Full field dependence of primary aberrations in perturbed double-plane symmetric systems with a circular pupil.

This paper deals with the theory of primary aberrations for perturbed double-plane symmetric optical systems consisting of a combination of tilted and decentered surfaces and a circular pupil. First, the analytical expressions describing the full field behavior of Zernike polynomials are derived from the fourth-order wavefront aberration function for this class of optical systems. Then, such expressions are combined to retrieve the full field dependence of primary coma, primary astigmatism, and field curvature. They are described by an elliptical conic-shaped surface with a variable apex location over the field of view, by a binodal surface with two nodes over the field of view, and by a general elliptical surface with one node. The proposed analytical expressions provide a better understanding of the primary aberration behavior for these systems and can be of great use in their optical design and aberration correction. An optical system constituted by a pair of tilted and decentered biconic lenses is studied to validate the proposed expressions.

Strained alkynes derived from 2,2'-dihydroxy-1,1'-biaryls; synthesis and copper-free cycloaddition with azides.

A series of strained alkynes were prepared from 2,2'-dihydroxy-biaryls. Several were characterised by X-ray crystallography, revealing strained C(sp)-C(sp)-C(sp3) bond angles in the range of 163-167°. Their cycloadditions with azides proceed without a catalyst. Functionalised versions of these reagents have potential applications to materials synthesis and bioconjugations.

Poplar woody taproot under bending stress: the asymmetric response of the convex and concave sides.

Background and Aims Progress has been made in understanding the physiological and molecular basis of root response to mechanical stress, especially in the model plant Arabidopsis thaliana, in which bending causes the initiation of lateral root primordia toward the convex side of the bent root. In the case of woody roots, it has been reported that mechanical stress induces an asymmetric distribution of lateral roots and reaction wood formation, but the mechanisms underlying these responses are largely unknown. In the present work, the hypothesis was tested that bending could determine an asymmetric response in the two sides of the main root axis as cells are stretched on the convex side and compressed on the concave side. Methods Woody taproots of 20 seedlings were bent to an angle of 90° using a steel net. Changes in the anatomy, lignin and phytohormone content and proteome expression in the two sides of the bent root were analysed; anatomical changes, including dissimilarities and similarities to those found in poplar bent woody stem, were also considered. Key Results Compression forces at the concave side of poplar root induced the formation of reaction wood which presented a high lignin content and was associated with the induction of cambium cell activity. Auxin seemed to be the main hormone triggering lignin deposition and cell wall strengthening in the concave sides. Abscisic acid appeared to function in the water stress response induced by xylem structures and/or osmotic alterations in the compression sides, whereas gibberellins may control cell elongation and gravitropisms. Conclusions Poplar root reaction wood showed characteristics different from those produced in bent stem. Besides providing biomechanical functions, a bent root ensures water uptake and transport in the deforming condition induced by tension and compression forces by two different strategies: an increase in xylem thickness in the compressed side, and lateral root formation in the tension side.

Mechanistic studies into amine-mediated electrophilic arene borylation and its application in MIDA boronate synthesis.

Direct electrophilic borylation using Y(2)BCl (Y(2) = Cl(2) or o-catecholato) with equimolar AlCl(3) and a tertiary amine has been applied to a wide range of arenes and heteroarenes. In situ functionalization of the ArBCl(2) products is possible with TMS(2)MIDA, to afford bench-stable and easily isolable MIDA-boronates in moderate to good yields. According to a combined experimental and computational study, the borylation of activated arenes at 20 °C proceeds through an S(E)Ar mechanism with borenium cations, [Y(2)B(amine)](+), the key electrophiles. For catecholato-borocations, two amine dependent reaction pathways were identified: (i) With [CatB(NEt(3))](+), an additional base is necessary to accomplish rapid borylation by deprotonation of the borylated arenium cation (σ complex), which otherwise would rather decompose to the starting materials than liberate the free amine to effect deprotonation. Apart from amines, the additional base may also be the arene itself when it is sufficiently basic (e.g., N-Me-indole). (ii) When the amine component of the borocation is less nucleophilic (e.g., 2,6-lutidine), no additional base is required due to more facile amine dissociation from the boron center in the borylated arenium cation intermediate. Borenium cations do not borylate poorly activated arenes (e.g., toluene) even at high temperatures; instead, the key electrophile in this case involves the product from interaction of AlCl(3) with Y(2)BCl. When an extremely bulky amine is used, borylation again does not proceed via a borenium cation; instead, a number of mechanisms are feasible including via a boron electrophile generated by coordination of AlCl(3) to Y(2)BCl, or by initial (heteroarene)AlCl(3) adduct formation followed by deprotonation and transmetalation.

The hydride-ion affinity of borenium cations and their propensity to activate H2 in frustrated Lewis pairs.

A range of frustrated Lewis pairs (FLPs) containing borenium cations have been synthesised. The catechol (Cat)-ligated borenium cation [CatB(PtBu(3))](+) has a lower hydride-ion affinity (HIA) than B(C(6)F(5))(3). This resulted in H(2) activation being energetically unfavourable in a FLP with the strong base PtBu(3). However, ligand disproportionation of CatBH(PtBu(3)) at 100 °C enabled trapping of H(2) activation products. DFT calculations at the M06-2X/6-311G(d,p)/PCM (CH(2)Cl(2)) level revealed that replacing catechol with chlorides significantly increases the chloride-ion affinity (CIA) and HIA. Dichloro-borenium cations, [Cl(2)B(amine)](+), were calculated to have considerably greater HIA than B(C(6)F(5))(3). Control reactions confirmed that the HIA calculations can be used to successfully predict hydride-transfer reactivity between borenium cations and neutral boranes. The borenium cations [Y(Cl)B(2,6-lutidine)](+) (Y = Cl or Ph) form FLPs with P(mesityl)(3) that undergo slow deprotonation of an ortho-methyl of lutidine at 20 °C to form the four-membered boracycles [(CH(2){NC(5)H(3)Me})B(Cl)Y] and [HPMes(3)](+). When equimolar [Y(Cl)B(2,6-lutidine)](+)/P(mesityl)(3) was heated under H(2) (4 atm), heterolytic cleavage of dihydrogen was competitive with boracycle formation.

A qualitative exploration of undergraduate nursing students' experience of emotional safety for learning during their clinical practice.

BACKGROUND: During their clinical practice, nursing students learn to manage patient safety through their experiences, emotions, and interpersonal relationships. OBJECTIVES: To explore contextual and mechanistic factors that facilitate a sense of emotional safety for learning in nursing students, particularly regarding patient safety events experienced during their placements. DESIGN: A descriptive qualitative study using narratives and thematic analysis. SETTINGS: A university in Northern Italy. PARTICIPANTS: Undergraduate nursing students recruited through purposive sampling. METHODS: Twenty cases relevant to the present study were selected from the "Sharing LearnIng from Practice for Patient Safety" (SLIPPS) project database containing 100 narratives collected using the patient safety learning Event Recording Tool. The data were analysed using thematic analysis according to Braun & Clarke's methodology. The themes that emerged from the thematic analysis were rearranged in Context-Mechanism-Outcomes. RESULTS: Students identified clinical practice experiences as important occasions for their personal and professional development. Emotional safety and tutoring were the elements that effectively "govern" the students' learning and development process. CONCLUSIONS: Emotional safety is key for nursing students because it enables them to constructively overcome any relational and emotional tensions that may develop during their clinical placements.

Involvement of lignin and hormones in the response of woody poplar taproots to mechanical stress.

Mechanical stress is a widespread condition caused by numerous environmental factors that severely affect plant stability. In response to mechanical stress, plants have evolved complex response pathways able to detect mechanical perturbations and inducing a suite of modifications in order to improve anchorage. The response of woody roots to mechanical stresses has been studied mainly at the morphological and biomechanical level, whereas investigations on the factors triggering these important alterations are still at the initial stage. Populus has been widely used to study the response of stem to different mechanical stresses and, since it has the first forest tree genome to be decoded, represents a model woody plant for addressing questions on the mechanisms controlling adaptation of woody roots to changing environments. In this study, a morphological and physiological analysis was used to investigate factors controlling modifications in Populus nigra woody taproots subjected to mechanical stress. An experimental model analyzing spatial and temporal mechanical force distribution along the woody taproot axis enabled us to compare the events occurring in its above-, central- and below-bending sectors. Different morphogenetic responses and local variations of lignin and plant hormones content have been observed, and a relation with the distribution of the mechanical forces along the stressed woody taproots is hypothesized. We investigated the differences of the response to mechanical stress induction during the time; in this regard, we present data referring to the effect of mechanical stress on plant transition from its condition of winter dormancy to that of full vegetative activity.

Modelling approaches for histology-independent cancer drugs to inform NICE appraisals: a systematic review and decision-framework.

BACKGROUND: The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals. METHODS: Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making. RESULTS: We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. CONCLUSIONS: Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide. FURTHER RESEARCH: Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 76. See the NIHR Journals Library website for further project information.

In May 2017, the US Food and Drug Administration granted the first approval for a cancer treatment based on a common biomarker rather than the location in the body at which the tumour originated (the tumour site); that is, a site-agnostic or 'histology-independent' indication was granted. Research from the National Institute for Health and Care Excellence suggests that there are approximately 20 technologies currently in development for histology-independent indications. The first marketing authorisation was granted in Europe in 2019. Histology-independent treatments have the potential to have important effects in patient populations for whom there are currently limited or no available treatment options. However, it is also important to ensure that the use of these treatments in the NHS is supported by systematic and robust assessments of clinical evidence (i.e. how well the medicine or treatment works) and economic evidence (i.e. the medicine's value for money). These assessments are undertaken by the National Institute for Health and Care Excellence, usually for treatments targeting specific tumours sites. However, a histology-independent marketing authorisation would probably include many tumour sites and it is not possible for the National Institute for Health and Care Excellence to conduct a separate assessment for each tumour site for which the treatment could be beneficial. As a result, the National Institute for Health and Care Excellence needs to consider how these products can be appropriately assessed without creating unnecessary delays in patient access. This research explores the extent to which the National Institute for Health and Care Excellence's existing approaches for assessing clinical and economic value can be applied to histology-independent indications, and any changes that might be required. We explore the nature and amount of evidence that is typically available at the point of initial marketing authorisation and develop recommendations to establish the evidence and analyses required to help inform the National Institute for Health and Care Excellence's decisions. We use case studies to highlight possible challenges and to explore ways that these challenges might be addressed. This research will help to inform future National Institute for Health and Care Excellence policy on how to appraise cancer drugs with histology-independent indications. It will also inform the development of guidance for those developing these treatments to help their understanding of the clinical effectiveness and cost-effectiveness assessments that will be required to inform the National Institute for Health and Care Excellence's appraisals.

Isolated Sphenoid Sinus Inflammatory Disease-A Report of 14 Cases.

INTRODUCTION: Isolated sphenoid sinus inflammatory diseases (ISSIDs) are responsible for about 75% of isolated sphenoid sinus opacifications. Computer tomography (CT) and magnetic resonance imaging (MRI) should be used in a complementary manner for the assessment of ISSIDs. This evaluation sheds some light on the extent of disease and intracranial and intra-orbital involvement. MATERIALS AND METHODS: The current study aimed to evaluate the medication histories of 14 patients who underwent endoscopic sinus surgery (ESS) for ISSIDs within 2015-2018. This assessment was carried out to analyze the presenting symptoms, diagnostic work-up, additional therapies, and complications. Moreover, it can help us compare our data with pertinent literature. RESULTS: As evidenced by the obtained results, ISSID lesions included bacterial sphenoiditis (42.9%), fungus ball (21.4%), invasive fungal sphenoiditis (14.3%), mucocele (14.3%), and retention cysts (7.1%). In addition, headache was found to be the major complaint, followed by nasal symptoms. Diplopia, and signs and symptoms of the involvement of other cranial nerves were less frequent. All patients underwent endoscopic transnasal sphenoidectomy. The overall survival rate was reported as 92.9% (13/14), and all patients with cranial nerve palsies demonstrated complete clinical remission. CONCLUSION: Both the review of related literature and our clinical cases were indicative of the dangerous consequences of ISSIDs. Their varied and unspecific presentation and the limited reliability of nasal endoscopy required the cooperation of ENT (ear, nose, and throat) team with other specialists to make an accurate diagnosis and decide on the most appropriate therapeutic choices. If the signs of intracranial complications were detected, surgery should be promptly performed to maximize the chances of recovery.

Cost-effectiveness of strategies preventing late-onset infection in preterm infants.

OBJECTIVE: Developing a model to analyse the cost-effectiveness of interventions preventing late-onset infection (LOI) in preterm infants and applying it to the evaluation of anti-microbial impregnated peripherally inserted central catheters (AM-PICCs) compared with standard PICCs (S-PICCs). DESIGN: Model-based cost-effectiveness analysis, using data from the Preventing infection using Antimicrobial Impregnated Long Lines (PREVAIL) randomised controlled trial linked to routine healthcare data, supplemented with published literature. The model assumes that LOI increases the risk of neurodevelopmental impairment (NDI). SETTING: Neonatal intensive care units in the UK National Health Service (NHS). PATIENTS: Infants born ≤32 weeks gestational age, requiring a 1 French gauge PICC. INTERVENTIONS: AM-PICC and S-PICC. MAIN OUTCOME MEASURES: Life expectancy, quality-adjusted life years (QALYs) and healthcare costs over the infants' expected lifetime. RESULTS: Severe NDI reduces life expectancy by 14.79 (95% CI 4.43 to 26.68; undiscounted) years, 10.63 (95% CI 7.74 to 14.02; discounted) QALYs and costs £19 057 (95% CI £14 197; £24697; discounted) to the NHS. If LOI causes NDI, the maximum acquisition price of an intervention reducing LOI risk by 5% is £120. AM-PICCs increase costs (£54.85 (95% CI £25.95 to £89.12)) but have negligible impact on health outcomes (-0.01 (95% CI -0.09 to 0.04) QALYs), compared with S-PICCs. The NHS can invest up to £2.4 million in research to confirm that AM-PICCs are not cost-effective. CONCLUSIONS: The model quantifies health losses and additional healthcare costs caused by NDI and LOI during neonatal care. Given these consequences, interventions preventing LOI, even by a small extent, can be cost-effective. AM-PICCs, being less effective and more costly than S-PICC, are not likely to be cost-effective. TRIAL REGISTRATION NUMBER: NCT03260517.

Antimicrobial-impregnated central venous catheters for preventing neonatal bloodstream infection: the PREVAIL RCT.

BACKGROUND: Clinical trials show that antimicrobial-impregnated central venous catheters reduce catheter-related bloodstream infection in adults and children receiving intensive care, but there is insufficient evidence for use in newborn babies. OBJECTIVES: The objectives were (1) to determine clinical effectiveness by conducting a randomised controlled trial comparing antimicrobial-impregnated peripherally inserted central venous catheters with standard peripherally inserted central venous catheters for reducing bloodstream or cerebrospinal fluid infections (referred to as bloodstream infections); (2) to conduct an economic evaluation of the costs, cost-effectiveness and value of conducting additional research; and (3) to conduct a generalisability analysis of trial findings to neonatal care in the NHS. DESIGN: Three separate studies were undertaken, each addressing one of the three objectives. (1) This was a multicentre, open-label, pragmatic randomised controlled trial; (2) an analysis was undertaken of hospital care costs, lifetime cost-effectiveness and value of information from an NHS perspective; and (3) this was a retrospective cohort study of bloodstream infection rates in neonatal units in England. SETTING: The randomised controlled trial was conducted in 18 neonatal intensive care units in England. PARTICIPANTS: Participants were babies who required a peripherally inserted central venous catheter (of 1 French gauge in size). INTERVENTIONS: The interventions were an antimicrobial-impregnated peripherally inserted central venous catheter (coated with rifampicin-miconazole) or a standard peripherally inserted central venous catheter, allocated randomly (1 : 1) using web randomisation. MAIN OUTCOME MEASURE: Study 1 - time to first bloodstream infection, sampled between 24 hours after randomisation and 48 hours after peripherally inserted central venous catheter removal. Study 2 - cost-effectiveness of the antimicrobial-impregnated peripherally inserted central venous catheter compared with the standard peripherally inserted central venous catheters. Study 3 - risk-adjusted bloodstream rates in the trial compared with those in neonatal units in England. For study 3, the data used were as follows: (1) case report forms and linked death registrations; (2) case report forms and linked death registrations linked to administrative health records with 6-month follow-up; and (3) neonatal health records linked to infection surveillance data. RESULTS: Study 1, clinical effectiveness - 861 babies were randomised (antimicrobial-impregnated peripherally inserted central venous catheter, n = 430; standard peripherally inserted central venous catheter, n = 431). Bloodstream infections occurred in 46 babies (10.7%) randomised to antimicrobial-impregnated peripherally inserted central venous catheters and in 44 (10.2%) babies randomised to standard peripherally inserted central venous catheters. No difference in time to bloodstream infection was detected (hazard ratio 1.11, 95% confidence interval 0.73 to 1.67; p = 0.63). Secondary outcomes of rifampicin resistance in positive blood/cerebrospinal fluid cultures, mortality, clinical outcomes at neonatal unit discharge and time to peripherally inserted central venous catheter removal were similar in both groups. Rifampicin resistance in positive peripherally inserted central venous catheter tip cultures was higher in the antimicrobial-impregnated peripherally inserted central venous catheter group (relative risk 3.51, 95% confidence interval 1.16 to 10.57; p = 0.02) than in the standard peripherally inserted central venous catheter group. Adverse events were similar in both groups. Study 2, economic evaluation - the mean cost of babies' hospital care was £83,473. Antimicrobial-impregnated peripherally inserted central venous catheters were not cost-effective. Given the increased price, compared with standard peripherally inserted central venous catheters, the minimum reduction in risk of bloodstream infection for antimicrobial-impregnated peripherally inserted central venous catheters to be cost-effective was 3% and 15% for babies born at 23-27 and 28-32 weeks' gestation, respectively. Study 3, generalisability analysis - risk-adjusted bloodstream infection rates per 1000 peripherally inserted central venous catheter days were similar among babies in the trial and in all neonatal units. Of all bloodstream infections in babies receiving intensive or high-dependency care in neonatal units, 46% occurred during peripherally inserted central venous catheter days. LIMITATIONS: The trial was open label as antimicrobial-impregnated and standard peripherally inserted central venous catheters are different colours. There was insufficient power to determine differences in rifampicin resistance. CONCLUSIONS: No evidence of benefit or harm was found of peripherally inserted central venous catheters impregnated with rifampicin-miconazole during neonatal care. Interventions with small effects on bloodstream infections could be cost-effective over a child's life course. Findings were generalisable to neonatal units in England. Future research should focus on other types of antimicrobial impregnation of peripherally inserted central venous catheters and alternative approaches for preventing bloodstream infections in neonatal care. TRIAL REGISTRATION: Current Controlled Trials ISRCTN81931394. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 57. See the NIHR Journals Library website for further project information.

Babies who are born too early or who are very sick require intensive care after birth and during early life. Most will have a long, narrow, plastic tube, called a catheter, inserted into a vein. The catheter is used to give babies fluids containing medicines and nutrition to keep them well and help them grow. The catheter can remain in place for several days or weeks. But the presence of plastic tubing in the vein increases the risk of infection. This study aimed to find out whether or not catheters coated with antimicrobial medicines, called rifampicin and miconazole, could reduce the risk of infection. These medicines act by stopping germs from growing on the catheter, but do not harm the baby or interfere with other treatments. A randomised controlled trial was carried out in 18 neonatal units in England. Whenever a baby needed a catheter, their parents were asked for consent to participate in the trial. The baby was then randomised, similar to tossing a coin, to receive either the antimicrobial catheter or a standard one. A total of 861 babies participated. We followed up all babies in the same way until after the catheter was removed to compare how often babies in each group had an infection. It was found that antimicrobial catheters were no better or worse at preventing infection than standard catheters. Antimicrobial catheters cost more and we found no evidence of benefit; these results suggest that their use in neonatal intensive care is not justified. It was calculated that further research on ways to reduce infection may be good value for money, depending on the costs of this research. The babies who took part in this study were typical of babies in England receiving catheters, meaning that the results can be applied across the NHS. Future research should focus on catheters that contain other types of antimicrobials and alternative ways of preventing infection.

Dihalogen-bridged NHC-palladium(i) dimers: synthesis, characterisation and applications in cross-coupling reactions.

A di-iodo-bridged PdI dimer bearing an N-heterocyclic carbene ligand was made accessible via the reduction of [(IPr)PdI2]2 in basic methanol solution. The structural features of [(IPr)PdI]2 were explored by single-crystal X-ray analysis. It was found to be a convenient one-component precatalyst with high activity in Suzuki-Miyaura, Buchwald-Hartwig, and Sonogashira reactions.

Brodalumab for the Treatment of Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence single technology appraisal process, brodalumab was assessed to determine the clinical and cost effectiveness of its use in the treatment of moderate-to-severe plaque psoriasis. The Centre for Reviews and Dissemination and the Centre for Health Economics Technology Assessment Group at the University of York were commissioned to act as the independent Evidence Review Group. This article provides a summary of the Evidence Review Group's review of the company's submission, the Evidence Review Group report and the National Institute for Health and Care Excellence Appraisal Committee's subsequent guidance issued in March 2018. The main clinical effectiveness data were derived from three well-conducted, multicentre, double-blind randomised controlled trials. The trials demonstrated that brodalumab statistically significantly reduced the severity of psoriasis and its impact on health-related quality of life, compared with placebo, at 12 weeks. In comparison with ustekinumab, statistically significantly more patients taking brodalumab had reduced psoriasis severity at 12 weeks. Psoriasis severity and quality of life also appeared improved at 52 weeks, although statistical significance was not assessed. Withdrawal rates were comparable to drug survival rates of other biological therapies and rates of adverse events were similar between brodalumab and ustekinumab. A network meta-analysis was presented, comparing brodalumab with other therapies available at the same point in the treatment pathway (i.e. in patients for whom standard systemic therapy or phototherapy is inadequately effective, not tolerated or contraindicated). The network meta-analysis ranked treatments in order of effectiveness, in terms of achieving different levels of Psoriasis Area and Severity Index response. The results indicated that brodalumab had a similar probability of response to ixekizumab, secukinumab and infliximab and a higher probability of response than ustekinumab, adalimumab, etanercept, apremilast, dimethyl fumarate and placebo. The company's economic model compared nine treatment sequences that included three lines of active therapy, consisting of brodalumab and other comparators recommended by the National Institute for Health and Care Excellence, followed by best supportive care. The sequence with brodalumab in the first-line position dominated sequences that started with adalimumab, infliximab, secukinumab and ustekinumab. The incremental cost-effectiveness ratio of the brodalumab sequence compared to less effective and non-dominated sequences ranged from £7145 (vs. the etanercept sequence) to £13,353 (vs. the dimethyl fumarate sequence) per quality-adjusted life-year gained. The incremental cost-effectiveness ratio for the more costly and effective ixekizumab sequence was £894,010 per quality-adjusted life-year gained compared to the brodalumab sequence. At a threshold of £20,000 per quality-adjusted life-year gained, the brodalumab sequence had the highest probability of being cost effective (96%). The main limitation of the company's economic model was the restrictive nature of the sequences compared. Twelve separate scenarios based on key uncertainties were explored by the Evidence Review Group. The only scenarios where brodalumab was ranked lower than first were not considered to be more appropriate or plausible than the assumptions or scenarios included in the company's base case. The treatment rankings identified in the Evidence Review Group's alternative base case were identical to those derived from the company's base case model. At the first National Institute for Health and Care Excellence Appraisal Committee meeting, the Committee concluded that brodalumab appears to be as effective as other anti-interleukin-17 agents and is cost effective, based on the discount agreed in the patient access scheme. Brodalumab is recommended as an option for treating adults with severe plaque psoriasis (defined by a total Psoriasis Area and Severity Index score of 10 or more and a Dermatology Life Quality Index score of more than 10) who have not responded to other systemic non-biological therapies. Brodalumab should be stopped at 12 weeks if the psoriasis has not responded adequately.

Synthesis and applications to catalysis of novel cyclopentadienone iron tricarbonyl complexes.

A series of cyclopentadienone iron tricarbonyl complexes with diverse structures were prepared, in each case using the intramolecular cyclisation of a diyne as a key step. The complexes were generated as enantiomerically enriched through (i) asymmetric synthesis of a C2-symmetric diol following a reported protocol, (ii) resolution of enantiomerically-enriched diastereoisomers formed from a chiral alcohol and (iii) kinetic resolution of a racemic ketone-containing iron tricarbonyl complex. The approaches underline the diversity of the synthetic routes which can be employed in the synthesis of homochiral cyclopentadienone iron tricarbonyl complexes. Although the complexes proved to be effective as catalysts for the reduction of ketones, the alcohol products were formed in low ees (not exceeding ca. 35%), highlighting the challenging nature of asymmetric catalysis using complexes of this type.

Iron cyclopentadienone complexes derived from C2-symmetric bis-propargylic alcohols; preparation and applications to catalysis.

A series of complexes containing the iron-cyclopentadienone structure were prepared by cyclising bis-propargylic alcohols and their derivatives with iron pentacarbonyl. The resulting complexes were characterised and tested in the catalysis of ketone reduction and alcohol oxidation. The complexes are competent catalysts for ketone reduction and alcohol oxidations.

Regioselective electrophilic borylation of haloarenes.

Haloarenes undergo direct borylation using amine : BCl3 : AlCl3 in the ratio of 1 : 1 : 2. After esterification the pinacol boronate esters are isolated in good yield with regioselectivity controlled by steric and electronic effects.

Complete reductive cleavage of CO facilitated by highly electrophilic borocations.

The addition of CO to [((R3N)BH2)2(µ-H)][B(C6F5)4] leads to formation of trimethylboroxine ((MeBO)3) and [(R3N)2BH2][B(C6F5)4]. When R = Et, [(Et3N)H2B(µ-O)B(CH3)NEt3][B(C6F5)4], is isolated and demonstrated to be an intermediate in the formation of (MeBO)3.

Anti-Proliferative Effect of Rosmarinus officinalis L. Extract on Human Melanoma A375 Cells.

Rosemary (Rosmarinus officinalis L.) has been used since ancient times in traditional medicine, while nowadays various rosemary formulations are increasingly exploited by alternative medicine to cure or prevent a wide range of health disorders. Rosemary's bioproperties have prompted scientific investigation, which allowed us to ascertain antioxidant, anti-inflammatory, cytostatic, and cytotoxic activities of crude extracts or of pure components. Although there is a growing body of experimental work, information about rosemary's anticancer properties, such as chemoprotective or anti-proliferative effects on cancer cells, is very poor, especially concerning the mechanism of action. Melanoma is a skin tumor whose diffusion is rapidly increasing in the world and whose malignancy is reinforced by its high resistance to cytotoxic agents; hence the availability of new cytotoxic drugs would be very helpful to improve melanoma prognosis. Here we report on the effect of a rosemary hydroalcoholic extract on the viability of the human melanoma A375 cell line. Main components of rosemary extract were identified by liquid chromatography coupled to tandem mass spectrometry (LC/ESI-MS/MS) and the effect of the crude extract or of pure components on the proliferation of cancer cells was tested by MTT and Trypan blue assays. The effect on cell cycle was investigated by using flow cytometry, and the alteration of the cellular redox state was evaluated by intracellular ROS levels and protein carbonylation analysis. Furthermore, in order to get information about the molecular mechanisms of cytotoxicity, a comparative proteomic investigation was performed.

Effect of short-term cadmium stress on Populus nigra L. detached leaves.

Pollution by toxic metals, accumulating into soils as result of human activities, is a worldwide major concern in industrial countries. Plants exhibit different degrees of tolerance to heavy metals, as a consequence of their ability to exclude or accumulate them in particular tissues, organs or sub-cellular compartments. Molecular information about cellular processes affected by heavy metals is still largely incomplete. As a fast-growing, highly tolerant perennial plant species, poplar has become a model for environmental stress response investigations. To study the short-term effects of cadmium accumulation in leaves, we analyzed photosystem II (PSII) quantum yield, hydrogen peroxide (H2O2) generation, hormone levels variation, as well as proteome profile alteration of 50µM CdSO4 vacuum-infiltrated poplar (Populus nigra L.) detached leaves. Cadmium management brought about an early and sustained production of hydrogen peroxide, an increase of abscisic acid, ethylene and gibberellins content, as well as a decrease in cytokinins and auxin levels, whereas photosynthetic electron transport was unaffected. Proteomic analysis revealed that twenty-one proteins were differentially induced in cadmium-treated leaves. Identification of fifteen polypeptides allowed to ascertain that most of them were involved in stress response while the remaining ones were involved in photosynthetic carbon metabolism and energy production.