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Michael Weekes

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

Guangming Wang

and 4 more

Tam Hunt

and 1 more

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.

Susanne Schilling*^

and 9 more

Jessica mead

and 6 more

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.  

Mark Ferris

and 14 more

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.

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ziyin wang

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:Vegetation blanket restoration techniques of different materials in mine drainage field provide different environments for plant growth, but effects of vegetation blanket cover on soil microbial community structure and their diversity characteristics were not well known, especially in arid areas. In this study, high-throughput sequencing was used on the study site, located at Dafeng Mine, the Helan Mountains, Ningxia, China. Soil microbial communities were analyzed under four different treatments: Straw, Straw-Coir, Coir vegetation blanket types, and a bare soil control. The results showed that the contents of soil total nitrogen, available potassium, urease, and catalase were significantly increased in different types of vegetation blankets. High-throughput sequencing showed that the straw vegetation blanket increased bacterial diversity while the coir vegetation blanket increased fungal diversity. The dominant bacterial phyla were Proteobacteria, Bacteroidetes, Actinobacteria, and Chloroflexi, whose main influencing factors were total nitrogen, catalase, urease, and protease. The dominant fungal phylum was Ascomycota, whose main influencing factors were alkaline phosphatase, soil organic carbon, total nitrogen, and electrical conductance. These results indicate that vegetation blanket cover can improve the physicochemical properties of soil, increase the diversity and richness of soil microorganisms, and improve the structural composition of the community, thus improving the soil environment in the mining areas in arid regions, while laying a good foundation for further restoration measures.

Yifei Xue

and 3 more

Background: Existing research focuses primarily on common adverse events (AEs) in adults using Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI), systematic reports from real-world settings and safety research on off-label use in children are lacking. Therefore, we aimed to investigate the safety profiles of VEGFR-TKIs via the FAERS. Method: Data regarding VEGFR-TKIs were extracted from the FAERS between 2004Q1 to 2022Q2. Reporting odds ratio (ROR) was performed to identify risk signals associations of VEGFR-TKIs with AEs. A reported AE would be defined as a potential risk signal if it simultaneously met the report cases ≥ 3, ROR ≥ 2, the lower limit of 95% CI ≥1, and χ2 ≥ 4. and categorized by the MedDRA terms. Results: A total of 51,841 reports containing 536 children were identified from May 18, 2005, to June 30, 2022. Despite some differences, 7 VEGFR-TKIs had similar safety profiles in the general population. The most significant ROR was PPES and the most frequent SOC was gastrointestinal disorders. In pediatrics, results varied in these agents, and the most frequent AE with significant ROR were PPES, followed by pneumothorax. Furthermore, blood and lymphatic system disorders and investigation abnormalities were both the most common SOCs. Conclusion: Disproportionality analysis based on the FAERS database is an effective path to recognize VEGFR-TKI-related AEs. Findings of the general population were largely consistent with real-world setting studies, and the widely recorded data in FAERS also made it possible to retrieve the safety of these agents in pediatrics.

youxuan Wu

and 7 more

Aim: This study has been designed to assess the bioequivalence of the newly developed delayed-release oral tablets (test) 30 mg nifedipine compared to its marketed counterpart (30 mg; reference) in healthy adult Chinese volunteers. Methods: We conducted randomized, open-label, four-period, crossover trials, including a fasting trial and a fed trial. The subjects were administered the test or reference products in a 1:1 ratio at random throughout each period with 7 days washout period. Then, in the next session, they got the alternate products. Liquid chromatography-tandem mass spectrometry and WinNonlin software were used to evaluate the bioequivalence of nifedipine peak blood concentration (Cmax) and area under the concentration-time curve (AUC). Result: A total of 46 subjects participated in the fasting trial and 48 subjects in the postprandial trial. In both cases, the 90% CI of the geometric mean ratios of Cmax, AUC0-t and AUC0-∞ were in the equivalence range (80-125%). When nifedipine was given concomitantly with a high-fat meal, tmax was approximately twofold earlier, absorption was approximately 4.8% less, and Cmax changed little compared to fasting conditions. In addition, no serious adverse events were observed in the subjects. Conclusion: This study confirms the bioequivalence of the test and reference formulations of nifedipine extended-release tablets under fasting and postprandial conditions. Food giving leads to a much earlier Tmax, which is different from the results of other studies. The effect of food effect on the pharmacokinetics of nifedipine needs to be further explored.

Ahmed Ali

and 2 more

Angelica Tiotiu

and 15 more

Background: Several biologics are now available as add-on treatment for severe asthma but, currently there are no universally accepted criteria to measure the response to these therapies. This survey aims to establish consensus criteria to use in practice for the initial evaluation of response to biologics after four months of treatment. Method: Using Delphi methodology, a questionnaire including ten items was developed and validated by a 13-member panel of international experts in asthma. The electronic survey circulated within the INterasma Scientific Network platform, Global Asthma Association membership, contact list of the co-authors, national associations for specialists, and social media. For each item, five answers were proposed graduated from “no importance” to “very high importance” and by a score (A=2 points; B=4 points; C=6 points; D=8 points; E=10 points). The final criteria were selected if the median score for the item was ≥7 and >60% of responses accorded “high importance” and “very high importance”. All selected criteria were validated by the thirteen experts. Results: Four criteria were identified to evaluate the efficacy of biologics in asthma: to reduce daily systemic corticosteroids dose by ≥50% (ideally complete withdrawal); to decrease the number of asthma exacerbations requiring systemic corticosteroids by ≥50%, (ideally no asthma exacerbation); to have no/minimal side-effects and to obtain asthma control according validated questionnaires. The consensual decision was that ≥3 criteria are needed to conclude a good response to biologics. Conclusions: Specific criteria were defined by an international panel of experts and could be used as tool in clinical practice.

Susan Sakimoto

and 1 more

To date, actively flowing lava has only been observed on Earth and on Jupiter’s moon Io. This lack of observation means that for the vast majority of volcanic systems in the Solar System, solidified lava-flow morphologies are used to infer important information about eruption and emplacement parameters. These include: lava supply rate, lava composition, lava rheology, and determination of laminar or turbulent emplacement regimes. Commonly used models that relate simple lava flow morphologic properties (e.g., width, thickness, length) to emplacement characteristics are based on assumptions that are readily misinterpreted. For example, the simplifying assumption of fully turbulent lava flow allows for a thermally mixed flow interior, but ignores the lava properties that naturally work to suppress full turbulence (such as thermal boundary layers encasing active lava flows, and a temperature-dependent lava rheology). However, full turbulence in silicate lava flows erupted into environments that have temperatures lower than the lava solidification temperature requires a rare combination of characteristics. We model Bingham Plastic, Newtonian, and Herschel-Bulkley fluids in rectangular channels, tubes, and sheets with computational fluid dynamics (COMSOL) software to obtain flow solutions and general flow rate equations and compare them to field measurements of volcanic velocity and flow rates. We present these as more realistic alternatives to older simpler rate-from-morphology models. We find that several lava rheology properties work together to delay the onset of turbulence as compared to isothermal Newtonian materials, and that while turbulent lavas flows certainly exist, they are not as prevalent as the published literature might indicate. Results obtained from models that assume full turbulence in silicate flows on the terrestrial planets should therefore be interpreted cautiously.

Max Moorkamp

and 3 more

The Southern African Magnetotelluric Experiment (SAMTEX) involved the collection of data at over 700 sites in Archean to Proterozoic southern Africa, spanning features including the Kalahari Craton, Bushveld Complex and voluminous kimberlites. Here, we present the first 3D inversions of the full SAMTEX dataset. In this paper, we focus on assessing the robustness of the 3D models by comparing two different inversion codes, jif3D and ModEM, and two different subsets of the data, one containing all acceptable data and the other containing a smaller selection of undistorted, high-quality data. Results show that the main conductive and resistive features are imaged by all inversions, including deep resistive features in the central Kaapvaal Craton and southern Congo Craton and a lithospheric-scale conductor beneath the Bushveld Complex. Despite this, differences exist between the jif3D and ModEM inverse models that derive mainly from the differences in regularization between the models, with jif3D producing models that are very smooth laterally and with depth, while ModEM produces models with more discrete conductive and resistive features. Analysis of the differences between these two inversions can provide a good indication of the model resolution. More minor differences are apparent between models run with different subsets of data, with the models containing all acceptable data featuring higher wavelength conductivity variations than those run with fewer stations but also demonstrating poorer data fit.

Hiroaki Koge

and 3 more

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Erik Amézquita

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Ian Williams

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Background: Partial anomalous pulmonary venous connection (PAPVC) occurs when at least one pulmonary vein drains into the right atrium or its tributaries rather than the left atrium, most commonly connecting with the superior vena cava (SVC). The Warden procedure involves transecting the SVC proximal to the uppermost connection of the pulmonary vein followed by proximal SVC reattachment to the right atrial appendage. However, descending thoracic aortic homograft replacement for SVC translocation has recently been introduced as a modified technique. Aims: This commentary aims to discuss the recent study by Said and colleagues who reported their experiences with 6 PAPVC cases undergoing a modified Warden procedure using thoracic aortic homograft SVC translocation. Methods: A comprehensive literature search was performed using multiple electronic databases in order to collate the relevant research evidence. Results: The Warden procedure is associated with a 10% incidence of SVC obstruction with many requiring reintervention. Meanwhile, using the aortic homograft for SVC translocation, Said et al. observed no SVC obstructions. In addition, this modified technique does not require anticoagulation and has demonstrated an improvement in long-term SVC patency. Nevertheless, it can be considered an expensive procedure. Moreover, since the thoracic aortic homograft utilised is biological tissue, only long-term follow-up will determine whether calcification and graft degeneration is an issue. Conclusion: It can be concluded that the modified Warden procedure is a safe and effective method to reconstruct the systemic venous drainage into the right atrium when a direct anastomosis under tension might be prone to re-stenosis.

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