails, respiratory manifestations and primary lymphedema [1]. Two out of three clinical characteristics are required to diagnose YNS [1]. First described in 1927, the current definition dates back to 1966 [2]. There are less than 400 cases described in literature with a prevalence < 1/1.000.000. YNS is a condition of unknown aetiology, usually sporadic and affecting adults over 50 years worldwide, with no gender predominance [1] The completed triad is present only in 27-60% of cases, with nail chromonychia being the main clinical manifestation, as shown in Table 1. The diagnosis is clinical, particularly based on nail abnormalities, pulmonary manifestations, lymphedema and sinusitis. Chromonychia (nail discoloration), together with xantonychia (yellow nail coloration), progressive thickening and hardening of the nail plate and a slow growth (reduced by half), are the main characteristics of the YNS [1]. Respiratory manifestations occur in 60-70% of patients, with chronic cough as the most frequent symptom [3, 4]. Pleural effusion presents in up to 46% of cases, usually bilateral with a lattescent appearance (chylothorax); bronchiectasis in 44% [1, 4]. Both chronic and acute rhinosinusitis are common, presenting in 14-83% of cases with daily mucopurulent rhinorrhea and nasal obstruction [1]. Lower limbs lymphedema is present in 29-80% of cases, usually bilateral [1]. A lymphatic disorder with defective lymphatic drainage has been hypothesised as a possible cause of lymphedema, pleural effusion and subungual tissue sclerosis with nail alterations [1]. Another hypothesis considers microvasculopathy and protein leakage [3, 5]. YNS may present as a paraneoplastic syndrome, associated with malignant diseases, such as lung and breast cancer or non-Hodgkin lymphoma [1]. The paraneoplastic presentation could be due to lymphatic micro-obstruction, possibly correlated with circulating tumour microemboli [6], or due to cancer histopathology. Other diseases described associated with YNS are autoimmune and immunodeficiency [1]. Differential diagnosis is broad and involves: asbestos-related disease, heart failure, connective tissue diseases, malignancies and onychomycosis are the main ones [4]. To date there is not a specific treatment for YNS. Resolution has been observed in up to 30% of patients, either spontaneously, or after cancer treatments in case of a paraneoplastic condition [1]. Oral α-tocopherol (vitamin E) at 1000-1200 IU/day, is considered the only partially effective agent nail alterations [1]. Regular antifungal treatment (itraconazole or fluconazole) and oral zinc sulphate were also tried, with scarce evidence [1]. A randomised study using topic vitamin E preparation showed no difference versus placebo [7]. Acute exacerbations of bronchiectasis and sinusitis can be treated with antibiotics and symptomatic drugs, whereas for recurrent flares up or poor symptom control, low dose oral azithromycin (250 mg 3 times/week), and a physiotherapy program should be prescribed. Flu and pneumococcal vaccinations are recommended [1]. Surgical intervention for recurrent or large pleural effusions can be useful, while somatostatin analogues as octreotide for chylothorax can be tried [1]. Complete decongestive therapy is an option for lymphedema volume reduction [1].

Background Respiratory infection is a common trigger for the episode of alveolar hemorrhage in the pediatric diffuse alveolar hemorrahge (DAH). Whereas, a futher detailed study hasn’t been conducted. The aim of this study was to explore the etiological spectrum, clinical features, treatment strategies and outcomes of the respiratory infection induced episode of alveolar hemorrhage (RIIEAH) in the pediatric DAH. Methods The cases of pediatric DAH who had RIIEAH and a definite etiological diagnosis were included. A retrospective study was conducted. Results 1. A total of 16 cases with 21 RIIEAHs were included. Twelve RIIEAHs occurred at the unstable stage, 6 RIIEAHs occurred at the stable stage and 3 RIIEAHs occurred at the end stage. All the RIIEAHs with respiratory failure (n=5) and requirment of invasive mechanical ventilation (n=3) occurred at the unstable or end stage. 2. In the majority of the RIIEAHs (n=19), etiological diagnosis was identified by detecting the nucleic acid of the pathogens. Of these, bronchoalveolar lavage fluid was the most commonly used specimen in 12 RIIEAHs. The majority of the RIIEAHs (n=19) were caused by a single pathogen including mycoplasma pneumoniae (Mp) in 7 RIIEAHs, coronavirus (CoV) in 3 RIIEAHs, haemophilus influenzae (Hi) in 3 RIIEAHs, chlamydia pneumoniae in 2 RIIEAHs, human metapneumovirus in 2 RIIEAHs, acinetobacter baumannii in 1 RIIEAH and pueumocystis carinii in 1 RIIEAH. The rest 2 RIIEAHs were caused by the mixed pathogens including klebsiella pneumoniae and streptococcus pneumoniae in 1 RIIEAH, rhinovirus and CoV in 1 RIIEAH. 3. The majority of the RIIEAHs (n=19) presented with prodromal symptoms and most of them (n=15) occurred within 3 days from the prodromal symptoms. Either worsening anemia or hemoptysis was found in 13 RIIEAHs and dyspnea was found in 9 RIIEAHs. All the 12 RIIEAHs in which bronchosopy had been performed presented with bleeding on bronchoscopy. 4. An intensive glucocorticoid therapy was administrated in the 19 RIIEAHs and a targeted anti-infection treatment was administrated in the 11 RIIEAHs. The majority of the RIIEAHs (n=19) resolved, whereas there was 1 case death. Conclusions 1. RIIEAH could be caused by a varity of pathogens and could occur at any disease stage of pediatric DAH. 2. It usually occurred at the early stage of respiratory infection and presented with worsening anemia or hemoptysis. 3. Bronchoscopy had a good diagnostic value for RIIEAH and idenifying the etiology. 4. An intensive glucocorticoid therapy seemed to be effective and necessary.

This study explores a combined strategy of Raman and reflectance spectroscopy for quantifying liver fat content and fat droplet size, crucial in assessing donor livers. By using Monte Carlo simulations and experimental setups with oil-in-water phantoms, our findings indicate that Raman scattering can solely differentiate between varying fat contents, while reflectance intensity is influenced by both fat content and oil droplet size, with a more pronounced sensitivity to fat droplet size. This study demonstrates the efficacy of combined Raman and reflectance spectroscopy in assessing liver steatosis and fat droplet size, potentially aiding in assessing donor livers for transplantation.

In this paper, we present an Augmented Reality (AR)-based application combined with a robotic system for percutaneous renal puncture navigation interaction and demonstrate its technical feasibility. Our system provides an intuitive interaction scheme between the surgeon and the robot without the need for traditional external input devices, and applies an image-target-based 3D registration scheme to transform the coordinate system between Hololens2 and the robot without using additional tracking devices. Users can visualise the abdominal puncture phantom and obtain 3D depth information of the lesion site by wearing Hololens2 and control the robot directly using buttons or gestures. To investigate the accuracy and feasibility of the proposed interaction scheme, six subjects were recruited to complete 3D registration alignment accuracy experiments, and puncture positioning accuracy experiments using ultrasound unaided navigation, AR unaided navigation and AR robotic navigation. The results showed that the average alignment error of 3D registration was 3.61±1.05 mm. The average positioning errors of ultrasound freehand navigation, AR freehand navigation and AR robotic navigation were 7.67±2.00 mm, 6.13±1.07 mm and 5.52±0.37 mm, respectively; the average puncture times were 34.86±1.67 s, 22.40±2.07 s, and 29.41±1.37 s.