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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

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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*^

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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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Laura Lorenzon

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Background: Recent literature documented the expression of miRs in gastric cancer (GC), however their clinical utility is still unclear. Methods and Results: 117 resected GCs were evaluated for miR21, miR135b, miR196a, miR196b relative expression (RE). The performance of miRs’ to differentiate cancer vs normal mucosa was tested using ROC curves. Univariable and multivariable analyses were conducted to correlate miRs RE with pathological features and survivals. Although all the 4 miRs were upregulated, ROC curves documented that this was not-significant in differentiating GC (p ns). miR135b significantly correlated with Lauren’s intestinal type and more advanced pT stages (p 0.017, and p 0.025), whereas miR196a and miR196b were more expressed in advanced pStages (p 0.016, and p 0.038). miR196b was also more expressed in nodal positive patients comparing N0 (p 0.035). Survival curves were non-significant for miRs RE, while pStages could significantly differentiate oncological outcomes (p<0.0001). On Cox analyses, pStages independently correlated with OS (HR 4.9, 95%CI 2.041-12.104), whereas increased age correlated with a worse DFS (HR 6.0, 95%CI 2.596-13.947), and lymph-node ratio with DSS (HR 14.4, 95%CI 4.213-49.373). Literature was reviewed a using PRISMA method focusing on miRs and response to therapy and the detection of peritoneal metastases: out of 116 manuscripts retrieved, just 41 were pertinent with the outcomes of interest, and 14.6% were from Western countries. miR21, miR135b and miR204 were reported to correlate with response to therapy. Conclusions: miR21, miR135b, miR196a and miR196b were documented up-regulated in GC, but their clinical utility is still to be fully investigated.

Shaoyi Wang

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Background: Coiled coil domain containing protein 51 (CCDC51), as the two transmembrane helical domains protein, little is known about the function of it in human cancer. Methods: TCGA, GEPIA, cBioPortal, GTEx, and TIMER were employed to analyze expression, immune cells infiltration, prognostic value, genetic alteration, cancer patients’ mutation burden, stem cell stability, and microsatellite instability of CCDC51 . Results: Decreased CCDC51 expression significantly related with poor overall survival (OS) of acute myeloid leukemia (LAML), adrenocortical carcinoma (ACC), glioma (GBMLGG), kidney chromophobe (KICH), liver hepatocellular carcinoma (LIHC), lung squamous cell carcinoma (LUSC), skin cutaneous melanoma (SKCM) and uveal melanoma (UVM), lung adenocarcinoma (LUAD), disease-specific survival (DSS) of ACC, GBMLGG, SKCM and UVM, and progression-free interval (PFI) of ACC, KICH and pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck (HNSC). In human cancer, immune cell infiltration, and tumor microenvironment, CCDC51 expression is associated with MSI, RNA modifications, and diverse cancer drug sensitivity. There is potential for it to be an independent factor contributing to OS in LIHC. CCDC51 was an independent factor for LIHC prognosis in Cox regression and nomogram analysis. The results of the the Kyoto Encyclopedia of Genes and Gene Ontology and Genomes indicated that CCDC51 was involved in aminoacyl-tRNA biosynthesis, RNA transport, colorectal cancer, Wnt signaling pathway, mismatch repair, mitochondrion, pseudo uridine synthase activity, mRNA processing, mitochondrial matrix, regulation of mRNA stability, and mitochondrial inner membrane. Conclusion: Our research can provide new-insights for LIHC prognostic biomarkers of CCDC51.
Off-label drug use which could be defined as the practice of prescribing a drug for a different purpose than what is permissible by the regulation is a common practice among clinicians, nevertheless, it is often subject to ethical and legal uncertainties. In general, clinicians must balance the need to provide patients with the best possible care while complying with the regulatory requirements governing drug use. This paper will review the current literature on off-label drug use, including its prevalence, the regulatory landscape, and the ethical issues involved with the aim of formulating an ethical and legal framework that could guide clinicians in using off-label drugs in clinical practice in Malaysia. The framework will include ethical considerations that are centred on the principles of beneficence, non-maleficence, and autonomy, which require clinicians to balance the benefits and risks of using off-label drugs while respecting patients’ autonomy. The legal framework consists of federal and state regulations governing drug use, including the Control of Drugs and Cosmetics Regulations (CDCR) 1984 and other regulations published by the National Pharmaceutical Regulatory Agency (NPRA). The aim of this paper is to provide guidance on how clinicians can navigate the ethical and legal terrain of off-label drug use by understanding the regulatory requirements, being obliged to the requirements of obtaining informed consent from patients and documenting the rationale for off-label use. Ultimately, by understanding the ethical and legal framework, clinicians can provide patients with the best possible care while complying with the regulatory requirements governing drug use.

Annelies Agten

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Mulugeta Tuji Dugda

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Large earthquakes, especially those occurring in a city or population centers, create devastation and havoc, and often times kindle several deaths and injuries, and significant infrastructure damage that lead to several billions of dollars in losses. Marine earthquakes are the leading cause of large tsunamis which cause deaths, destruction, displacement of population, and a possible nuclear meltdown. Thus, prediction of earthquake or its aftershocks or earthquake early warning system has a great potential to mitigate the loss of life as well as different kinds of damage. Earthquake prediction would mean forecasting the occurrence of an earthquake by providing both its magnitude estimate and accurate location. Earthquake prediction has been an important area of seismology research for quite a while, and it looks like it will continue to be an important area of research. Recently, with the implementation of deep learning in seismology, scientists have been able to detect, predict, and model seismic waves and earthquake aftershocks. Earthquake aftershocks are generally triggered by changes in stress formed by large earthquakes that happen within, or surrounding a given fault network system. The main goal of this study is to investigate the improvement of aftershock pattern predictions with the implementation of tuning and optimizing of deep learning parameters. To achieve these goals, we have developed an algorithm that can help first gather mainshock-aftershock sequence data. Some of the criteria used in identifying earthquakes that initiate an aftershock is to look at earthquakes that happen within a certain radius, the values we attempted are within about 0.5 degrees range, and within a certain period, from few seconds to several weeks of the occurrence of the main shock. For the sequence identification, we have been using seismic data from the United States Geological Survey (USGS)-National Earthquake Information Center (NEIC). We are also looking at different open-source data gathered by researchers for a similar study. The deep neural networks we are implementing make use of Keras python Toolkit, and Theano and Tensorflow libraries, with a plan to use PyTorch python library instead of Theano library in the future because of some maintenance issues. To this point our attempts have shown a good progress.

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