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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: [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.

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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Liam MacNeil

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Aim: The range and biomass distribution of marine fish species offer insights into their underlying niches. Quantitative data are rare compared to occurrences and remain underused in species distribution models (SDMs) to explore patterns of realized niches– the actual space occupied by a species shaped by abiotic and biotic factors. Local densities drive differences in species contributions to ecological processes and ecosystem function rather than through presence alone, thus if a species growth rate is strongly controlled by macro-environmental conditions, then predicting geographical abundance or densities should be possible. Location: Baltic Sea Methods: We collated twenty years of standardized scientific bottom trawl surveys to fit an ensemble of SDMs to biomass (kg km-2) of four dominant demersal species (Common dab, European flounder, European plaice, Atlantic cod) within seasonal (winter and autumn) and decadal (2001-2010; 2011-2020) time windows. Covariates were represented with high-resolution oceanographic and habitat variables. Final prediction maps for each species were produced by weighted ensemble averages. Results: This work shows four distinct cases of spatiotemporal patterns. 1) Relative stasis in dab that is linked to the macro-environmental salinity gradient in the western Baltic Sea. 2) Flounder biomass showed spatial seasonality alongside increasing trends in the western Baltic Sea and declines in Bornholm Basin deeps. 3) Plaice have broadly increased in biomass density throughout the western Baltic Sea towards present, associated with bottom salinity and temperature. 4) Both juvenile and adult cod (≥35 cm) declined in biomass and distribution, greatest among juvenile cod in the Gdańsk deeps and for adult cod in Bornholm Basin by 2011-2020. Main Conclusions: This study maps biomass of the dominant Baltic Sea demersal fish, including seasonally-explicit patterns available from survey data. The biogeographic patterns described here expand beyond common occurrence data and suitability maps, which rarely discriminate between areas of high and low abundance.

Aziza Jamal-Allial

and 8 more

Purpose Ascertainment of mortality is critical to epidemiologic studies. Secondary collected database studies face challenges given the need to record mortality data in health claims or electronic medical records. The National Death Index (NDI) is the gold standard for mortality data in the U.S. Methods This study is a secondary analysis of an advanced cancer cohort in the U.S. between January 2010 and December 2018, with an established NDI linkage. Mortality data sources, inpatient discharge, disenrollment, death master file (DMF), Center for Medicare and Medicaid Services (CMS), Utilization management data (U.M.), and online obituary data were compared to NDI. We calculated sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and 95% confidence intervals (95% CI). Per each source, death identified 60 days before and 30 days after NDI death was deemed a match. Results Among 40,692 patients, 25,761 (63.3%) had a death date using NDI; the composite algorithm had a sensitivity of 88.9% (95% CI= 88.5%, 89.3%), specificity was 89.1% (95% CI= 88.6%, 89.6%). At the same time, PPV was 93.4% (95% CI= 93.1%, 93.7%), NPV was 82.3% (95% CI= 81.7%, 82.9%), and when comparing each individual source, each had a high PPV but limited sensitivity. Conclusion The composite algorithm was demonstrated to be a sensitive and precise measure of mortality in advanced cancer patients in the U.S. from 2010 to 2018, while individual database sources were accurate but had limited sensitivity compared to the NDI.

Hamed Heydari

and 2 more

Abstract: This study proposes a novel fusion-based approach using Google Earth Engine (GEE) to accurately model distinct drought phenomena in various environmental regions, with Iran as a case study. The method integrates Environmental Parameters (EPs) - Vegetation (Veg), Temperature (Tem), Humidity (Hum), and Evaporation-Transpiration (ET) - with auxiliary parameters such as land-cover, topography, and wind-speed to improve modeling accuracy. A 39-year (1982-2020) time series of 14 Remote Sensing (RS) indices and 18 Ground-Based (GB) drought indices were used as input and output, respectively, for training and testing machine learning algorithms in three phases. The results obtained during the test period (2015-2020) from each phase were employed in the next phase based on a hereditary procedure to evaluate the potential of the proposed indices and their associated EPs (group of indices). The Consolidated Fusion-Based Drought Model (CFDM) was developed as the final product, which demonstrated superior accuracy and stability compared to other models, with an overall accuracy (OA) higher than 90% for all GB indices. As a result, the CFDM has utilized for generating drought maps in Iran. Furthermore, the effectiveness of the simultaneous use of auxiliary parameters and EPs was demonstrated through the Prevalent Fusion-Based Drought Model (PFDM). Our approach entails a systematic framework that incorporates innovative parameters (indices/indicators) to accurately model drought phenomena. This can contribute to the development of effective management strategies.
Aim: Affective disorders such as depression and anxiety are one of the most prevalent symptoms observed in patients following coronavirus disease 2019 (COVID-19). The aim of the TELESPHOR study was to evaluate the antidepressant effectiveness and tolerability of agomelatine therapy in daily clinical practice in patients with major depressive episodes (MDE) post-COVID-19. Methods: This multicenter, observational study enrolled outpatients aged 18-65 years who experienced an MDE (17 item Hamilton Rating Scale for Depression [HAMD-17] total score of 8-24) within 3 months of laboratory confirmed SARS-CoV-2 infection and who had initiated treatment with agomelatine. Study visits occurred at weeks 2, 4 and 8. The primary outcome was the antidepressant effectiveness of agomelatine assessed by change in HAMD-17 total score at week 8. Secondary outcomes included changes in HAMD-17 item 10 (anxiety psychic) and item 11 (anxiety somatic), the proportion of responders (≥50% decrease in baseline HAMD-17) and remitters (HAMD-17 score ≤7 at week 8), and impact on quality of life (QoL) (Short Form Survey [SF-36] questionnaire). Tolerability was assessed at each study visit. Results: The full analysis set comprised 103 patients of whom 73 (70.9%) were women. Median age was 45 years, and in the past 3 months 81 (78.6%) had experienced mild and 22 (21.4%) moderate COVID-19. The mean time from onset of infection to study inclusion was 2.1±0.7 months. At study entry, 55 (53.4%) had mild and 48 (46.6%) had moderate MDE. Agomelatine was associated with a significant improvement in depression severity with decreases in mean total HAMD-17 score compared with baseline of 2.6±3.3, 6.7±5.3, and 10.9±4.9 at weeks 2, 4, and 8, respectively (P<0.0001 for all). Significant reductions in anxiety psychic and anxiety somatic were also observed. Mental and physical components of SF-36 were significantly improved compared with baseline (P<0.0001). The proportion of responders was 81.4% and the proportion of remitters was 71.6%. Agomelatine was well tolerated over the 8-week follow-up. Conclusion: Treatment with agomelatine was associated with rapid and significant antidepressive and anxiolytic effectiveness, improved QoL, and good tolerability in the treatment of patients with an MDE after COVID-19.

Loïc Pittet

and 4 more

Pleistocene climate oscillations influenced the biogeographical history of most species. In the European Alps, mountain plants were restricted to refugial areas during cold phases of glacial cycles and recolonized newly available habitats during warm periods. The current ranges of alpine plants represent a transient stage of a continuous and dynamic recolonization process that started after the last glaciations. Differences in recolonization rate and range filling are observed between different mountain plant species, but the reasons remain insufficiently explored. Here, we investigated the effects of secondary contact hybridization on range expansion between two related willow species pairs that came into secondary contact. RAD sequencing data was used to identify potential refugial areas and characterize the secondary contact zones. Leaf phenotypes were measured using morphometrics. Distribution modeling was used to find current suitable habitats. Results suggests that peripheral glacial refugia played a major role in the history of the species. For both species' pairs, the secondary contact zones showed homoploid hybridization between parents, which is also supported by the morphometric analyses. The hybrid zones are broader than expected and characterized by introgression. Current projections of species distribution identified suitable habitats beyond the secondary contact zone. We suggest that the parents' range expansion is blocked by the hybrid zones. Indeed, due to the high genetic similarity, each dispersal beyond the secondary contact zone results in the long term in hybridization and introgression with the already established parent. Therefore, hybridization acts here as a barrier to further recolonization.

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Karma Norbu

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Introduction: Scrub typhus is a neglected life threatening acute febrile illness caused by bacteria Orientia tsutsugamushi and it is a vector-borne zoonotic disease. In 2009, scrub typhus outbreak at Gedu has awakened Bhutan on the awareness and testing of the disease.Information and data of the study highlights the need for in depth surveillance, awareness among prescribers and initiate preventive measures in the country. Methods: We used retrospective descriptive study through review of laboratory registers across three health centres in Zhemgang district, south central Bhutan. The laboratories registers have been transcribed into CSV file using Microsoft excel. Variables of interest were collected from the registers and then analysed using open statistical software R, (R Core Team (2020). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.) And use of mStats package, (MyoMinnOo (2020). mStats: Epidemiological DataAnalysis. R package version 3.4.0.) Results: Of the total 922 tests prescribed for suspected scrub typhus in the three health centers in Zhemgang, only 8.2 % (n=76) were tested positive. Of these, Panbang Hospital had highest reported positive for scrub typhus with 56.6 %( n=43) followed by Yebilaptsa Hospital 35.5 %( n=27) and Zhemgang Hospital with 7.9 %( n=6). The female gender is comparably more affected as opposed to male with 57.9% (n=44) of the positive cases being female. The prevalence of scrub typhus seems to be affected by the seasonal variation as the months of Spring, Summer and Autumn together accounts for 98.7%(n=75) of total positive cases. The year 2019 noted significant scrub typhus cases accounting to 89.5 %(n=68) of the total positive cases over the two years. Conclusions:The overall tests tested positive of the scrub typhus infection within two years was 8.2%.

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