Circulatory proteins relate cardiovascular disease to cognitive performance: a Mendelian randomisation study

Background and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment. Methods: We applied Mendelian randomisation (MR) and colocalization analysis to investigate the causal relationships of 90 CVD-related proteins measured by the Olink CVD I panel with cognitive traits. Genetic instruments for circulatory protein concentrations were obtained using a meta-analysis of genome-wide association studies (GWAS) from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis-pQTL (pQTL within ±500 kb from the coding gene); and 3) brain-specific cis-expression QTL (cis-eQTL) which accounts for coding gene expression based on GTEx8. Genetic associations of cognitive performance were obtained from GWAS for either: 1) general cognitive function constructed using Principal Component Analysis (N = 300,486); or, 2) g Factor constructed using genomic structural equation modelling (N = 11,263–331,679). Findings for candidate causal proteins were replicated using a separate protein GWAS in Icelanders (N = 35,559). Results: A higher concentration of genetically predicted circulatory myeloperoxidase (MPO) was nominally associated with better cognitive performance (p < 0.05) using different selection criteria for genetic instruments. Particularly, brain-specific cis-eQTL predicted MPO, which accounts for protein-coding gene expression in brain tissues, was associated with general cognitive function (βWald = 0.22, PWald = 2.4 × 10−4). The posterior probability for colocalization (PP.H4) of MPO pQTL with the g Factor was 0.577. Findings for MPO were replicated using the Icelandic GWAS. Although we did not find evidence for colocalization, we found that higher genetically predicted concentrations of cathepsin D and CD40 were associated with better cognitive performance and a higher genetically predicted concentration of CSF-1 was associated with poorer cognitive performance. Conclusion: We conclude that these proteins are involved in shared pathways between CVD and those for cognitive reserve or affecting cognitive decline, suggesting therapeutic targets able to reduce genetic risks conferred by cardiovascular disease

Resolving the unresolved: online microdialysis coupled to ICPQQQ for the simultaneous sampling and analysis of dissolved elements in soil solution

Assessing rapid chemical-elemental reactions in soils is significantly inhibited by the spatial and temporal resolution of current sampling techniques [RhizonTM samplers, diffusive gradients in thin films (DGTs)]1 . Soil chemistry is typically investigated over hours-days-weeks and with poor sampling density; the vast majority of reactions occur within seconds-minutes. Microdialysis (MD) is a new technique in the field of soil science that uses small probes to sample compounds dissolved in soil solution, with minimal disturbance to the external environment2 . Initially developed for use in neuroscience, MD has the potential for translation to environmental geochemistry to define soil chemical/physical parameters, and better inform predictive models for soil-to-plant transfer of potentially harmful elements (PHEs) or essential nutrients. One considerable experimental challenge for MD is balancing the target analyte recovery efficiency with the sample volume required for the analytical chemistry technique, which can significantly affect how often elemental speciation changes and soil fixation events can be measured3 . To overcome this challenge, we have begun development of a novel integrated online MD sampling and analysis technique, through direct coupling of MD probes with triple quadrupole inductively coupled plasma mass spectrometry (ICP-QQQ) using a microflow total consumption nebulizer with no additional modifications. This poster will present the initial setup, optimisation and application of the technique to the sampling and analysis of multiple elements in soil solution, alongside future perspectives on how information gained from this promising technique can contribute to the management of global societal and agricultural issues (e.g. nutrient supply to staple crops, contaminated land remediation)

Associations of genetically predicted vitamin B12 status across the pohenome

Variation in vitamin B12 levels has been associated with a range of diseases across the life-course, the causal nature of which remains elusive. We aimed to interrogate genetically predicted vitamin B12 status in relation to a plethora of clinical outcomes available in the UK Biobank. Genome-wide association study (GWAS) summary data obtained from a Danish and Icelandic cohort of 45,576 individuals were used to identify 8 genetic variants associated with vitamin B12 levels, serving as genetic instruments for vitamin B12 status in subsequent analyses. We conducted a Mendelian randomisation (MR)-phenome-wide association study (PheWAS) of vitamin B12 status with 945 distinct phenotypes in 439,738 individuals from the UK Biobank using these 8 genetic instruments to proxy alterations in vitamin B12 status. We used external GWAS summary statistics for replication of significant findings. Correction for multiple testing was taken into consideration using a 5% false discovery rate (FDR) threshold. MR analysis identified an association between higher genetically predicted vitamin B12 status and lower risk of vitamin B deficiency (including all B vitamin deficiencies), serving as a positive control outcome. We further identified associations between higher genetically predicted vitamin B12 status and a reduced risk of megaloblastic anaemia (OR = 0.35, 95% CI: 0.20–0.50) and pernicious anaemia (0.29, 0.19–0.45), which was supported in replication analyses. Our study highlights that higher genetically predicted vitamin B12 status is potentially protective of risk of vitamin B12 deficiency associated with pernicious anaemia diagnosis, and reduces risk of megaloblastic anaemia. The potential use of genetically predicted vitamin B12 status in disease diagnosis, progression and management remains to be investigated

Policy, Performativity and Partnership: an Ethical Leadership Perspective

This article identifies the need to think differently about educational partnerships in a changing and turbulent post compulsory policy environment in England. The policy and institutional contexts in which universities and colleges currently operate seem to be fuelling performativity at the expense of educational values. There appears to be a sharp interruption in the steady increase in educational partnerships as a vehicle for increasing and widening participation in higher education. We are witnessing a marked change in university / college relationships that appears to be a consequence of government calling a halt to increased participation in higher education, creating an increasingly competitive market for a more limited pool of student places. The implication that educational policy at the national level determines a particular pattern or mode of leadership decision making throughout an institution should however be resisted. Policy developments that challenge the moral precepts of education should not be allowed to determine how a leader acts, rather they should prompt actions that are truly educational, rooted in morality, and atached to identifiable educational values. Educational leaders have agency to resist restricted discourses in favour of ethical and principled change strategies that are a precondition for sustainable transformative partnerships in post compulsory education. University leaders in particular are called upon to use their considerable influence to resist narrow policy or managerial instrumentalism or performativity and embrace alternatives that are both educationally worthwhile and can enhance institutional resilience

Genetically determined blood pressure, antihypertensive drug classes and risk of stroke subtypes

Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH. Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH. Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease

Rendering sexism invisible in workplace narratives. A narrative analysis of female entrepreneurs’ stories of not being talked to by men

Taking a social constructionist and narrative approach to identity, in the analyses of a corpus of stories concerning sexism in the entrepreneurial world, we use positioning theory to provide a fine-grained analysis of the (gendered) identity work that female entrepreneurs perform to answer three research questions: 1) how female entrepreneurs themselves construct their (gendered) identities 2) how this differs from, or resembles, academic constructs of sexism and 3) what this identity work ‘means’ in terms of larger societal Discourses or ideologies that are invoked. Findings suggest that paradoxically these stories construct gender identities in which the female entrepreneurs are positioned as inferior to, and different from, their male interlocutors. However, the interviewees themselves fail to evaluate their stories as sexism-in-action. Consequently, they enforce and (re)create the often noted masculine and sexist nature of the entrepreneurial world

A review of the challenges, glycaemic risks and self-care for people with type 1 diabetes when consuming alcoholic beverages

Evidence‐based information for people with type 1 diabetes mellitus (T1DM) when consuming alcoholic beverages is sparse and simplistic. In clinical practice, erratic blood glucose levels with hypoglycaemia and hyperglycaemia are regularly observed, with episodes of severe hypoglycaemia being a potential risk. Preventative health behaviour strategies are often based on trial and error, with deliberately caused hyperglycaemia being a common tactic. Although important, there are no systematic reviews that synthesise the research evidence on the acute effects of alcohol on blood glucose and the impact in real‐life.We aimed to investigate the acute effect of alcoholic beverages on blood glucose, and to use appropriate evidence to recommend self‐care advice to help maintain safe glycaemic control in people with T1DM.A literature search from eight bibliographic databases was performed. Fifteen appropriate publications were identified. Most original research was performed in a laboratory environment and demonstrated inconsistencies in the effects of alcohol on blood glucose. Few studies were conducted in the real‐life environment, with advice from ‘diabetes associations’ focusing on abstinence rather than alcohol harm reduction strategies.In conclusion, key components to consider when designing future interventions include: the biochemical response to alcohol; the role of exogenous insulin; the presence and timing of carbohydrate foodstuffs in relation to alcohol; the impact of the constituents and amount of an alcoholic beverage consumed; and the effects of alcohol on cognition and behaviours

Provision of ECPR during COVID-19: evidence, equity, and ethical dilemmas

The use of extracorporeal cardiopulmonary resuscitation (ECPR) to restore circulation during cardiac arrest is a time-critical, resource-intensive intervention of unproven efficacy. The current COVID-19 pandemic has brought additional complexity and significant barriers to the ongoing provision and implementation of ECPR services. The logistics of patient selection, expedient cannulation, healthcare worker safety, and post-resuscitation care must be weighed against the ethical considerations of providing an intervention of contentious benefit at a time when critical care resources are being overwhelmed by pandemic demand

Infection control and the prevalence, management and outcomes of SARS-CoV-2 infections in mental health wards in London, UK: lessons learned from wave 1 to wave 2

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has high morbidity and mortality in older adults and people with dementia. Infection control and prevention measures potentially reduce transmission within hospitals. Aims: We aimed to replicate our earlier study of London mental health in-patients to examine changes in clinical guidance and practice and associated COVID-19 prevalence and outcomes between COVID-19 waves 1 and 2 (1 March to 30 April 2020 and 14 December 2020 to 15 February 2021). Method: We collected the 2 month period prevalence of wave 2 of COVID-19 in older (≥65 years) in-patients and those with dementia, as well as patients’ characteristics, management and outcomes, including vaccinations. We compared these results with those of our wave 1 study. Results: Sites reported that routine testing and personal protective equipment were available, and routine patient isolation on admission occurred throughout wave 2. COVID-19 infection occurred in 91/358 (25%; 95% CI 21–30%) v. 131/344, (38%; 95% CI 33–43%) P < 0.001 in wave 1. Hospitals identified more asymptomatic carriers (26/91; 29% v. 16/130; 12%) and fewer deaths (12/91; 13% v. 19/131; 15%; odds ratio = 0.92; 0.37–1.81) compared with wave 1. The patient vaccination uptake rate was 49/58 (85%). Conclusions: Patients in psychiatric in-patient settings, mostly admitted without known SARS-CoV-2 infection, had a high risk of infection compared with people in the community but lower than that during wave 1. Availability of infection control measures in line with a policy of parity of esteem between mental and physical health appears to have lowered within-hospital COVID-19 infections and deaths. Cautious management of vulnerable patient groups including mental health patients may reduce the future impact of COVID-19

How functional programming mattered

In 1989 when functional programming was still considered a niche topic, Hughes wrote a visionary paper arguing convincingly ‘why functional programming matters’. More than two decades have passed. Has functional programming really mattered? Our answer is a resounding ‘Yes!’. Functional programming is now at the forefront of a new generation of programming technologies, and enjoying increasing popularity and influence. In this paper, we review the impact of functional programming, focusing on how it has changed the way we may construct programs, the way we may verify programs, and fundamentally the way we may think about programs