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Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC) : a randomised controlled trial
Get PDFFunding: CCB acknowledges part support as Senior Investigator of the National Institute of Health Research, the NIHR Community Healthcare Medtech and In-Vitro Diagnostics Co-operative, and the NIHR Health Protection Research Unit on Health Care Associated Infections and Antimicrobial Resistance. FDRH acknowledges his part-funding from the NIHR Applied Research Collaboration. GH is funded by the NIHR Advanced Fellowship and by the NIHR Community Healthcare Medtech and In-Vitro Diagnostics Co-operative. JD is funded by the Wellcome Trust PhD Programme for Primary Care Clinicians (grant number 216421/Z/19/Z). SP has received support as an NIHR Senior Investigator (grant number NF-SI-0616–10103) and from the UK NIHR Applied Research Collaboration Oxford and Thames Valley. OG-T has received funding from the European Clinical Research Alliance on Infectious Diseases (project number 101046109). This work is supported by the UK Research and Innovation and NIHR (grant number NIHR135366). This work is independently funded by the NIHR.Background No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation. Methods This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (0·99; number needed to treat [NNT] 62·5; 6 months: –1·9% [–2·9% to –0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference –2·1% [–2·9% to –1·5%]; p(sup)>0·99; NNT 47·6; 6 months: –2·5% [–3·3% to –1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference –1·6% [–2·6% to –0·6%]; p(sup)=0·99; 6 months: –1·9% [–2·9% to –0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference –1·4% [–2·3% to –0·4%]; p(sup)>0·99; NNT 71·4; 6 months: –0·5% [–1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up. Interpretation In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat.Peer reviewe
600 leagues under the sea : maritime communities and commercial connectivity in the western Mediterranean world of late antiquity
No full textThis thesis focuses on the relational connections inherent in the maritime economies of the late antique western Mediterranean, combining archaeological material from both land and sea along with environmental and literary evidence to produce a new account of the dynamic changes in interconnectivity and distribution networks which occurred over the course of this period. By employing social network analysis coupled with an investigation of maritime cultural landscapes, it sheds light on how maritime
exchange was structured in late antiquity, as increased fragmentation and regionalisation, combined with changing economies, saw major shifts in the organisation of the western Mediterranean system. After detailing the methodology that is utilised for modelling maritime networks, the fijirst part of the thesis focuses on the social, environmental, and archaeological background to maritime commerce. This includes examining ships, navigation, sea routes, and mercantile business before shifting to deliver an overview of what the material we possess from shipwreck sites can truly tell us about seaborne trade given the issues inherent in its collection and analysis. The second part is centred around outlining the distribution networks and trading communities represented by the remains included in the collected archaeological dataset. Drawing on a combination of network and geostatistical models, it examines the ties between types of goods being shifted across the Mediterranean, using them to better understand the connections between areas of production and consumption as well as the formation and spatial limits of communities. These are then combined with an overview of archaeological fijinds from on land in a series of case studies which explore how the models which were created line up with this source of information and what a synthesis of this data can tell us about regional dynamics and gaps within the underwater record. From the evidence that is presented in the thesis as a whole, I argue that regionalisation accelerated over the course of late antiquity as longdistance connections became increasingly selective, creating new patterns of maritime distribution and heavily disturbing pre-existing webs of connectivity. However, this process was uneven and also significantly mediated by specific conditions within the maritime landscape of each region."Finally, this thesis would not have been possible without the generous support provided by the Scottish Graduate School for Arts and Humanities. I am extremely grateful for their willingness to fund my research over these four years. I would also like to thank both SGSAH and the University for providing travel funds, without which I would not have been able to attend nearly as many conferences as I did."--Fundin
Synaptopathy in the TDP43ΔNLS mouse model of sporadic amyotrophic lateral sclerosis
Get PDFFunding: This research was funded by Tenovus Scotland, RS Macdonald Charitable Trust and The Lundbeck Foundation Ascending Investigator grant to C.F.M. (Grant R434-2023-347).Sporadic cases of Amyotrophic Lateral Sclerosis (sALS) represent the most common form of motor neuron disease. sALS is characterised by pathological cytoplasmic inclusions of TDP-43, so-called reactive astrocyte pathology, and motor neuron degeneration. Alterations in certain subpopulations of synapses between neurons are thought to be a key driver of the pathological mechanisms of ALS. However, we do not have a clear understanding of which types of synapses are impacted in ALS. Identifying vulnerable synapses affected in sALS models may provide insights into the key sites of disease pathogenesis. In this study we have performed quantitative high-resolution microscopy to survey different synapse subtypes, including excitatory (glutamatergic), inhibitory (glycinergic) and modulatory (cholinergic C-Boutons) synapses, in the spinal cord of a mouse model of sALS showing inducible TDP-43 pathology (TDP43ΔNLS) restricted to neurons. We have identified changes in cholinergic synapses and a subpopulation of excitatory synapses. Mice display robust neuronal TDP-43 pathology and evidence of TDP-43 changes at cholinergic C-boutons. We also observe no evidence of astrocytic pathology nor changes in the fraction of synapses that are contacted by astrocytes. Overall, our findings highlight the selective vulnerability of distinct synapse populations in ALS. Peer reviewe
Enhanced aperiodic threshold sensitive stable election protocol (EATSEP) for WSNs
Get PDFWireless sensor networks (WSNs) have emerged as vital technologies for safety-critical applications due to their flexibility, scalability, and reliability. However, existing models such as LEACH, SEP, and TSEP exhibit limitations in energy efficiency, stability, and adaptability to heterogeneous node conditions. To address these gaps, this research proposes a multilevel heterogeneity-based WSN model that optimizes cluster-head (CH) selection and energy utilization for enhanced network performance. Simulations were conducted in MATLAB under unequal energy level variations and compared with established protocols. Results demonstrate that the proposed model consistently outperforms existing approaches in terms of network lifetime, throughput, and energy efficiency. Statistical analysis reveals a best-case improvement of approximately 9000 rounds and a worst-case gain of about 3000 rounds when four heterogeneity levels are employed, compared to three levels. These findings highlight that both the degree of energy diversity and the distribution of energy nodes across levels are crucial for achieving optimal performance. Overall, the proposed architecture significantly enhances reliability, stability, and energy efficiency, making it well-suited for disaster management and other safety-critical applications.Peer reviewe
Volcanism and carbon cycle perturbations in the High Arctic during the Late Jurassic – Early Cretaceous
Get PDFFunding: Funding for fieldwork for this study was provided by a Ph.D. scholarship from the University of Plymouth, U.K. with additional funding to MLV for field campaigns to sample the Lower Cretaceous of Festningen from the Geological Society, London, UK (Gloyne Outdoor Geological Research fund, 2014); to MLV, MEJ and IM from the National Geographic Society's Committee for Research and Exploration grant number CP-038R-17; and to MLV from The British Sedimentological Research Group Gill Harwood Memorial Fund (2015), and an American Association of Petroleum Geologists grant-in-aid (William E. Gipson Named Grant, 2015). Field work to collect samples from the uppermost Jurassic-lowermost Cretaceous portion of the Festningen section was supported by Bundesanstalt für Geowissenschaften und Rohstoffe (BGR) [Federal Institute for Geosciences and Natural Resources] under the Circum-Arctic Structural Events (CASE) program in 2015 (lead Dr. Karsten Piepjohn). Collections were made by JMG with assistance from SG and LR. Canadian field work was supported by the GeoMapping for Energy and Minerals (GEM) Program (Natural Resources Canada, Geological Survey of Canada) with funding to JMG. Mercury, elemental, and sequential pyrolysis of the samples from the uppermost Jurassic-lowermost Cretaceous portions of the Festningen section were funded by a AIAS-COFUND II fellowship programme supported by the Marie Skłodowska-Curie actions under the European Commission's Horizon 2020 (grant agreement no. 754513) and the Aarhus University Research Foundation to JMG (2019-2020). This grant also financially supported Hg analysis of the Kvalvågen section. Funding was also provided for this study by the European Commission, Horizon 2020 (ICECAP; grant no. 101024218, to MLV), and from the Research Council of Norway through the Centres of Excellence funding scheme, project number 223272. Further funding was provided by the Danish Council for Independent Research–Natural Sciences (project DFF-7014-00142), to CK.; the Canada Research Chairs program to FW. Mercury analyses at the University of Oxford were supported by the Leverhulme Trust and Natural Environment Research Council Grant NE/G01700X/1 and ERC consolidator Grant (ERC-2018-COG-818717-V-ECHO) (to TAM) and PhD studentship NE/L501530/1 (to LMEP).Large perturbations in the global carbon cycle recorded as carbon-isotope (δ13C) excursions (CIEs) in both organic carbon and carbonate records have been linked to volcanism during the emplacement of Large Igneous Provinces (LIPs). This link is based primarily on the purported temporal coincidence between CIEs and LIP emplacement. Mercury (Hg) concentration in sedimentary rocks has been used as a regional to global tracer of large-scale volcanic activity, yet few studies have been undertaken on Upper Jurassic – Lower Cretaceous sediments from Boreal localities compared to those for Tethyan (northern mid-latitude) successions. This has limited our understanding of the regional-to-global spatial impact of volcanic activity during this period. This study examines the Hg record as a proxy for volcanism, and the δ13C records from organic matter (δ13Corg) of CIEs from the uppermost Jurassic to Lower Cretaceous (Callovian – Aptian) successions from Axel Heiberg and Spitsbergen in the Canadian Arctic and Svalbard archipelagos, respectively. This interval includes three regional- to global CIEs. These sections show no significant variation in the ratio of Hg to total organic carbon (TOC) across the Boreal-wide Volgian negative CIE (Volgian Isotopic Carbon Excursion, “VOICE”), which has not been associated with LIP volcanism. The examined successions spanning this interval all show some influence from changing environmental or post-burial parameters, however, which could have (partially) overprinted a volcanic signal. Despite some problems in stratigraphically constraining the Weissert Event, increased Hg/TOC ratios are observed across this interval, which may be partially driven by volcanism associated with the emplacement of the Paraná-Etendeka Traps. A spike in Hg/TOC is observed immediately prior to the negative peak of the Aptian Oceanic Anoxic Event (OAE1a) CIE, supporting recent evidence of a pulse of High Arctic Large Igneous Province (HALIP) volcanic activity preceding this oceanic anoxic event.Peer reviewe
The influence of creeping slope failure on turbidity current behaviour
Get PDFFunding: This work was funded by the Natural Environment Research Council (NERC) as part of the Centre for Doctoral Training (CDT) programme.Erosional scars, slumps, slides and debrites (mass-transport deposits) on submarine slopes form relief that influences turbidity current behaviour. However, the interaction of mass-transport deposit emplacement kinematics (i.e. rapid emplacement versus creep), the morphology of the evolving seafloor topography and subsequent flow types is complicated. This study describes two outcrop examples of deep-water, predominantly turbiditic, deposits overlying mass-transport deposits, from the Eocene slope succession of the Aínsa Basin (Spanish Pyrenees). In both examples, the mass-transport deposit substrate continued to creep contemporaneously with turbidity current deposition and bypass. In the first case study, structures in the mass-transport deposits are extensional and oriented parallel to flow. In the second, structures are compressional and oriented perpendicular to flow. Mudstones dominate the slope succession, but deposits overlying mass-transport deposits form sandstone-prone accumulations. Lateral confinement by flow-parallel extensional faults enhanced channel-formation. Channel incision occurred close to the exhumed fault plane on the hangingwall. Incision ceased as the fault gradually locked-up, and channels avulsed to the hangingwall of a newly active normal fault, while the abandoned channel was filled by a thinning and fining-upward succession. Barriers formed where the long axes of compressional anticlines developed in mass-transport deposits formed perpendicular to flow. Here, turbidites filled the bathymetric lows in the axes of synclines. Continued tightening of synclinal depocentres led to repeated stoss side trapping and upslope accretion of coarse-grained sediment accumulation. This generated thickening and coarsening-up, followed by thinning and fining-upward successions, tracking the decreasing, then increasing flow bypass associated with topographic expression on the mass-transport deposit. This study shows how post-emplacement creep, and orientation of topographic features on mass-transport deposits, influence the routing and deposition of contemporaneous turbidity currents, and illustrates examples of facies successions that could be misinterpreted as the product of other autogenic submarine slope processes, such as lateral migration of sinuous channels, or compensational lobe stacking.Peer reviewe
Early Cretaceous giant glendonites : a record of (sub-)millennial-scale cooling?
Get PDFFunding: This work was funded by the Kempe foundation grant HotSeas (grant number JCSMK23–0220) to Morgan T. Jones; the European Commission, Horizon 2020 project ICECAP; grant no. 101024218 to Madeleine L. Vickers, and the Research Council of Norway through the Centres of Excellence funding scheme (project no. 332523, PHAB). Morgan T. Jones is also supported by the PETROMAKS programme from The Research Council of Norway, with the RCN project number 336293 (PALMAR). Mads E. Jelby gratefully acknowledges the Carlsberg Foundation for funding an Internationalisation Fellowship (grant number CF22–0122) during which this work was partly undertaken. Maria A. Jensen received support from the Svalbard Science Forum programme of The Research Council of Norway, with the RCN project number 337325.The Lower Cretaceous succession in Svalbard contains numerous glendonites, pseudomorphs after the cold-water carbonate mineral ikaite, which have been used in conjunction with other evidence to argue for episodic global cooling punctuating the greenhouse climates of the Early Cretaceous. Recent fieldwork in central Spitsbergen has recovered giant bladed glendonites of up to half a metre long, the largest ever recorded in a Lower Cretaceous site, and comparable in size to outlier glendonites found in similar-aged strata of the Sverdrup Basin in Arctic Canada. Unlike the rosette to pineapple-like morphologies seen in some of the largest Canadian Arctic specimens, the new finds in Svalbard appear only as single or crossed blades. These large glendonites, found clo indicate that very local variations in pore water chemistry governed whether numerous small ikaite crystals or few large crystals grew. Taken with evidence from modern ikaite and other large ancient glendonites, we argue that large glendonites such as these (>30 cm long) are pseudomorphs after ikaites that took, at the shortest, decades, but potentially millennia to even tens of millennia to attain their massive size. As growth of the parent ikaite took place in the sediments just below the seafloor of the shallow, epicontinental seas of the High Arctic (then situated at c. 63–66°N), this is consistent with the hypothesis that geologically short-term cooling episodes interrupted the background warmth of the Early Cretaceous greenhouse, although the duration, extent, and cause of such cooling is still debated.Peer reviewe
Contemporary poetic responses to John Clare in the British Isles, 1966-present
No full textThis study explores John Clare’s poetic reception in the British Isles from 1966 to the present, acknowledging that, since the publication of his first collection, Poems Descriptive of Rural Life and Scenery (1821), Clare’s work has existed in a matrix of poetic exchanges. Within such poetic exchanges (with, for example, Eliza Emmerson, and John Taylor), Clare’s work has generated diverse creative responses. Later twentieth-century poet-editors Arthur Symons and Edmund Blunden have contributed significantly to the twentieth-century revival of Clare. Their editions of Clare – Poems, by John Clare (1907) and Poems, Chiefly from Manuscript (1920), respectively – are driven by their own critical and creative conceptions of Clare, which recent work by Stephanie Kuduk Weiner has viewed in dynamic relationship.
Influenced by Kuduk Weiner’s methodology, this study argues that post-war critical conceptions of Clare are fundamentally shaped by poetic responses to Clare in the British Isles, given the editorial and critical influence these poets have necessarily exerted. In two parts, my thesis configures two principal streams within Clare’s reception history. In Part One, following Mina Gorji and Jonathan Bate, this thesis studies Seamus Heaney’s extensive creative and critical relationship with Clare. The study’s chronology commences with the publication of Heaney’s first collection, Death of a Naturalist (1966), which marks his seminal response to Clare grounded in the pastoral tradition and in traditional poetic form. It identifies recent examples of this stream of influence in Scotland, in the work of John Burnside and Kathleen Jamie, in the first chapter, and in England, in Paul Farley and James Fenton, in the second chapter. In Part Two, the thesis moves to Iain Sinclair’s contrasting “open-field” understanding of Clare, and positions Tom Raworth, Wendy Mulford within this stream of influence in the third chapter, along with Elizabeth-Jane Burnett and Maggie O’Sullivan in the fourth chapter
Synthesis and investigation of phosphorus peri-substituted acenaphthenes
No full textThe work presented in this thesis builds upon previous investigations by the Kilian group into dealkacoupling reactions of phosphorus peri-substituted acenaphthenes. The focus of this thesis was to investigate the effect of introducing different aryl substituents into the peri region on dealkacoupling and to determine the switching behaviour of these compounds. The effect of introducing other pnictogens (As, Sb) was also investigated.
Previously the Kilian group has reported a novel method for the synthesis of ferrocenyl and dichloroferrocenylphosphine via a dithiadiphosphetane. This synthetic route was expanded beyond ferrocene to allow access to both novel and known primary/dichlorophosphines in good yields and without the need for purification.
A series of novel bis(phosphine) peri-substituted acenaphthene compounds with aryl substituents bearing differing steric and electronic properties was synthesised. These compounds were investigated for their ability to undergo dealkacoupling under conditions previously used by the Kilian group (75°C in the presence of a radical initiator (AIBN) and by exposure to sunlight). Results from both the thermal and light induced dealkacoupling reactions indicate that sterics play an important role as a greater steric profile may impede any free rotation necessary. In addition, light induced dealkacoupling reactions revealed the formation of both cis and trans isomers in varying ratios dependant on the nature of the aryl substituent. Introduction of arsenic into the peri region showed favourable results with dramatic reductions in reaction time compared with comparable P/P systems. P/Sb peri-substituted compounds displayed interesting reactivity forming Sb-Sb bonds through dehydrocoupling and the double activation of C-Cl bonds in DCM, which has never been seen in peri-substituted acenaphthenes previously.
Investigations into the molecular switching behaviour of the P/P and P/As systems demonstrated that peri-substituted acenaphthenes do possess molecular switch like properties. The effectiveness of these compounds as molecular switches relies heavily on the nature of the substituents, with low steric profile high electron rich moieties giving the most favourable results. Interestingly, the P/As system showed improved switching properties in comparison to the P/P. Full conversion to the relevant cis isomers was unfortunately not achieved and this should be an area of significant research in the future
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