We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.
To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure no-reply@cambridge.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Objectives/Goals: Pharmacogenomic (PGx) testing identifies genetic variations affecting medication response but is not yet in routine clinical whole-genome sequencing (WGS) workflows. We aimed to establish a streamlined bioinformatics pipeline for incorporating PGx reporting into clinical WGS and to determine clinical implications for medication treatment. Methods/Study Population: A PGx profiling pipeline based on existing WGS data was developed, integrating three WGS-based PGx calling tools: Aldy, PyPGx, and Cyrius (CYP2D6 only), to provide genotype calls for 17 key pharmacogenes. The pipeline was validated using WGS data from 70 individuals with diverse backgrounds (36% European, 27% African, 27% Asian, and 10% admixed) from the Genetic Testing Reference Materials Coordination Program (GeT-RM). Results were manually reviewed against published data. The validated pipeline was then applied to 144 clinical patients previously screened for neurodevelopmental disorders or suspected hereditary diseases, followed by diplotype-to-phenotype translation and preemptive PGx-guided medication recommendations based on consensus guidelines and FDA labeling for commonly used medications. Results/Anticipated Results: Congruent phenotype call rates for GeT-RM samples were 100% for 13 genes (CFTR, CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP4F2, DPYD, G6PD, IFNL3, NAT2, NUDT15, TPMT, and VKORC1), 99% for three genes (CYP3A5, SLCO1B1, UGT1A1), and 97% for CYP2D6, indicating strong pipeline performance. Among 144 clinical patients, 99.3% had at least one clinically actionable PGx results relevant to 36 of top 300 medications in the USA across psychotropic, cardiovascular, musculoskeletal, gastrointestinal, and other therapeutic areas. The most prevalent drug–gene interactions involved sertraline and CYP2B6, affecting 49% patients: 41% were intermediate metabolizers who may require slower titration and lower maintenance doses, while 8% poor metabolizers may benefit from a lower starting dose or alternative antidepressants. Discussion/Significance of Impact: Our validated WGS-based PGx profiling pipeline successfully extracted actionable PGx data from clinical WGS. By aligning PGx profiles with guideline-recommended clinical actions, we demonstrated the clinical value of integrating PGx reporting in WGS workflows, improving personalized medication management.
The viability of small island developing states (SIDS) is threatened by three distinct processes – a backlash against globalisation; rising geopolitical competition between powers; and accelerating climate change – which are pulling at the threads binding the liberal international order together. We suggest that this order has been kinder to SIDS than is often acknowledged because its underpinning norms – sovereign equality, non-interference, and right to development – are inherently permissive and thus provide SIDS with choices rather than imperatives. Their leaders should fight for the continuation and enhancement of that order rather than be seduced by alternatives. We provide a rationale for and examples of policies to achieve this, including reforms to the way ODA is measured, debt restructured, climate finance allocated, and global governance organised. These enhancements represent the most plausible pathway for SIDS in a period of significant global upheaval. This title is also available as Open Access on Cambridge Core.
As the most internally rigorous design, randomized controlled trials (RCTs) are the gold standard for assessing the efficacy and safety profile of interventions. Increasingly, health technology assessment (HTA) considers evidence from non-randomized studies. Guidance recommends synthesizing different study designs separately due to their different inherent biases/limitations. But when authors or reviewers misclassify studies, this could affect which studies are included and therefore have an impact on review results.
Methods
We are conducting a methods project to (i) identify a clear study design classification system, (ii) explore whether its use produces consistent study design categorizations among reviewers, and (iii) iteratively improve the classification system. We performed a pragmatic web-based search for study design categorization tools and used the resulting schemas to develop a clear algorithm for use by reviewers of all levels of experience, specifically in reviews of treatment interventions. Next, we tested tool consistency and user experience by web-based survey in a small internal sample of reviewers, each independently using the system to categorize 18 published studies.
Results
A median of seven reviewers (range four to eight) categorized each study. Rater agreement using the chart varied widely, with 100 percent agreement on the designs of three studies (17%), and at least 75 percent of reviewers agreeing on one design for nine studies (50%). The most common agreement was reached on RCTs and non-randomized controlled trials. The most common sources of disagreement were between different types of cohort studies and between case series and controlled cohort studies, largely due to inconsistent reporting. We also identified several improvements: the wording of prompt questions, the ordering of designs, and the addition of new elements.
Conclusions
The classification system as initially designed led to too much variation in study design categorization to be useful. Consequently, we present a revised version that we now aim to evaluate in a larger sample of reviewers. Further research will also investigate whether using the tool would change the results of systematic reviews, using a small sample of published reviews.
Delinquent boys are compared with non-delinquents with respect to their attitudes towards a series of “good” and “bad” social acts, by the use of scales having rational origins of measurement. A new technique, essentially an extension of Thurstone's Method of Successive Intervals, is found to give results similar to Horst's Method of Balanced Values. Significant differences in mean attitude between the two groups are not found.
The European question has divided the Labour Party and the progressive left for over fifty years. The contemporary left-wing antithesis to the EU harks back to Bennite anti-marketeer narratives: a neoliberal EU undermines the potential for national progressive policies in relation to labour markets, state intervention and finance. However, many make the case that the EU's four freedoms support a progressive politics: the single market project embeds social and workers' rights, challenges member state support for large corporate interests and facilitates free movement for EU citizens.
There is, in short, a progressive dilemma for the British left in relation to the European issue, which the authors navigate through the analysis of four policy issues that arose during the Brexit debate and remain significant for British politics and for the left in particular: free trade and the single market, industrial policy and state aid, free movement of persons and finance. Crucially, they point to a route beyond this dilemma for both Europe and the British left.
There is increasing recognition of the crucial need for robust community engagement in health research and clinical trials. Despite this awareness, challenges persist in bridging the gap between researchers and communities. Much of the current discourse focuses on addressing issues such as cultural humility and equitable partnerships. To expand this conversation, we conducted community engagement studios, following the model by Joosten et al. We wanted to gather perspectives on research involvement across New Mexico. This process and resultant findings offer valuable insights into effective community engagement practices and advance clinical and translational science by amplifying community voices and needs.
Agriculture can be pivotal in mitigating climate change through soil carbon sequestration. Land conversion to pasture has been identified as the most effective method to achieve this. Yet, it creates a perceived trade-off between increasing soil carbon and maintaining arable food crop production. In this on-farm study, we assessed the potential of incorporating a 2-year diverse ley (consisting of 23 species of legumes, herbs, and grasses) within a 7-year arable crop rotation for soil organic matter accumulation. We established upper and lower boundaries of soil organic matter accumulation by comparing this approach to positive (permanent ley, akin to conversion to permanent pasture) and negative (bare soil) references. Our findings in the 2-year diverse ley treatment show greater soil organic matter accumulation in plots with lower baseline levels, suggesting a potential plateau of carbon sequestration under this management practice. In contrast, the positive reference consistently showed a steady rate of organic matter accumulation regardless of baseline levels. Moreover, we observed a concurrent increase in labile carbon content in the 2-year ley treatment and positive reference, indicating improved soil nutrient cycling and ecological processes that facilitate soil carbon sequestration. Our results demonstrate that incorporating a 2-year diverse ley within arable rotations surpasses the COP21 global target of a 0.4% annual increase in soil organic carbon. These findings, derived from a working farm's practical and economic constraints, provide compelling evidence that productive arable agriculture can contribute to climate change mitigation efforts.
Background: Carbapenem-resistant Enterobacterales (CRE) infections are an urgent public health threat. An estimated 12,700 CRE (including E. coli, Klebsiella spp., and Enterobacter spp.) infections occurred in the United States in 2020. While the estimated incidence of CRE infections has been relatively stable between 2012 and 2020, organism-specific trends, including those for organisms not typically included in CRE surveillance definitions, have not been described. We estimated the annual rate of carbapenem-resistant Enterobacterales infections, disaggregated by organism, from 2012 to 2022. Methods: Data on inpatient hospitalizations from a dynamic cohort of short-term acute care hospitals reporting microbiology data between 2012 and 2022 were obtained from the PINC AI Database and the BD Insights Research Database. We included patients with clinical isolates of E. coli, Enterobacter spp., Klebsiella spp., Citrobacter spp., Serratia marcescens, Proteus mirabilis, and Morganella spp. and sufficient susceptibility results to identify carbapenem resistance. We limited our analysis to incident isolates, defined as a patient’s first isolate of a given organism and carbapenem resistance phenotype in a 14-day period. We calculated the annual rate of carbapenem-resistant infections per 10,000 hospitalizations for each organism. Results: There were 3,018,792 incident isolates from 55.8 million hospitalizations included in the analysis. Overall, 31,226 incident carbapenem-resistant isolates were identified. The rate of carbapenem-resistant infections varied by organism and over time (Table 1). The rate of carbapenem-resistant Klebsiella spp. infections appeared to decline from 3.94 in 2012 to 2.44 infections per 10,000 hospitalizations in 2022. The rate of carbapenem-resistant Enterobacter spp. infections appeared to increase from 1.05 in 2012 to 1.44 infections per 10,000 hospitalizations in 2022. The rate of carbapenem-resistant E. coli infections also appeared to increase, from 0.61 in 2012 to 0.85 infections per 10,000 hospitalizations in 2022. Rates of carbapenem-resistant Proteus mirabilis, Morganella spp., Citrobacter spp., or Serratia marcescens infections were similar in 2022 compared to 2012. Conclusions: Disaggregating data by organism revealed heterogeneous trends, with apparent increases in rates of carbapenem-resistant Enterobacter spp. and E. coli infections and apparent decreases in rates of carbapenem-resistant Klebsiella spp. infections. Organism-specific CRE analyses may provide additional insight into CRE epidemiology.
To make a valid will, a person should be able to understand the nature and consequences of doing so, the extent of their estate and the claims others may have on it. No disorder of mind should be present that would affect their testamentary decisions, and clinicians are therefore often asked to give an opinion on whether a person has testamentary capacity. This article discusses the legal issues involved, with reference to UK case law (in particular, the legal test of Banks v Goodfellow (1870)), and outlines the requirements of testamentary capacity assessment (including retrospective assessments), the clinician's responsibilities when requested by a solicitor to make an assessment of capacity (‘the golden rule’) and what they might expect if appearing in court to give expert witness regarding testamentary capacity. Fictitious case studies are presented illustrating certain points in testamentary capacity assessment.
At a time when the Parthenon Sculptures refuse to go away (in every sense of the phrase) and uncatalogued items were allegedly found to have been sold off by a member of staff, The British Museum needs some good news. There must have been sighs of relief all round when their new exhibition in the (itself often controversial: Puffett 2023) BP Gallery, Legion: life in the Roman Army, opened to almost universal press acclaim (e.g. Clark 2024; Jones 2024); it runs from 1 February to 23 June 2024. However, some (perfectly valid) observations in her blog by a scholar qualified in the field triggered a ‘woke alarm’ in some less-qualified quarters (McGrath 2024). It was always likely to be a crowd pleaser, with something for every “exercitologist” (Bishop 2014: 24), whether amateur or professional. For those visitors who had cut their Roman military teeth on Graham Webster's seminal Roman Imperial Army (Webster 1969, 1979, 1985), it was going to have its work cut out to satisfy.
This is the transcript of an interview with Glasgow-based Australian composer Dr Jane Stanley. The interviewer is Dr Judith Bishop, an Australian poet and lyricist whose words appear in two of the works discussed: ‘14 Weeks’ (from Interval (UQP, 2018) and ‘The Indifferent’ (from Event (Salt Publishing UK, 2007)). The interview was recorded at the University of Glasgow on 29 May 2023 and edited for clarity, length and concision. It was recorded a day after the world premiere of Jane Stanley's 14 Weeks at the Glasgow School of Art Choir Composeher concert in City Halls, Glasgow. In response to a recent survey which revealed huge gender inequalities in the granting of music commissions, Composeher had commissioned seven female composers to write choral works of around ten minutes, of which 14 Weeks was one. The interview ranges widely, from the composer's textural style to her creative process, and touches on her forthcoming composer portrait album, to be released by Delphian Records in 2024.
From its entry to the EEC in 1973 to its formal exit from the EU in 2020, the UK's commercial and trade policies were governed by a diverse and changing set of supranational rules and institutions. When the country joined the EEC it also joined a European customs union and Common Commercial Policy (CCP), removing tariffs on goods traded within Europe and adopting a common external tariff in relation to imports from outside Europe. When the EEC became the EU in 1992, and the single market became a reality, EU policy focused on removing “non-tariff barriers’ (NTBs): both within EU member states and in external FTAs with individual countries and trading blocs. This move reflects how the concept of “free trade” has shifted from a focus on eliminating tariffs on goods to harmonizing behind-the-border regulation of goods and services where “any divergence in regulatory practice” is increasingly viewed as “a trade irritant to be eliminated” (De Ville & Siles-Brugge 2018: 243). Tariffs have thus decreased while highly technical and complex regulatory concepts and processes continue to multiply. The single market, enshrining the free movement of goods as well as services, capital and people – the so-called four freedoms – at its core and setting its sights on NTBs, makes Europe the quintessential twenty-first-century liberal trade power.
In the wake of the 2016 EU referendum, the British Conservative Party under Theresa May chose to pursue a “hard” form of Brexit: fully exiting all EU economic institutions, from the customs union to the single market. The subsequent 2020 TCA, which, despite the rhetoric of the Johnson government, strongly reflected the outline deal negotiated by May before she was deposed, was remarkable in that, for the first time in modern trading history, two deeply integrated and highly proximate advanced economies signed an FTA that made commercial relations between them less free. The UK thereafter faced the painful task of reconstituting its trade panorama from a position that seriously disadvantaged its exporters. Moreover, it had to do so immediately, since, as noted in the book's Introduction, the TCA came into force essentially overnight.
Nowhere was the political debate on the free movement of people in the EU more heated and divisive than in Brexit Britain, including on the British left. But in government at the turn of the century, the Labour Party had enthusiastically supported the free movement regime. Indeed, Prime Minister Tony Blair decided to immediately open UK labour markets to citizens of the new member states following the 2004 “big bang” enlargement, when he was not legally obliged to do so (Watt & Wintour 2015). For New Labour, this policy of opening had economic benefits and was consistent with a broader cosmopolitan Third Way ideology and its embrace of the EU as a single market (see Chapters 1 and 4). But the numbers of people that came to the UK from central and eastern Europe far exceeded the estimates (largely because they had assumed most member states, including Germany, would also open their labour markets in 2004) (Dustmann et al. 2003) and the issue grew in political salience, particularly after the 2007 economic crisis. As a result, long before the Brexit referendum in 2016, many in the Labour Party had come to regard Blair's 2004 decision as a spectacular policy failure: a critical juncture in the party's subsequent electoral decline. And with hindsight, given the breadth of opposition to the free movement regime by 2016, it is often regarded as a key moment in the country's drift towards Brexit (Constardine 2015; Geddes 2014; Evans & Mellon 2019).
Those associated with an old right Blue Labour and hard left anti-marketeer/ Lexiteer position discussed in Chapter 2 (position B, Figure 1.1), are among the most longstanding and vociferous critics of the free movement of persons regime. They opposed it in part for strategic reasons: as broad public opinion became critical of the regime it made little electoral sense to continue supporting the status quo. As we detail below, it was largely on this basis that many pro-European MPs in Labour and on the broader British left came to also express concerns about the party's positioning on the issue, both before and after the 2016 referendum.
In March 1998, Tony Blair gave the first-ever speech by a British prime minister to the French National Assembly. This coincided with the UK beginning its sixmonth rotating EU Council presidency. He delivered the speech in immaculate French to a parliament dominated by a Socialist Party sceptical of New Labour's market-friendly direction of travel. Blair emphasized the importance of “global political engagement” and insisted it was about more than simply “commercial exchange”, encompassing all areas of legal, social and cultural life. The “cohabitation” of French people living in Britain (and vice versa), he argued, was a great success worth celebrating. He remarked that his “neither laissez-faire nor rigidly statist” Third Way project sought to reconcile the supposed contradictions between free enterprise and competition, on the one hand, and social action and poverty reduction, on the other, in a world of rapid and inevitable economic and social change. He also came to “dispel any doubts” that the UK would be anything other than “a full partner of Europe”. Noting the country's absence from monetary union, he carefully suggested that the door remained open to joining in the future. He also discussed how fears of distant institutions and dilution of national identity drive Euroscepticism, arguing that purposeful reform and striking a balance between supranationalism and nationalism could ward them off by ensuring “integration, when justified; diversity permitted by subsidiarity, when not” (Blair 1998).
This represented a vision for Europe and, crucially, for Britain in Europe. At the time, it seemed like a watershed domestically. The battles that had disfigured and, when combined with Black Wednesday (see Keegan, Marsh & Roberts 2017), ultimately destroyed John Major's Conservative government over Maastricht just five years earlier appeared to be from an entirely different era. Blair's young, modern, metropolitan party wore its pro-European sympathies comfortably. It had changed the terms of debate decisively since coming to power with an enormous majority. From signing a Social Chapter that Major had resisted, to laying the groundwork for potential membership of the single currency, it was difficult to envisage anything other than the gradual intensification of meaningful UK participation in EU affairs. But what agenda would be pursued via that engagement?
During the 1975 referendum campaign, Roy Jenkins spoke of the implications of a no vote: ‘For Britain to withdraw from Europe would be to retire into an old people’s home for fading nations. I do not think it would be a very comfortable old people’s home … I do not like the look of some of the wardens’ (cited in Campbell 2015: 448). Jenkins was prescient. Nearly half a century after Britain’s first membership referendum and close to a decade after it voted, by a narrow margin, to leave the EU in 2016, post-Brexit Britain found itself to be a particularly uncomfortable ‘fading nation’. It lagged behind almost all other advanced industrial economies on almost every relevant indicator, including growth, productivity, real wages and inequality (OBR 2022). As for the wardens, the Conservative Party had elected five different leaders in fewer than ten years, having been consumed with infighting over the terms and content of Brexit. The cheerleaders who once promised to ‘guide Britain to the sunlit uplands’ could not muster a modicum of enthusiasm for the project, instead turning on each other for its failures.
For their part, many on the Eurosceptic British left were suggesting by the mid-2020s that leaving the EU had been a necessary but insufficient step towards transforming the nation into a more inclusive, sustainable and democratic state (see Chapter 2; Cunliffe et al. 2023). But it was not obvious what would constitute a sufficient step, nor how it could actually be achieved. Indeed, the Lexiteers own ‘sunlit uplands’ were apparently, just like those very different uplands of their right-wing Brexiteer fellow travellers, still just over the next hill. At the time of writing in early 2024, there was a very real risk that a Labour government and prime minister in waiting were succumbing to similar wishful thinking. Echoing Boris Johnson’s ‘get Brexit done’ slogan, the Labour leader Keir Starmer promised to ‘make Brexit work’. But it was entirely unclear how it could be made to work in support of any meaningfully progressive agenda.
Industrial policy was a key issue in debates leading up to and following the EU referendum. The 2007 GFC and its aftermath exacerbated stark disparities in the UK, which had been widening since the 1970s. The decline of mining, steel, shipbuilding and other manufacturing industries in the central and northern regions of Britain since the 1970s proceeded in parallel with the ongoing concentration of wealth in the City of London (see Chapter 7). Inner London is among the wealthiest regions in the EU, while as many as nine British regions are among the relatively poorest in Europe and the absolute poorest among other northern European industrial countries. By 2017, the UK recorded by far the largest gap between domestic regions as measured in GDP per capita. Inner London was over six times the EU average, with Luxembourg in second place at just two and a half times that average. Almost every region outside of the southeast was below, and in many cases well below, the EU mean. Notably, this EU average included the post-2004 central and eastern European accession countries (Eurostat 2019). At the same time, many wealthy EU states, in contrast, had registered declining regional inequality, even though the gaps between their richest regions and the poorest parts of the southern periphery (and the British periphery) had widened (see MacKinnon 2017).
The period of austerity following the 2008 GFC, and the election of the CameronâClegg coalition government in 2010, with its subsequent pursuit of a radical austerity agenda, drastically exacerbated these inequalities. The 2010 coalition government invested less in public services, including the NHS, and infrastructure, including public transport links. They cut social support just as many citizens and their communities, reeling from the aftermath of the financial crisis, required further government assistance. The meagre economic growth that recommenced once the initial period of austerity abated did little to assuage this situation, and actually reinforced Britain's dysfunctional pre-crisis development model (see Berry 2013; Chapter 7). Brexit arose in this specific, even peculiar, context.