Visualizing tephra deposits and sedimentary processes in the marine environment: The potential of X‐ray microtomography

Localized tephra deposition in marine sequences is the product of many complex primary and secondary depositional processes. These can significantly influence the potential applicability of tephra deposits as isochronous marker horizons and current techniques, used in isolation, may be insufficient to fully unravel these processes. Here we demonstrate the innovative application of X-ray microtomography (µCT) to successfully identify tephra deposits preserved within marine sediments and use these parameters to reconstruct their internal three-dimensional structure. Three-dimensional visualizations and animations of tephra dispersal in the sediment permit a more thorough assessment of postdepositional processes revealing a number of complex microsedimentological features that are not revealed by conventional methods. These features include bioturbation burrows and horizontally discontinuous tephra packages, which have important ramifications for the stratigraphic placement of the isochron in a sedimentary sequence. Our results demonstrate the potential for utilizing rigorous two and three-dimensional microsedimentological analysis of the ichnofabric to enhance and support the use of tephra deposits as isochronous marker horizons and to identify the stratigraphic position that best reflects the primary fallout of ash. The application also provides an exceptional insight into the style and rate of sedimentation processes and permits an assessment of the stratigraphic integrity of a tephra deposit. We discuss the possibility of applying these µCT methods to the identification of cryptotephras within various paleoclimatic sequences and to enhance our understanding of marine sedimentation processes

Tracing marine cryptotephras in the North Atlantic during the last glacial period: Improving the North Atlantic marine tephrostratigraphic framework

Tephrochronology is increasingly being recognised as a key tool for the correlation of disparate palaeoclimatic archives, underpinning chronological models and facilitating climatically independent comparisons of climate proxies. Tephra frameworks integrating both distal and proximal tephra occurrences are essential to these investigations providing key details on their spatial distributions, geochemical signatures, eruptive sources as well as any available chronological and/or stratigraphic information. Frameworks also help to avoid mis-correlation of horizons and provide important information on volcanic history. Here we present a comprehensive chronostratigraphic framework of 14 tephra horizons from North Atlantic marine sequences spanning 60-25 cal ka BP. Horizons previously discovered as visible or coarse-grained deposits have been combined with 11 newly recognised volcanic deposits, identified through the application of cryptotephra identification and characterisation methods to a wide network of marine sequences. Their isochronous integrity has been assessed using their physical characteristics. All horizons originated from Iceland with the vast majority having a basaltic composition sourced from the Grímsvötn, Kverkfjöll, Hekla/Vatnafjöll and Katla volcanic systems. New occurrences, improved stratigraphic placements and a refinement of the geochemical signature of the NAAZ II are reported and the range of the FMAZ IV has been extended. In addition, several significant geochemical populations that further investigations could show to be isochronous are reported. This tephra framework provides the foundation for the correlation and synchronisation of these marine records to the Greenland ice-cores and European terrestrial records to investigate the phasing, rate, timing and mechanisms controlling rapid climate changes that characterised the last glacial period

The Role of Side Chains and Hydration on Mixed Charge Transport in <i>n</i> ‐Type Polymer Films

Introducing ethylene glycol (EG) side chains to a conjugated polymer backbone is a well‐established synthetic strategy for designing organic mixed ion‐electron conductors (OMIECs). However, the impact that film swelling has on mixed conduction properties has yet to be scoped, particularly for electron‐transporting (n‐type) OMIECs. Here, the authors investigate the effect of the length of branched EG chains on mixed charge transport of n‐type OMIECs based on a naphthalene‐1,4,5,8‐tetracarboxylic‐diimide‐bithiophene backbone. Atomic force microscopy (AFM), grazing‐incidence wide‐angle X‐ray scattering (GIWAXS), and scanning tunneling microscopy (STM) are used to establish the similarities between the common‐backbone films in dry conditions. Electrochemical quartz crystal microbalance with dissipation monitoring (EQCM‐D) and in situ GIWAXS measurements reveal stark changes in film swelling properties and microstructure during electrochemical doping, depending on the side chain length. It is found that even in the loss of the crystallite content upon contact with the aqueous electrolyte, the films can effectively transport charges and that it is rather the high water content that harms the electronic interconnectivity within the OMIEC films. These results highlight the importance of controlling water uptake in the films to impede charge transport in n‐type electrochemical devices

Selective αv integrin depletion identifies a core, targetable molecular pathway that regulates fibrosis across solid organs

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not existed. We report that Pdgfrb-Cre inactivates genes in murine HSCs with high efficiency. We used this system to delete the αv integrin subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Depletion of the αv integrin subunit in HSCs protected mice from CCl4-induced hepatic fibrosis, whereas global loss of αvβ3, αvβ5 or αvβ6 or conditional loss of αvβ8 on HSCs did not. Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of αv integrins using this system was also protective in models of pulmonary and renal fibrosis. Critically, pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated both liver and lung fibrosis, even when administered after fibrosis was established. These data identify a core pathway that regulates fibrosis, and suggest that pharmacological targeting of all αv integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases

Tracing marine cryptotephras in the North Atlantic during the last glacial period: Protocols for identification, characterisation and evaluating depositional controls

Tephrochronology is increasingly being utilised as a key tool for improving chronological models and correlating disparate palaeoclimatic sequences. For many sedimentary environments, however, there is an increased recognition that a range of processes may impart a delay in deposition and/or rework tephra. These processes can affect the integrity of tephra deposits as time-synchronous markers, therefore, it is crucial to assess their isochronous nature, especially when cryptotephras are investigated in a dynamic marine environment. A methodology for the identification and characterisation of marine cryptotephras alongside a protocol for assessing their integrity is outlined. This methodology was applied to a wide network of North Atlantic marine sequences covering the last glacial period. A diverse range of cryptotephra deposits were identified and, based on similarities in physical characteristics (e.g. glass shard concentration profiles and geochemical homogeneity/heterogeneity), indicative of common modes of tephra delivery and post depositional reworking, a deposit type classification scheme was defined. The presence and dominance of different deposit types within each core allowed an assessment of spatial and temporal controls on tephra deposition and preservation. Overall, isochronous horizons can be identified across a large portion of the North Atlantic due to preferential atmospheric dispersal patterns. However, the variable influence of ice-rafting processes and an interplay between the high eruptive frequency of Iceland and relatively lower sedimentation rates can also create complex tephrostratigraphies in this sector. Sites within a wide sector to the south and east of Iceland have the greatest potential to be repositories for isochronous horizons that can facilitate the synchronisation of palaeoclimatic records

Modelling climate and societal resilience in the Eastern Mediterranean in the last Millennium

This article analyses high-quality hydroclimate proxy records and spatial reconstructions from the Central and Eastern Mediterranean and compares them with two Earth System Model simulations (CCSM4, MPI-ESM-P) for the Crusader period in the Levant (1095–1290 CE), the Mamluk regime in Transjordan (1260–1516 CE) and the Ottoman crisis and Celâlî Rebellion(1580–1610 CE). During the three time intervals, environmental and climatic stress tested the resilience of complex societies.We find that the multidecadal precipitation and drought variations in the Central and Eastern Mediterranean cannot be explained by external forcings (solar variations, tropical volcanism); rather they were driven by internal climate dynamics. Our research emphasises the challenges, opportunities and limitations of linking proxy records, palaeoreconstructions and model simulations to better understand how climate can affect human history

Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL)

International audienceAbstractRare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP’s is realised

Targeting of alpha(v) integrin identifies a core molecular pathway that regulates fibrosis in several organs

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not existed. We report that Pdgfrb-Cre inactivates genes in murine HSCs with high efficiency. We used this system to delete the αv integrin subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Depletion of the αv integrin subunit in HSCs protected mice from CCl(4)-induced hepatic fibrosis, whereas global loss of αvβ3, αvβ5 or αvβ6 or conditional loss of αvβ8 on HSCs did not. Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of αv integrins using this system was also protective in models of pulmonary and renal fibrosis. Critically, pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated both liver and lung fibrosis, even when administered after fibrosis was established. These data identify a core pathway that regulates fibrosis, and suggest that pharmacological targeting of all αv integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS