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To understand how the risk of different assisted reproductive technology (ART) failure types varies by ethnic group and explore the role of mediation by maternal age and suspected etiology.An observational study of 48,750 women who undertook treatment with ART in the United Kingdom between January 2017 and December 2018.The Human Fertilisation and Embryology Authority national ART registry of the United Kingdom.Women who commenced a first cycle of ART for the purpose of primary fresh embryo transfer using their own oocytes were included.Maternal ethnic group.The ART failure types were modeled on the maternal ethnic group using the Poisson regression to produce relative risks (RRs) with 95% confidence intervals. The potential indirect effects of maternal age and etiology of subfertility were estimated, and the RRs with 95% confidence intervals were produced.Black women were at greater risk of treatment failure with respect to live birth than women who were white: cycle cancellation, RR of 2.15 (1.78-2.62); failed fertilization, RR of 2.36 (1.90-2.93); unintended freeze-all, RR of 1.71 (1.43-2.05); failed implantation, RR of 1.23 (1.12-1.34); and pregnancy loss, RR of 1.38 (1.15-1.64). Women who were Asian were at moderately increased risk: RRs of 1.31 (1.17-1.47), 1.60 (1.42-1.80), 1.25 (1.14-1.38), 1.11 (1.07-1.16), and 1.13 (1.03-1.23), across the same outcomes, respectively. Inequality may have been reduced had women of all ethnicities initiated treatment at the same age.Black women were at greatest risk of all failure types, and women who were Asian were at intermediate risk compared with women who were white. Some of the risks among women who were black may be mediated by maternal age.

Asbestos, due to its unique physical properties and abundance, was widely used in commercial applications at the beginning of the 20th century. By the 1930s, reports of respiratory illnesses in workers with occupational exposure to asbestos began to surface. Inhalation of asbestos leads to a localized inflammatory response that attempts to clear inhaled asbestos fibers. This inflammatory response and retained asbestos fibers are central to the pathogenesis of asbestosis-related pulmonary disease. Asbestos causes a range of pulmonary diseases ranging from benign, incidental pleural abnormalities to progressive, fatal pulmonary fibrosis to malignant neoplasms of the lung and pleura. The benign manifestations of asbestos exposure, the focus of this chapter, can be grouped into pleural and parenchymal diseases. Asbestosis is a fibrotic, parenchymal disease caused by asbestos exposure. After several decades from initial asbestos exposure, patients develop dyspnea, exercise intolerance, and hypoxia with restrictive physiology on pulmonary function testing similar to other interstitial lung diseases. The most common pleural manifestation is pleural plaques, which are localized areas of pleural fibrosis that are often found incidentally. While normally asymptomatic, they are a marker of asbestos exposure. Other pleural manifestations tend to be symptomatic and include diffuse pleural thickening and acute benign pleural effusion. This chapter discusses pathogenesis, clinical presentation, radiographic and physiologic manifestations, and management of benign asbestos lung diseases.

Objective\ud Predicting the outcomes of assisted reproductive technology (ART) treatments is desirable, but adopting prediction models into clinical practice remains limited. We aimed to review available prediction models for ART treatments by conducting a systematic review of the literature to identify the best performing models for their accuracy, generalisability and applicability.\ud \ud Evidence review\ud We searched electronic databases (MEDLINE, EMBASE, and CENTRAL) until June 2020. We included studies reporting on the development or evaluation of models predicting the reproductive outcomes before (pre-ART) or after starting (Intra-ART) treatment in couples undergoing any ART treatment. We evaluated the models’ discrimination, calibration, type of validation, and any implementation tools for clinical practice.\ud \ud Results\ud We included 69 cohort studies reporting on 120 unique prediction models. Half the studies reported on pre-ART (48%) and half on intra-ART (56%) prediction models. The commonest predictors used were maternal age (90%), tubal factor subfertility (50%), and embryo quality (60%).\ud \ud Only fourteen models were externally-validated (14/120, 12%) including eight pre-ART models (Templeton, Nelson, LaMarca, McLernon, Arvis, and the Stolwijk A/I,C,II models), and five intra-ART models (Cai, Hunault, van Loendersloot, Meijerink, Stolwijk B, and the McLernon post-treatment model) with a reported c-statistics ranging from 0.50 to 0.78. Ten of these models provided implementation tools for clinical practice with only two reported online calculators.\ud \ud Conclusion\ud We identified externally validated prediction models that could be used to advise couples undergoing ART treatments on their reproductive outcomes. The quality of available models remains limited and more research is needed to improve their generalizability and applicability into clinical practice.

Background The Medical Certificate of Stillbirth (MCS) records data about a baby’s death after 24 weeks of gestation but before birth. Major errors that could alter interpretation of the MCS were widespread in two UK-based regional studies. Methods A multicentre evaluation was conducted, examining MCS issued 1 January 2018 to 31 December 2018 in 76 UK obstetric units. A systematic case-note review of stillbirths was conducted by Obstetric and Gynaecology trainees, generating individual ‘ideal MCSs’ and comparing these to the actual MCS issued. Anonymized central data analysis described rates and types of error, agreement and factors associated with major errors. Results There were 1120 MCSs suitable for assessment, with 126 additional submitted data sets unsuitable for accuracy analysis (total 1246 cases). Gestational age demonstrated ‘substantial’ agreement [K = 0.73 (95% CI 0.70–0.76)]. Primary cause of death (COD) showed ‘fair’ agreement [K = 0.26 (95% CI 0.24–0.29)]. Major errors [696/1120; 62.1% (95% CI 59.3–64.9%)] included certificates issued for fetal demise at Conclusion This study demonstrates widespread major errors in MCS completion across the UK. MCS should only be completed following structured case-note review, with particular attention on the fetal growth trajectory.

To systematically review all studies that developed or validated a vaginal birth after cesarean (VBAC) prediction model.MEDLINE, EMBASE, CINAHL, Cochrane Library, and ClinicalTrials.gov were searched from inception until February 2022.We included observational studies that developed or validated a multivariable VBAC prediction model in women with a singleton pregnancy and one previous lower segment cesarean delivery. A total of 3,758 articles were identified and screened.For 57 included studies, data were extracted in duplicate using a CHARMS (Critical Appraisal and Data Extraction for Systematic Review of Prediction Modelling Studies) checklist-based tool and included participants' characteristics, sample size, predictors, timing of application, and performance. PROBAST (Prediction model Risk of Bias Assessment Tool) and TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis) were used to assess risk of bias and transparency of reporting. Several studies developed or validated more than one model. There were 38 unique prediction models, 42 external validations of 10 existing prediction models, and six modifications of existing models. Of the 38 unique models, only 19 (19/38, 50%) were internally validated in the initial study. No studies externally validated their model in the initial study. Age, previous vaginal birth, and previous cesarean delivery for labor dystocia were the commonest predictors. The area under the curve in included studies ranged from 0.61 to 0.95. Models used close to delivery generally outperformed those used earlier in pregnancy. Most studies demonstrated a high risk of bias (45/57, 79%), the remainder were unclear (7/57, 12%) and low (5/57, 9%). Median TRIPOD checklist adherence was 70% (range 32-93%).Several prediction models for VBAC success exist, but many lack external validation and are at high risk of bias. Models used close to delivery outperformed those used earlier in pregnancy; however, their generalizability and applicability remain unclear. High-quality external validation and effect studies are required to guide clinical use.PROSPERO, CRD42020190930.

Funder: DFG, Funder: Max Planck Society, Although long-read sequencing can often enable chromosome-level reconstruction of genomes, it is still unclear how one can routinely obtain gapless assemblies. In the model plant Arabidopsis thaliana, other than the reference accession Col-0, all other accessions de novo assembled with long-reads until now have used PacBio continuous long reads (CLR). Although these assemblies sometimes achieved chromosome-arm level contigs, they inevitably broke near the centromeres, excluding megabases of DNA from analysis in pan-genome projects. Since PacBio high-fidelity (HiFi) reads circumvent the high error rate of CLR technologies, albeit at the expense of read length, we compared a CLR assembly of accession Eyach15-2 to HiFi assemblies of the same sample. The use of five different assemblers starting from subsampled data allowed us to evaluate the impact of coverage and read length. We found that centromeres and rDNA clusters are responsible for 71% of contig breaks in the CLR scaffolds, while relatively short stretches of GA/TC repeats are at the core of >85% of the unfilled gaps in our best HiFi assemblies. Since the HiFi technology consistently enabled us to reconstruct gapless centromeres and 5S rDNA clusters, we demonstrate the value of the approach by comparing these previously inaccessible regions of the genome between the Eyach15-2 accession and the reference accession Col-0.

Background: The autotransporter protein secretion system has previously been used to target the secretion of heterologous proteins to the bacterial cell surface and the extracellular milieu at laboratory scale. The platform is of particular interest for the production of “difficult” recombinant proteins that might cause toxic effects when produced intracellularly. One such protein is IrmA. IrmA is a vaccine candidate that is produced in inclusion bodies requiring refolding. Here, we describe the use and scale-up of the autotransporter system for the secretion of an industrially relevant protein (IrmA).Results: A plasmid expressing irmA was constructed such that the autotransporter platform could secrete IrmA into the culture supernatant fraction. The autotransporter platform was suitable for the production and purification of IrmA with comparable physical properties to the protein produced in the cytoplasm. The production of IrmA was translated to scale-up protein production conditions resulting in a yield of 29.3 mg/L of IrmA from the culture supernatant.Conclusions: The autotransporter platform is a viable method for the production, secretion, and purification of a “difficult” to produce protein on an industrially relevant scale. Use of the autotransporter platform could reduce the number of downstream processing operations required thus accelerating the development time and reducing costs for recombinant protein production.

Three distinct procedures for obtaining the effective Gibbs energies of activation from computed energies for a reaction involving multiple reactant-state (RS) and transition-state (TS) conformers are shown to be equivalent. If Boltzmann-weighted average Gibbs energies for RS and TS are evaluated, then the Gibbs energy contribution from entropy of mixing of both RS and TS conformers must also be included in order to obtain the correct value for the effective Gibbs energy of activation. Application to a solvolytic reaction of 4,4’-dimethoxybenzhydrylpyridinium cation, which is shown to satisfy the Curtin-Hammett principle with rapid interconversion of RS conformers, demonstrates the use of each procedure for evaluation of the effective Gibbs energy of activation.

Background The association between mode of delivery and postnatal depression is uncertain. Mental health history may modify the association. Objectives The objective of this study was to determine whether the association between caesarean and postnatal psychological distress (PPD) differs according to long-standing depression/anxiety. Methods Analysis of the UK-based Millennium Cohort Study of women who gave birth 2000-2002 was carried out. The outcomes were PPD at 9 months by Rutter Malaise Inventory and actively treated physician-diagnosed depression/severe anxiety at 3 years. The exposure was mode of delivery. Adjusted relative risks were estimated using Poisson regression. Effect modification according to long-standing depression/anxiety was investigated multiplicatively and additively. Results We included 15,936 women, of whom 2346 (13.4%, weighted) reported PPD. Women with long-standing depression/anxiety were at 34% lower risk of PPD following elective caesarean, compared with vaginal birth: relative risk (RR) 4.36 (95% confidence interval [CI] 3.76, 5.05), RR 3.25 (95% CI 2.23, 4.75) and RR 4.92 (95% CI 3.67, 6.59) for vaginal, elective and emergency caesarean births, respectively, with relative excess risk due to interaction (RERI) -1.28 (95% CI -2.73, 0.16), ratio of RRs 0.66 (95% CI 0.42, 1.05). Women with long-standing depression/anxiety were at greatest risk of later treatment following emergency caesarean, with RR 4.95 (95% CI 3.86, 6.34), RR 4.09 (95% CI 2.51, 6.65) and RR 6.74 (95% CI 4.87, 9.32), for vaginal, elective and emergency caesarean births, respectively; RERI 1.79 (95% CI -0.13, 3.71), ratio of RRs 1.36 (95% CI 0.94, 1.99); all RRs with reference to vaginal birth in the absence of long-standing depression/anxiety. There was no evidence of a similar association between emergency caesarean and PPD nor elective caesarean and later treatment. Conclusions Women with long-standing depression or anxiety who had elective caesarean had a lower risk of postnatal distress. When this group had emergency caesarean, there was greater risk of actively treated depression/anxiety at 3 years. These associations were not observed in women without long-standing depression/anxiety.

Gestational hypertension may confer risk of atopic disease in offspring through a direct biological mechanism, but another possibility is that risk is mediated through complications of pregnancy. To explore these associations, we conducted an analysis of a nationally representative birth cohort based in the UK involving children born 2000–2002. We included 12,450 mother-child pairs. We used logistic regression to estimate the association between hypertensive disease and asthma, hay fever, or eczema by age 5, and parentally reported early wheeze and severe wheeze. Mediation by gestation at delivery and caesarean delivery was explored using causal mediation analysis. Odds ratios (95% CI) for gestational hypertension and childhood asthma, hay fever, and eczema were 1.32 (1.09, 1.59), 1.22 (0.97, 1.55), and 1.12 (0.96, 1.32) respectively, adjusted for confounding. The population attributable fractions were 2.4% (1.0–3.8%), 0.9% (−0.3% to 2.1%), and 1.8% (0.0–3.7%), respectively. Accounting for mediation by gestational age and caesarean delivery, odds ratios (95% CI) for the potential direct effects of gestational hypertension were 1.21 (0.97, 1.50), 1.17 (0.91, 1.49), and 1.11 (0.94, 1.31) for the same.Conclusion: Gestational hypertension was weakly positively associated with asthma and this was partly mediated by earlier delivery. Only a small proportion of early childhood asthma was attributable to gestational hypertensive disease in this representative UK-based birth cohort. What is known:• Gestational hypertension has been shown to be an inconsistent risk factor for the atopic diseases.• The in utero immune environment may modify the risk of atopy in offspring; alternatively, complications of pregnancy including caesarean delivery and prematurity may explain an association between hypertensive disease and atopy. What is new:• Self-reported gestational hypertension was a weak risk factor for asthma and wheeze in the Millennium Cohort Study.• Part of the association between gestational hypertensive disease and asthma was explained by earlier delivery.

Objective: To determine the value of uterine CD138+ cells, as a marker of chronic endometritis, in predicting subsequent reproductive outcome in women with history of recurrent pregnancy loss.\ud Design: A prospective longitudinal study.\ud Setting: Tertiary specialised clinic.\ud Patients: Women with history of recurrent pregnancy loss or implantation failure over a 12-months follow-up period. \ud Intervention: We quantified the CD138+ cells/high powered field (hpf) using immunohistochemistry and image analysis of endometrial biopsies obtained during the secretory stage post ovulation. \ud Main Outcome Measures: live birth and subsequent pregnancy loss. We calculated the receiver operator curve for predicting subsequent pregnancy loss and reported using relative risk (RR) and 95% confidence intervals (CI).\ud Results: We enrolled 344 women of whom eighty-eight became pregnant (88/344, 25.5%). Half of them had a subsequent live birth (47/88, 53%) and the rest lost their pregnancy (41/88, 46%). The median CD138+ score was significantly lower in the live birth group (p

Objectives\ud In bladder drainage, an essential part of post-hysterectomy care, the optimal timing for removing the urinary catheter is unclear. Our objective was to evaluate the risks and benefits of early (6 h) catheter removal post-hysterectomy.\ud Study design\ud A systematic review searching MEDLINE, EMBASE and Cochrane CENTRAL from inception till May 2019 for randomised trials of women undergoing hysterectomy. We reported on urinary retention, positive urine culture, urinary tract infection (UTI) (defined by symptoms and/or antibiotic use), post-operative pyrexia, time to ambulation, and length of hospital stay. We assessed risk of bias in included trials and used a random-effect model to generate risk ratios (RR) for dichotomous outcomes and weighted mean differences (WMD) for continuous outcomes, with 95 % confidence intervals (CI).\ud Results\ud Of 1020 potentially relevant citations, we included 10 randomised trials (1120 women). Four trials had low risk of bias for randomisation and allocation concealment while five had low risk for outcome assessment and selective reporting. Compared to delayed removal, women in the early catheter removal group had a higher risk of urinary retention and needing re-catheterisation (10 RCTs, RR 3.61, 95 %CI 1.21–9.21, I 2 = 56 %). There was some reduction in the risk of post-operative UTI (6 RCTs, RR 0.42, 95 %CI 0.18 to 0.96, I 2 = 0 %), but we did not find a significant difference in post-operative pyrexia (6 RCTs, RR 0.73, 95 %CI 0.43–1.24, I 2 = 18 %) or positive urine cultures (6 RCTs, RR of 0.56, 95 %CI 0.27–1.12, I 2 = 55 %). There was no significant difference in the average time to ambulation (3RCTs, WMD −4.6, 95 %CI −9.16 to −0.18, I 2 = 98 %) and length of hospital stay (3RCTs, WMD −1.05, 95 %CI −2.42 to 0.31, I 2 = 98 %). Our meta-regression on the provision of prophylactic antibiotics did not show a significant effect on the reported outcomes. Our analysis was limited by our inability to adjust for potential effect modifiers such as the surgical route.\ud Conclusions\ud Early removal of the urinary catheter

Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µmol/kg) and pregabalin (63-377 µmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µmol/kg) in combination with the minimum effective dose of pregabalin (75 µmol/kg) or gabapentin (146 µmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions.

The principle of proportionality protects civilians and civilian objects against expected incidental harm from an attack that is excessive to the military advantage anticipated from the attack. However, despite its status as a fundamental norm of IHL, key terms are not defined in relevant treaties nor benefit from critical judicial explanation. This has caused challenges for both academics and military commanders alike in explaining and applying the test for proportionality. The article expands upon two points that were raised and generated interesting discussion at The Second Israel Defense Forces International Conference on the Law of Armed Conflict during a panel that dealt with contemporary issues in proportionality. Those two issues are: a. What does the “reasonable military commander” standard for assessing proportionality entail? b. Should “reverberating effects” (i.e., collateral effects that are only expected to materialize in the long term) be accounted for as part of the assessment of collateral damage?

In civil engineering, composite construction has become increasingly widespread due to the improvement of mechanical properties it provides. Recently, research on the development of post installed or retrofitted shear connectors has been conducted. The benefits of this are the ease of installation and the ease of removal for decommissioning structures at the end of their life. Most of the research in this area is concerned with modified versions of welded shear studs or various threaded rod and nut configurations and refers to only one type of shear connector. Therefore, the suitability of the proposed models across differing shear connection types is unknown. In the first of two companion papers an experimental study has been undertaken to ascertain the dynamic behaviour of identical steel–concrete composite beams with differing shear connection systems. Two blind bolt connector types were used as shear connection systems in steel–concrete composite beams. Alongside these, a welded shear stud specimen, and a non-composite specimen were tested for comparison.

In the first paper of these two companion papers an experimental study was undertaken to ascertain the dynamic behaviour of identical steel–concrete composite beams with differing shear connection systems. Two blind bolt connector types were used as shear connection systems in steel–concrete composite beams. Alongside these, a welded shear stud specimen, and a non-composite specimen were tested for comparison. In this, the second paper a Timoshenko beam model for steel–concrete composite beams is developed and is compared with the experimental results. An uncertain boundary condition is investigated using the Timoshenko beam model and an empirical relation between the displacements at the beam supports and the rotation of the cross section face is proposed.

In accounts of garden history, the garden itself, its physical attributes and spatial organization, is often strangely absent. The focus instead often appears to be on attributing meaning derived f...

The use of blind bolts in steel–concrete composite beams is beneficial for promoting sustainable design and for retrofitting existing steel structures. This paper presents an experimental study as well as finite element (FE) modelling analyses for the time-dependent behaviour of composite beams with blind bolts subjected to sustained loads. Four full-scale simply supported beams utilising different types of bolts and studs were tested under long-term static loads. The mid-span deflections were monitored for a period of over 260 days. Short-term push-out tests were also carried out on the connectors used in the composite beams, and their slip deformation was recorded for determining the initial stiffness. The experimental results were modelled by using a three-dimensional FE model, in which the creep of the concrete was simulated through defining a viscoelastic response and the shrinkage of concrete was incorporated by means of notional thermal expansion. The FE model was validated against the experimental results reported herein and other independent results of composite beams using conventional welded studs reported elsewhere, and it was subsequently applied to carry out parametric studies. An extensive body of parameters was considered to clarify their effects on the time-dependent behaviour of composite beams with blind bolts, including the mechanical properties and configuration details of shear connectors, the concrete strength, the loading conditions, the span-to-depth ratio and the reinforcement ratio. It was demonstrated that the time-dependent behaviour was sensitive to the stiffness and the bolt-to-hole clearance of connectors, and some other parameters also possessed effects with different degrees. The research findings implied that using blind bolts in composite beams was beneficial to the time-dependent response due to their relatively lower deflections resulting from the creep and shrinkage of the concrete over time. The outcome may provide an important basis and guidance for designing such composite beams when considering their long-term response with time effects.

Introduction There is a paucity of evidence in diagnostic radiography evaluating a career path into industrial imaging despite several higher education institutes stating this route as a career option on graduation. The link between a career in industrial radiography and diagnostic routes is unknown although there are anecdotal examples of individuals transferring between the two. Successfully obtaining a first post job following graduation in diagnostic radiography can be challenging in the current financial climate. A partnership was formed with an energy sector company that offered non-destructive testing/non-destructive evaluation (NDT/NDE) employing industrial radiographic technicians. Method As an initial pilot, 5 ( n = 5) final year diagnostic radiography students visited an industrial radiography site and underwent theoretical and practical training. Following this placement they engaged in a focus group and the student perceptions/responses were explored and recorded. Results Common themes were identified and categorised via a thematic analysis. These were; radiation safety, physics and technology, widening access, graduate attributes/transferable skill sets and working conditions. Conclusion Student discussion focussed around the benefits of working conditions in healthcare, the value of technology, safety and physics education in alternative placements and the transferability of skills into other/industrial sectors (e.g. NDT/NDE). Contemporary practice placements are a useful pedagogical approach to develop complex conceptual theoretical constructs, such as radiation physics. An in depth evaluation between the two industries skill sets is postulated. Additionally, this could offer alternative/emerging roles to interested diagnostic radiographers potentially meeting the skill shortage in industrial radiography.

The long and tragic history of human warfare manifests an endless quest for more effective ways to conduct attacks and defeat adversaries. This has in turn driven innovation in means and methods of defence against attacks. Remote warfare exemplifies both streams of development. The ability to conduct effective attacks at great distance from your own forces is a significant advantage in attack. Similarly, the ability to distance military personnel from the effective range of enemy weapons is a significant advantage in defence. Military forces have sought these advantages since time immemorial.Modern remote weapon systems, including vehicles that can be operated remotely, are but the latest element in this continuum of development. For a variety of reasons, the means of remote warfare that involve armed remotely operated vehicles have evoked significant social, political and legal reactions. The next evolution, autonomous weapon systems (AWS), inherent in which is the concept of autonomous decision making by machines to conduct attacks on human beings, arouses visceral trepidation for many and has given rise to calls for bans before the technology can be developed. The potential development of remote AWS is an important topic for legal and ethical discussion by governments, non-government organisations and scholars. This chapter discusses the legal dimensions of remote AWS, analysing how the precautions in attack in Article 57 of Additional Protocol I might apply to such systems and how the persons creating or using such systems may be held accountable under international humanitarian law for outcomes of their use.The authors suggest that this analysis of the law has demonstrated that neither remote warfare systems nor autonomous weapon systems are means of warfare that are currently proscribed by the law of armed conflict. Like all means of warfare, there are methods of use of these systems that may contravene the law of armed conflict. There is no doubt that continued developments in remote and automated systems will inspire further study of the law as it applies to such systems and further advocacy for what the law ought to be. It also seems that the developments in remote and autonomous systems may be destined to change the role played by combatants; but it appears unlikely that this will reduce the role played by lawyers.

Background Peer-assisted learning provides a means through which individuals can learn from one another through a reciprocal process. Radiographic image interpretation skills are fundamental to both diagnostic radiography students and medical students due to their shared role in preliminary evaluation of conventional radiographic images. Medical students on graduation, may not be well prepared to carry out image interpretation, since evidence suggests that they perform less well than radiographers in e.g. Accident and Emergency situations. Method A review of literature was conducted exploring the application of peer-assisted learning within diagnostic radiography and health education more widely as well as the practice of initial image interpretation. An extensive and systematic search strategy was developed which provided a range of material related to the areas. Findings An overview was obtained of the effectiveness of peer-assisted learning and the issues associated with development of image interpretation skills and a degree of discrepancy was identified between the two cohorts regarding their interpretative competence and confidence. This inconsistency may create an opportunity to apply peer-assisted learning, better preparing both disciplines for the practical application of image interpretation skills. Conclusion The review identified the lack of a substantial evidence base relating to peer-assisted learning in radiography. Peer-assisted learning is not widely embraced in an interprofessional context. Multiple positive factors of such an intervention are identified which outweigh perceived negative issues. Student teacher and learner may benefit as should the clinical service from enhanced practitioner performance. The findings justify further research to develop the evidence base.

Background Recent evidence has suggested an association between postoperative non-steroidal anti-inflammatory drugs (NSAIDs) and increased operation-specific complications. This study aimed to determine the safety profile following gastrointestinal surgery across a multicentre setting in the UK. Methods This multicentre study was carried out during a 2-week interval in September–October 2013. Consecutive adults undergoing elective or emergency gastrointestinal resection were included. The study was powered to detect a 10 per cent increase in major complications (grade III–V according to the Dindo–Clavien classification). The effect of administration of NSAIDs on the day of surgery or the following 2 days was risk-adjusted using propensity score matching and multivariable logistic regression to produce adjusted odds ratios (ORs). The type of NSAID and the dose were registered. Results Across 109 centres, early postoperative NSAIDs were administered to 242 (16·1 per cent) of 1503 patients. Complications occurred in 981 patients (65·3 per cent), which were major in 257 (17·1 per cent) and minor (Dindo–Clavien grade I–II) in 724 (48·2 per cent). Propensity score matching created well balanced groups. Treatment with NSAIDs was associated with a reduction in overall complications (OR 0·72, 95 per cent confidence interval 0·52 to 0·99; P = 0·041). This effect predominately comprised a reduction in minor complications with high-dose NSAIDs (OR 0·57, 0·39 to 0·89; P = 0·009). Conclusion Early use of NSAIDs is associated with a reduction in postoperative adverse events following major gastrointestinal surgery.

This article explores the relationship between Victorian and Ngaiwong ways of knowing by bringing a ‘planetary’ framework to bear upon an extraordinary meeting which took place at Buckingham Palace on 26 January 1846. To do so, it invokes the long history of the Antipodes; deploys, modifies and comments upon methodologies for conceiving and analysing ‘world literature’ by Americanist Wai Chee Dimock; and engages with the role of the imagination in Gayatri Chakravorty Spivak's concept of ‘planetarity’.

Development of allosteric inhibitors into efficient drugs is hampered by their indirect mode-of-action and complex structure-kinetic relationships. To enable the design of efficient allosteric drugs targeting the polymerase of hepatitis C virus (NS5B), the interaction characteristics of three non-nucleoside compounds (filibuvir, VX-222, and tegobuvir) inhibiting HCV replication via NS5B have been analyzed. Since there was no logical correlation between the anti-HCV replicative and enzyme inhibitory effects of the compounds, surface plasmon resonance biosensor technology was used to resolve the mechanistic, kinetic, thermodynamic and chemodynamic features of their interactions with their target and their effect on its interaction with RNA. Tegobuvir could not be seen to interact with NS5B at all while filibuvir interacted in a single reversible step (except at low temperatures) and VX-222 in two serial steps, interpreted as an induced fit mechanism. Both filibuvir and VX-222 interfered with the interaction between NS5B and RNA. They competed for binding to the enzyme, suggesting that they had a common inhibition mechanism and identical or overlapping binding sites. The greater anti-HCV replicative activity of VX-222 over filibuvir is hypothesized to be due to a greater allosteric conformational effect, resulting in the formation of a less catalytically competent complex. In addition, the induced fit mechanism of VX-222 gives it a kinetic advantage over filibuvir, exhibited as a longer residence time. These insights have important consequences for the selection and optimization of new allosteric NS5B inhibitors.

The ATP-dependent SWR1 chromatin remodeling complex (SWR1-C) exchanges the histone H2A-H2B dimer with the H2A.Z-H2B dimer, producing variant nucleosomes. Arabidopsis thaliana SWR1-C contributes to the active transcription of many genes, but also to the repression of genes that respond to environmental and developmental stimuli. Unlike other higher eukaryotic H2A.Z deposition mutants (which are embryonically lethal), Arabidopsis SWR1-C component mutants, including arp6, survive and display a pleiotropic developmental phenotype. However, the molecular mechanisms of early flowering, leaf serration, and the production of extra petals in arp6 have not been completely elucidated. We report here that SWR1-C is required for miRNA-mediated developmental control via transcriptional regulation. In the mutants of the components of SWR1-C such as arp6, sef, and pie1, miR156 and miR164 levels are reduced at the transcriptional level, which results in the accumulation of target mRNAs and associated morphological changes. Sequencing of small RNA libraries confirmed that many miRNAs including miR156 decreased in arp6, though some miRNAs increased. The arp6 mutation suppresses the accumulation of not only unprocessed primary miRNAs, but also miRNA-regulated mRNAs in miRNA processing mutants, hyl1 and serrate, which suggests that arp6 has a transcriptional effect on both miRNAs and their targets. We consistently detected that the arp6 mutant exhibits increased nucleosome occupancy at the tested MIR gene promoters, indicating that SWR1-C contributes to transcriptional activation via nucleosome dynamics. Our findings suggest that SWR1-C contributes to the fine control of plant development by generating a balance between miRNAs and target mRNAs at the transcriptional level.

Summary The Schoonebeek heavy-oil field was first developed by Nederlandse Aardolie Maatschappij B.V. (NAM) in the late 1940s. Because of economics, it was abandoned in 1996. In 2008, the Schoonebeek Redevelopment Project, using a gravity-assisted-steamflood (GASF) design concept, was initiated with 73 wells (44 producers, 25 injectors, and 4 observation wells). Steam injection and cool-down cycles subject a cement sheath to some of the most severe load conditions in the industry. Wellbore thermal modeling predicted that surface and production sections would experience temperatures in excess of 285°C (545°F) and considerable stress across weak formations. A key design requirement was long-term integrity of the cement sheath over an expected 25- to 30-year field life span. Complicating this requirement was the need for lightweight cementing systems, because lost-circulation issues were expected in both hole sections, particularly in the mechanically weak Bentheim sandstone. The long-term integrity challenge was divided into chemical and mechanical elements. Prior research on high-temperature cement performance by the operator provided necessary guidance for this project. Laboratory mechanical and analytical tests were conducted to confirm the high-temperature stability of the chosen design. In addition to using lightweight components, foaming the slurry allowed the density, mechanical, and economic targets to be met. A standardized logistical plan was put in place to allow use of the same base blend for the entire well, adjusted as needed, using liquid additives, and applying the foaming process when necessary. This single-blend approach greatly simplified bulk-handling logistics, allowing use of dedicated bulk-handling equipment. The first well was constructed in January 2009; all 73 wells have been successfully cemented to surface. The steaming process, initiated in May 2011, has progressed with no well integrity issues to date.

BACKGROUND AND PURPOSE The chemokine receptor CXCR3 directs migration of T-cells in response to the ligands CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC. Both ligands and receptors are implicated in the pathogenesis of inflammatory disorders, including atherosclerosis and rheumatoid arthritis. Here, we describe the molecular mechanism by which two synthetic small molecule agonists activate CXCR3. EXPERIMENTAL APPROACH As both small molecules are basic, we hypothesized that they formed electrostatic interactions with acidic residues within CXCR3. Nine point mutants of CXCR3 were generated in which an acidic residue was mutated to its amide counterpart. Following transient expression, the ability of the constructs to bind and signal in response to natural and synthetic ligands was examined. KEY RESULTS The CXCR3 mutants D112N, D195N and E196Q were efficiently expressed and responsive in chemotaxis assays to CXCL11 but not to CXCL10 or to either of the synthetic agonists, confirmed with radioligand binding assays. Molecular modelling of both CXCL10 and CXCR3 suggests that the small molecule agonists mimic a region of the ‘30s loop’ (residues 30–40 of CXCL10) which interacts with the intrahelical CXCR3 residue D112, leading to receptor activation. D195 and E196 are located in the second extracellular loop and form putative intramolecular salt bridges required for a CXCR3 conformation that recognizes CXCL10. In contrast, CXCL11 recognition by CXCR3 is largely independent of these residues. CONCLUSION AND IMPLICATIONS We provide here a molecular basis for the observation that CXCL10 and CXCL11 are allosteric ligands of CXCR3. Such findings may have implications for the design of CXCR3 antagonists. LINKED ARTICLE This article is commented on by O'Boyle, pp. 895–897 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01759.x