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Predicting the final embedment depth of a dynamically installed anchor is a key prerequisite for reliable calculation of anchor capacity. This paper investigates the embedment characteristics of dynamically installed anchors in normally consolidated and overconsolidated clay through a series of centrifuge tests involving a model anchor instrumented with a microelectric mechanical system (MEMS) accelerometer, enabling the full motion response of the anchor to be established. The data are used to assess the performance of an anchor embedment model based on strain-rate- dependent shearing resistance and fluid mechanics drag resistance. Predictions of a database of over 100 anchor installations--formed from this study and the literature--result in calculated anchor embedment depths that are within [+ or - ]15% of the measurements. An interesting aspect, consistent across the entire database, relates to the strain rate dependence on frictional resistance relative to bearing resistance. The predictions reveal that strain rate dependency may indeed be higher for frictional resistance, although only if a soil strength lower than the fully remoulded strength is considered as the reference strength, which suggests that water may be entrained along a boundary layer at the anchor-soil interface during installation. Key words: dynamically installed anchor, microelectric mechanical system (MEMS), soft soil, centrifuge modelling. Predire la profondeur d'enrobage finale d'un ancrage installe dynamiquement est une condition prealable essentielle pour un calcul fiable des capacites d'ancrage. Cet article etudie les caracteristiques d'enrobage des ancrages installes dynamiquement dans des argiles consolidees normalement et sur consolides par une serie d'essais centrifuge mettant en cause un ancrage modele instrumente avec un accelerometre mecanique du systeme microelectrique (MSME), activant la reponse de mouvement complet de l'ancrage a etablir. Les donnees sont utilisees pour evaluer la performance d'un modele d'enrobage d'ancrage base sur la resistance au cisaillement dependante de la deformation et du taux et la resistance a la trainee mecanique des fluides. Les predictions d'une base de donnees de plus de 100 installations d'ancrages, formes a partir de cette etude et de la litterature, aboutissent dans des profondeurs d'enrobage d'ancrage calcule qui se retrouvent a l'interieur de ±15 % des mesures. Un aspect interessant, coherent dans l'ensemble de la base de donnees entiere se rapporte a la dependance de taux de deformation sur la resistance de frottement par rapport a la resistance de roulement. Les predictions revelent que la dependance du taux de deformation peut en effet etre plus elevee pour la resistance de frottement, bien que seulement si une resistance du sol inferieure a la resistance entierement remaniee est consideree comme etant la resistance de reference, ce qui suggere que l'eau peut etre entrainee le long d'une couche limite a l'interface ancrage-sol lors de l'installation. [Traduit par la Redaction] Mots-cles: ancrage installe dynamiquement, mecanique du systeme microelectrique (MSME), sol mou, modelisation a centrifuge., Introduction The shift of oil and gas operations towards more remote locations, often in deeper water, tends to increase the costs associated with installing the anchors and laying the moorings. [...]

The capacity of dynamically installed anchors in soft normally consolidated clay was examined experimentally through a series of field tests on a 1:20 reduced-scale anchor. The anchors were installed through free fall in water, achieving tip embedment of 1.5-2.6 times the anchor length, before being loaded under undrained conditions at various load inclinations. Vertical anchor capacities were between 2.4 and 4.1 times the anchor dry weight and were satisfactorily predicted using the American Petroleum Institute approach for driven piles. Anchor capacity under inclined loading increased as the load inclination approached horizontal; the field data indicated this increase to be up to 30% for the minimum achievable inclination of about 20° to the horizontal. Corresponding large-deformation finite element analyses showed a similar response, with the maximum capacity occurring at a load inclination between 30° and 45° to the horizontal. The finite element results demonstrate that, for the anchor geometry considered, an inclined load at the anchor padeye could be decomposed into ultimate vertical and moment loading at the anchor centroid. The establishment of a vertical and moment loading yield envelope for the geometry investigated forms the basis of a simple design procedure presented in the paper. Key words: dynamically installed anchor, field tests, capacity, finite element method. Resume: La capacite de charge d'ancres installees de maniere dynamique dans de l'argile plastique normalement consolidee a ete etudiee de facon experimentale par le biais d'une serie d'essais realises sur une ancre a echelle reduite 1:20. Les ancres ont ete mises en place en effectuant une chute libre dans l'eau, l'encastrement de l'extremite etant compris entre 1,5 et 2,6 fois la longueur de l'ancre, puis ont ete soumis a des charges dans des conditions detrempees selon differents angles d'inclinaison. La capacite de charge verticale des ancres equivalait a 2,4 a 4,1 fois le poids sec de ces dernieres et a pu etre predite de maniere satisfaisante par la methode de l'American Petroleum Institute pour les pieux battus. La capacite de charge des ancres soumises a une charge inclinee a augmente lorsque son angle par rapport a l'horizontale s'est approche de zero. Les donnees de terrain ont montre que cette augmentation pouvait atteindre 30 % pour un angle d'inclinaison minimale possible d'environ 20° par rapport a l'horizontale. Les analyses par elements finis correspondantes, appliquees aux deformations importantes, ont donne un resultat similaire, la capacite de charge maximale etant atteinte pour un angle d'inclinaison de charge compris entre 30° et 45° par rapport a l'horizontale. Les resultats des analyses par elements finis ont revele que, pour la geometrie d'ancre consideree, une charge inclinee appliquee au niveau du piton de fixation de l'ancre pouvait etre decomposee en une charge verticale ultime et une charge de moment au centre de masse de l'ancre. L'etablissement d'une enveloppe de plasticite associee a une charge verticale et une charge de moment, dans le cas de la geometrie etudiee, forme labase du mode de conception simple qui est decrit dans le present article. [Traduit par la Redaction] Mots-cles: ancre installee de maniere dynamique, essais sur le terrain, capacite de charge, methode des elements finis., Introduction Dynamically installed anchors are rocket or torpedo shaped and are installed by allowing the anchor to free fall from a designated height above the seabed (see Fig. 1). Since [...]

Drug resistance observed with many anti-infectives clearly highlights the need for new broad-spectrum agents to treat especially neglected tropical diseases (NTDs) caused by eukaryotic parasitic pathogens, including fungal infections. Herein, we show that the simple modification of one of the most well-known antifungal drugs, fluconazole, with organometallic moieties not only improves the activity of the parent drug but also broadens the scope of application of the new derivatives. These compounds were highly effective in vivo against pathogenic fungal infections and potent against parasitic worms such as Brugia , which causes lymphatic filariasis and Trichuris , one of the soil-transmitted helminths that infects millions of people globally. Notably, the identified molecular targets indicate a mechanism of action that differs greatly from that of the parental antifungal drug, including targets involved in biosynthetic pathways that are absent in humans, offering great potential to expand our armamentarium against drug-resistant fungal infections and neglected tropical diseases (NTDs) targeted for elimination by 2030.

The ongoing SARS-CoV-2 pandemic has caused a high demand for novel innovative antiviral drug candidates. Despite promising results, metal complexes have been relatively unexplored as antiviral agents in general and in particular against SARS-CoV-2. Here we report on silver NHC complexes with chloride or iodide counter ligands that are potent inhibitors of the SARS-CoV-2 papain-like protease (PL pro ) but inactive against 3C-like protease (3CL pro ) as another SARS-CoV-2 protease. Mechanistic studies on a selected complex confirmed zinc removal from a zinc binding domain of PL pro as relevant factor of their activity. In addition, enzyme kinetic experiments revealed that the complex is an uncompetitive inhibitor and with this rare type of inhibition it offers great pharmacological advantages in terms selectivity. The silver NHC complexes with iodide ligands showed very low or absent host cell toxicity and triggered strong effects on viral replication in cells infected with SARS-CoV-2, making them promising future antiviral drug candidates., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

The urgent need to combat antibiotic resistance and develop novel antimicrobial therapies has triggered studies on novel metal-based formulations. N -heterocyclic carbene (NHC) complexes coordinate transition metals to generate a broad range of anticancer and/or antimicrobial agents, with ongoing efforts being made to enhance the lipophilicity and drug stability. The lead silver(I) acetate complex, 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) (SBC3), has previously demonstrated promising growth and biofilm-inhibiting properties. In this work, the responses of two structurally different bacteria to SBC3 using label-free quantitative proteomics were characterised. Multidrug-resistant Pseudomonas aeruginosa (Gram-negative) and Staphylococcus aureus (Gram-positive) are associated with cystic fibrosis lung colonisation and chronic wound infections, respectively. SBC3 increased the abundance of alginate biosynthesis, the secretion system and drug detoxification proteins in P. aeruginosa , whilst a variety of pathways, including anaerobic respiration, twitching motility and ABC transport, were decreased in abundance. This contrasted the affected pathways in S. aureus , where increased DNA replication/repair and cell redox homeostasis and decreased protein synthesis, lipoylation and glucose metabolism were observed. Increased abundance of cell wall/membrane proteins was indicative of the structural damage induced by SBC3 in both bacteria. These findings show the potential broad applications of SBC3 in treating Gram-positive and Gram-negative bacteria.

The antimicrobial properties of silver have been exploited for many centuries and continue to gain interest in the fight against antimicrobial drug resistance. The broad-spectrum activity and low toxicity of silver have led to its incorporation into a wide range of novel antimicrobial agents, including N-heterocyclic carbene (NHC) complexes. The antimicrobial activity and in vivo efficacy of the NHC silver(I) acetate complex SBC3, derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*), have previously been demonstrated, although the mode(s) of action of SBC3 remains to be fully elucidated. Label-free quantitative proteomics was applied to analyse changes in protein abundance in the pathogenic yeast Candida parapsilosis in response to SBC3 treatment. An increased abundance of proteins associated with detoxification and drug efflux were indicative of a cell stress response, whilst significant decreases in proteins required for protein and amino acid biosynthesis offer potential insight into the growth-inhibitory mechanisms of SBC3. Guided by the proteomic findings and the prolific biofilm and adherence capabilities of C. parapsilosis, our studies have shown the potential of SBC3 in reducing adherence to epithelial cells and biofilm formation and hence decrease fungal virulence., (© The Author(s) 2022. Published by Oxford University Press.)

Antibiotic resistance is a growing problem for public health and associated with increasing economic costs and mortality rates. Silver and silver-related compounds have been used for centuries due to their antimicrobial properties. In this work, we show that 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver(I) acetate/NHC*-Ag-OAc (SBC3) is a reversible, high affinity inhibitor of E. coli thioredoxin reductase (TrxR; K i =10.8±1.2 nM). Minimal inhibition concentration (MIC) tests with different E. coli and P. aeruginosa strains demonstrated that SBC3 can efficiently inhibit bacterial cell growth, especially in combination with established antibiotics like gentamicin. Our results show that SBC3 is a promising antibiotic drug candidate targeting bacterial TrxR., (© 2020 Wiley-VCH GmbH.)

N-heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesized virulence targeting substituents into NHC-silver systems via salt metathesis, an atom-efficient complexation process can be used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process. Biological evaluation was conducted with in vitro toxicology assays showing these novel complexes had excellent inhibition against Gram-negative strains E. coli, P. aeruginosa, and K. pneumoniae; further studies also confirmed the ability to inhibit biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA) and C. Parapsilosis. In vivo testing using a murine thigh infection model showed promising inhibition of MRSA for the lead compound SBC3, which is derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*)., (© The Author(s) 2020. Published by Oxford University Press.)

Objective: The objective of this review is to characterize the experiences of Widening Participation students in undergraduate medical education in the United Kingdom (UK)., Introduction: Most Widening Participation research in the UK is focused on medical school recruitment. Although this is important, there is a paucity of research examining whether the experience of medical school itself is an equal experience for both traditional and Widening Participation students. The aim of this review is to explore and to characterize the experiences of Widening Participation students within medical education during their studies in the UK., Inclusion Criteria: This review will include qualitative research conducted in the UK examining any aspect of the lived experience of undergraduate medical education according to Widening Participation students, including identity formation, learning experience in pre-clinical environments and clinical placements, and the relation to social, cultural, and financial capital., Methods: The study will consider articles found through searching the databases MEDLINE, PubMed, Web of Science, CINAHL, Embase, PsycINFO, and ERIC, as well as gray literature. Studies published from 2000 onwards in the English language will be included. Studies will be assessed against the inclusion criteria at all stages by two independent reviewers. Eligible studies will be critically appraised for methodological quality. Regardless of methodological quality, all studies retrieved will be included in the review. The final synthesized findings will be graded according to the ConQual approach., Systematic Review Registration Number: Submitted and awaiting registration on PROSPERO (ID 167879)., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 JBI.)

The anticancer drug candidates 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative exhibited nanomolar in-vitro activity against prostate cancer cells advanced prostate cancer (PC3) and micromolar inhibition of mammalian thioredoxin reductase. Encouraging maximum tolerable dose experiments led to human prostate cancer subcutaneous xenograft experiments; 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative were applied twelve times at two doses in groups of n = 5 PC3 to tumor-bearing NMRI:nu/nu mice. 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative at the dose of 10 and 20 mg/kg showed good tolerability, while no significant body weight loss was seen in both groups. In particular, for the drug 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate the tumor growth inhibition suggested to be dose dependent, reflected by the respective optimal T/C values of 0.45 at the dose of 10 mg/kg and of 0.31 at the dose of 20 mg/kg. By contrast, the 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative treated groups showed no indication for dose-dependent antitumoral activity, as reflected by the optimal T/C values of 0.44 for the 10 mg/kg and for the 20 mg/kg treated mice. Immunohistochemical experiments involving Ki67 staining of tumor tissue showed that both compounds reduced PC3 cell proliferation against the difficult to treat advanced human prostate tumors derived from PC3.

This was an observational study investigating the efficacy and side effects associated with ulipristal acetate (UPA), a progesterone receptor modulator, and the possible benefits to women who have co-existing pre-menstrual syndrome (PMS). 80 women returned a questionnaire on the bleeding, menstrual pain and side effects, and changes on PMS were recorded. 67 women (84%) showed improvement in their menses. 54 women (67%) became amenorrhoeic. Of those, 67% were within 10 days of commencing UPA. Menses returned in 33 amenorrhoeic women within 4 weeks of stopping UPA. 58 women (70%) reported an improvement in their pain score but 41 women had a return of their pain after stopping UPA. The majority of the women had no or infrequent side effects. 80% had demonstrable improvement in their PMS symptoms. UPA is effective in controlling symptoms due to uterine fibroids with infrequent side effects. Our data also showed new evidence of a concurrent dramatic improvement in PMS in these women. Impact statement The observational study explored the drug profile of ulipristal acetate (UPA), a selective progesterone receptor modulator, which has been licenced as pre-treatment for surgical therapies of fibroids since 2012. We aimed to investigate the efficiency and side effects of UPA. Since the introduction of UPA in clinical practice, there has yet to be a study looking at the drug profile outside a research setting. We have also decided to investigate the effect of UPA on pre-menstrual syndrome (PMS) in this group of women with symptomatic fibroids. As such this case report should be of interest to a broad readership including those interested in the medical management of symptomatic fibroids.

Gold monochloride and monobromide can be transformed into monomeric complexes by ligands such as CO, PPh 3 or Me 2 S, and such ligand-stabilized gold monochloride compounds have been investigated as catalysts, luminescent materials and anticancer drugs, especially when coordinated to a lipophilic benzyl-substituted N-heterocyclic carbene (NHC) ligand. The triclinic structures of NHC-Au-Cl {chlorido(1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene)gold, [AuCl(C 29 H 24 N 2 )]} and NHC-Au-Br {bromido(1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene)gold, [AuBr(C 29 H 24 N 2 )]}, determined by X-ray crystallography at 100 K, have one and four molecules, respectively, in their asymmetric units. The chloride compound shows an almost linear C-Au-Cl fragment [179.76 (8)°], with an Au-C distance of 1.976 (3) Å and an Au-Cl distance of 2.3013 (6) Å, while the bromide compound shows surprisingly large geometry deviations, from 1.969 (12) to 2.016 (10) Å for the Au-C distance and from 2.4279 (14) to 2.4796 (12) Å for the Au-Br distance, in the four independent molecules.

Objective: To determine whether differences exist in the rates of obstetric intervention between women with type 1 diabetes and those with type 2 diabetes, and whether there has been any change in cesarean rates over time, paralleling that seen in the general obstetric population., Methods: Data were examined from a prospectively collected series on the outcomes of 1030 deliveries (382 by women with type 1 diabetes, 648 by women with type 2 diabetes) from 1988 to 2008., Results: There was a secular trend to increasing maternal age (type 1, P < 0.003; type 2, P < 0.03). Intervention rates (induction of labor or elective cesarean) did not differ between type 1 (88%) and type 2 (85%) diabetes. The overall cesarean rate was 52%-55% with no secular trend. Poorer glycemic control in early pregnancy and primiparity were associated with primary cesarean in both groups. In women with type 1 diabetes, greater maternal obesity and retinopathy were also associated with primary cesarean., Conclusion: Intervention rates are high in pregnancies among women with type 1 diabetes and those with type 2 diabetes but they have not changed significantly. Secular trends toward increasing maternal age and obesity suggest that intervention rates are unlikely to decrease in the near future., (© 2013.)

Aims: The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies: the asthma/rhinitis care pathway is the third such pathway. Asthma and rhinitis have been considered together. These conditions co-exist commonly, have remarkably similar immuno-pathology and an integrated management approach benefits symptom control., Method: The asthma/rhinitis pathway was developed by a multidisciplinary working group and was based on a comprehensive review of evidence. The pathway was reviewed by a broad group of stakeholders including the public and was approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee., Results: The pathway entry points are defined by symptom type and severity at presentation. Acute severe rhinitis and life-threatening asthma are presented as distinct entry routes to the pathway, recognising that initial care of these conditions requires presentation-specific treatments. However, the pathway emphasises that ideal long term care should take account of both conditions in order to achieve maximal improvements in disease control and quality of life., Conclusions: The pathway recommends that acute presentations of asthma and/or rhinitis should be treated separately. Where both conditions exist, ongoing management should address the upper and lower airways. The authors recommend that this pathway is implemented locally by a multidisciplinary team (MDT) with a focus on creating networks. The MDT within these networks should work with patients to develop and agree on care plans that are age and culturally appropriate.

Bloodstream forms of Trypanosoma brucei, when aggregated in the presence of either acute immune plasma, acute immune serum, purified IgM anti-VSG antibodies or purified IgG anti-VSG antibodies, subsequently disaggregated with a t1/2 for disaggregation of 15 min at 37 degrees C as long as the trypanosomes were metabolically active at the beginning of the experiment and maintained during the experiment in a suitable supporting medium. The t1/2 for disaggregation was found to be directly dependent upon temperature and inversely proportional to the antibody concentration. The trypanosomes were always motile and metabolically active during aggregation and after disaggregation and were fully infective for a mammalian host following disaggregation as well as able to grow and divide normally during axenic culture. The disaggregation was strictly energy dependent and was inhibited when intracellular ATP levels were reduced by salicylhydroxamic acid or following addition of oligomycin while respiring glucose. In addition the process of disaggregation was dependent upon normal endosomal activity as evidenced by its sensitivity to a wide variety of inhibitors of various endosomal functions. Disaggregation was not due to separation of immunoglobulin chains by either disulphide reduction or disulphide exchange reactions and gross proteolytic cleavage of the immunoglobulins attached to the surface of the parasite was not detected. In addition, gross cleavage or release of the VSG from the surface of the cell did not occur during disaggregation but proteolytic cleavage of a small proportion of either the VSG or the immunoglobulins could not be eliminated from consideration. Finally the mechanism of disaggregation was found to be a regulated process, independent of Ca2+ movements but dependent upon the activity of protein kinase C or related kinases and inhibited by the activity of protein kinase A as evidenced by the effects of a panel of inhibitors and cAMP analogues on the process of disaggregation. The mechanism of disaggregation displayed by trypanosomes aggregated by anti-VSG antibody is proposed to form part of the parasite's defence against the host immune system and functions to aid survival of trypanosomes in the presence of antibody in the host prior to the occurrence of a VSG switching event.

Periampullary adenomas in the duodenum of Familial Adenomatous Polyposis (FAP) patients are among the most frequent and clinically important extracolonic neoplasms in FAP. The purpose of this study was to characterize the frequency and nature of somatic adenomatous polyposis coli (APC) gene and K-ras codon 12 mutations in periampullary adenomas and carcinomas in FAP. These molecular changes have been shown to be important during the early stages of colorectal carcinogenesis. DNA was prepared from endoscopic periampullary biopsies and paraffin blocks from 49 FAP patients. Of 143 samples, 77 were histologically normal, 29 were biopsies from small periampullary adenomas, 29 biopsies were from 19 large adenomas and eight samples were from periampullary cancers. APC mutations in the mutation cluster region and K-ras codon 12 mutations were detected by polymerase chain reaction based techniques. Somatic APC mutations consisting of deletions at codons 1464 and 1465 were detected in one small and two large periampullary adenomas. Loss of heterozygosity was seen in one periampullary carcinoma. K-ras codon 12 mutations were detected in seven of 19 large periampullary adenomas and in one of eight periampullary carcinomas. These data suggest that K-ras codon 12 mutations may be important during periampullary tumorigenesis in FAP but somatic APC mutations in the mutation cluster region are infrequent. Local environmental factors in the duodenum may contribute to differences in the molecular changes which occur during the adenoma-to-carcinoma sequence in periampullary compared to colonic tumorigenesis.