Mill and Pettit on Freedom, Domination, and Freedom-as-Domination

Pettit endorses a ‘republican’ conception of social freedom of the person as consisting of a state of non-domination, and takes this to refute Mill’s ‘liberal’ claim that non-domineering but coercive interference can compromise social freedom of choice. This paper argues that Pettit’s interpretation is true to the extent that Mill believes that the legitimate, non-arbitrary and just coercion of would-be dominators, for the sake of preventing them from dominating others, can render them unfree to choose to do so without rendering them socially unfree (qua dominated) persons in their own right. However, contra Pettit, Mill is correct to reject the ‘republican’ view for at least two reasons. Firstly, it enables him to avoid commitment to the implausible implication that would-be dominators who sincerely deny any interest in a shared system of basic liberties are automatically rendered unfree persons by the coercion necessary to uphold such a system. Secondly, it enables him to avoid begging the question against ‘immoralists’ like Nietzsche, whose opposition to systems of reciprocal non-domination is at least partly motivated by the losses of social freedom of choice they entail for those they deem to be worthy of dominating others

J. S. Mill on Higher Pleasures and Modes of Existence

The passage of Mill’s Utilitarianism that sets out the condition in which one pleasure has a superior quality than another stokes interpretive controversy. According to the Lexical Interpretation, Mill takes one pleasure, P1, to be of a superior quality than another, P2, if, and only if, the smallest quantity of P1 is more valuable than any finite quantity of P2. This paper argues that, while the Lexical Interpretation may be supported with supplementary evidence, the passage itself does not rule out qualitative superiority without lexical dominance, as it only requires P1 to be more valuable than any quantity of P2 that it is possible for someone to experience. Some will object that this concession to opponents of the Lexical Interpretation still renders Mill’s condition for qualitative superiority too demanding to be plausible. However, if Mill’s qualitative rankings apply to higher-order pleasures taken in modes of existence as such rather than to the pleasures of different activities chosen from within these modes, the objection loses much of its force. One upshot is that Mill may have more to contribute to debates in contemporary population axiology than is usually acknowledged

Integrated methodologies of economics and socio-economics assessments in ocean renewable energy : private and public perspectives

This paper offers a holistic approach to the evaluation of an ocean renewable energy (ORE) technology type or specific project in order to provide a comprehensive assessment of both narrow economic and broader socio-economic performance. This assessment incorporates methods from three pillars areas: Economic - financial returns and efficient use of resources, Social - employment, social and community cohesion and identity, and Environmental - including the physical environment and pollution. These three pillars are then considered in the broader context of governance. In order to structure this evaluation, a novel parameter space model was created, defined by the three pillars and by the scale of the system under assessment. The scale of the system ranged from individual components of an ORE project; to projects comprising of a number of devices; through to a geographic regions in which multiple farms may be deployed. The parameter space consists of an inner circle representing the boundary of interest for a private investor, or a firm, developing an ORE project. The outer circle is characterised by assessment tools typically employed at the broader stakeholder level including economic, social, and environmental methods that can be employed at local, regional or national scale and which are typically employed to inform policy and decision making regarding ORE. Governance sets the stage within which management occurs. Wider impacts to the firm undertaking the project will take into account “externalities” of the project across the three fields. In this model, key methods identified are mapped onto this parameter space and the connectivity explored. The paper demonstrates that the three pillars are inter-connected and each must be considered in any meaningful assessment of ORE sustainability. An integrated assessment approach has the ability to address both the private and the public aspects of an ORE development,. This analysis provides insights on existing best practice, but also reveals the potential for disconnect between an ORE project’s commercial viability and its contribution to environmental and social goals

Metabolomic profiling to dissect the role of visceral fat in cardiometabolic health

OBJECTIVE: Abdominal obesity is associated with increased risk of type 2 diabetes (T2D) and cardiovascular disease. The aim of this study was to assess whether metabolomic markers of T2D and blood pressure (BP) act on these traits via visceral fat (VF) mass. METHODS: Metabolomic profiling of 280 fasting plasma metabolites was conducted on 2,401 women from TwinsUK. The overlap was assessed between published metabolites associated with T2D, insulin resistance, or BP and those that were identified to be associated with VF (after adjustment for covariates) measured by dual‐energy X‐ray absorptiometry. RESULTS: In addition to glucose, six metabolites were strongly associated with both VF mass and T2D: lactate and branched‐chain amino acids, all of them related to metabolism and the tricarboxylic acid cycle; on average, 38.5% of their association with insulin resistance was mediated by their association with VF mass. Five metabolites were associated with BP and VF mass including the inflammation‐associated peptide HWESASXX, the steroid hormone androstenedione, lactate, and palmitate. On average, 29% of their effect on BP was mediated by their association with VF mass. CONCLUSIONS: Little overlap was found between the metabolites associated with BP and those associated with insulin resistance via VF mass

Signatures of early frailty in the gut microbiota

Background: Frailty is arguably the biggest problem associated with population ageing, and associates with gut microbiome composition in elderly and care-dependent individuals. Here we characterize frailty associations with the gut microbiota in a younger community dwelling population, to identify targets for intervention to encourage healthy ageing. Method: We analysed 16S rRNA gene sequence data derived from faecal samples obtained from 728 female twins. Frailty was quantified using a frailty index (FI). Mixed effects models were used to identify associations with diversity, operational taxonomic units (OTUs) and taxa. OTU associations were replicated in the Eldermet cohort. Phenotypes were correlated with modules of OTUs collapsed by co-occurrence. Results: Frailty negatively associated with alpha diversity of the gut microbiota. Models considering a number of covariates identified 637 OTUs associated with FI. Twenty-two OTU associations were significant independent of alpha diversity. Species more abundant with frailty included Eubacterium dolichum and Eggerthella lenta. A Faecalibacterium prausnitzii OTU was less abundant in frailer individuals, and retained significance in discordant twin analysis. Sixty OTU associations were replicated in the Eldermet cohort. OTU co-occurrence modules had mutually exclusive associations between frailty and alpha diversity. Conclusions: There was a striking negative association between frailty and gut microbiota diversity, underpinned by specific taxonomic associations. Whether these relationships are causal or consequential is unknown. Nevertheless, they represent targets for diagnostic surveillance, or for intervention studies to improve vitality in ageing

Cross-genotype AR3-specific neutralizing antibodies confer long-term protection in injecting drug users after HCV clearance

Background & AimsUnderstanding immune protection against hepatitis C virus (HCV) infection is necessary for designing an effective vaccine. A number of broadly-reactive, neutralizing antibodies have been isolated from B cells of HCV-infected subjects. However, it remains unclear whether B cells producing such antibodies contribute to the clearance and long-term immune protection against HCV.MethodsWe analysed the B-cell repertoire of thirteen participants from the Amsterdam Cohort Study among injecting drug users with a median follow-up of 17.5 years. Five subjects ultimately became chronically infected either after primary infection or after reinfection. Eight subjects, at the end of study follow-up, were HCV RNA negative following spontaneous clearance of one or multiple infections. From each subject, 10,000 CD27+IgG+ B cells, collected 0.75 year after HCV infection, were cultured to characterize the antibody repertoire.ResultsUsing a multiplex flow cytometry-based assay to study the antibody binding to E1E2 from genotype 1 to 6, we found that a high frequency of cross-genotype antibodies was associated with spontaneous clearance of one or multiple infections (p-value=0.03). Epitope specificity of these cross-genotype antibodies was determined by alanine mutant scanning in four subjects, who were HCV RNA negative following spontaneous clearance of one or multiple infections. Interestingly, the cross-genotype antibodies were mainly AR3-specific and showed cross-neutralizing activity against HCV. In addition to AR3 antibodies, three subjects developed antibodies recognizing AR4 of which one monoclonal antibody showed cross-neutralizing capacity.ConclusionsTogether, these data suggest that a strong B-cell response producing cross-genotype and neutralizing antibodies, especially targeting AR3, contribute to HCV clearance and long-term immune protection against HCV

Heritable components of the human fecal microbiome are associated with visceral fat

Background: Variation in the human fecal microbiota has previously been associated with body mass index (BMI). Although obesity is a global health burden, the accumulation of abdominal visceral fat is the specific cardio-metabolic disease risk factor. Here, we explore links between the fecal microbiota and abdominal adiposity using body composition as measured by dual-energy X-ray absorptiometry in a large sample of twins from the TwinsUK cohort, comparing fecal 16S rRNA diversity profiles with six adiposity measures.Results: We profile six adiposity measures in 3666 twins and estimate their heritability, finding novel evidence for strong genetic effects underlying visceral fat and android/gynoid ratio. We confirm the association of lower diversity of the fecal microbiome with obesity and adiposity measures, and then compare the association between fecal microbial composition and the adiposity phenotypes in a discovery subsample of twins. We identify associations between the relative abundances of fecal microbial operational taxonomic units (OTUs) and abdominal adiposity measures. Most of these results involve visceral fat associations, with the strongest associations between visceral fat and Oscillospira members. Using BMI as a surrogate phenotype, we pursue replication in independent samples from three population-based cohorts including American Gut, Flemish Gut Flora Project and the extended TwinsUK cohort. Meta-analyses across the replication samples indicate that 8 OTUs replicate at a stringent threshold across all cohorts, while 49 OTUs achieve nominal significance in at least one replication sample. Heritability analysis of the adiposity-associated microbial OTUs prompted us to assess host genetic-microbe interactions at obesity-associated human candidate loci. We observe significant associations of adiposity-OTU abundances with host genetic variants in the FHIT, TDRG1 and ELAVL4 genes, suggesting a potential role for host genes to mediate the link between the fecal microbiome and obesity.Conclusions: Our results provide novel insights into the role of the fecal microbiota in cardio-metabolic disease with clear potential for prevention and novel therapies

The impact of the COVID-19 pandemic on recovery from cardiac surgery: 1-year outcomes

AIMS: The outbreak of COVID-19 was potentially stressful for everyone, and possibly heightened in those having surgery. We sought to explore the impact of the pandemic on recovery from cardiac surgery. METHODS AND RESULTS: A prospective observational study of 196 patients who were ≥18years old undergoing cardiac surgery between 23rd March and 4th July 2020 (UK lockdown) was conducted. Those too unwell or unable to give consent/complete the questionnaires were excluded. Participants completed (on paper or electronically) the impact of event (IES-R) (distress related to COVID-19), depression (CES-D) and EQ-5D-5L (quality of life, HRQoL) questionnaires at baseline, one week after hospital discharge, and six weeks, six months and 1-year post-surgery.Questionnaire completion was >75.0% at all timepoints, except at one week (67.3%). Most participants were male (147 (75.0%)), white British (156 (79.6%)) with an average age 63.4years. No patients had COVID-19. IES-R sand CES-D were above average at baseline (indicating higher levels of anxiety and depression) decreasing over time. HRQoL pre-surgery was high, reducing at one week but increasing to almost pre-operative levels at six weeks, and exceeding pre-operative levels at six months and 1-year. IES-R and CES-D scores were consistently higher in women and younger patients with women also having poorer HRQoL up to 1-year after surgery. CONCLUSION: High levels of distress were observed in patients undergoing cardiac surgery during the COVID-19 pandemic with women and younger participants particularly affected. Psychological support pre- and post-operatively in further crises or traumatic times, should be considered to aid recovery. REGISTRATION: Clinicaltrials.gov ID:NCT04366167

Generation of Human Antigen-Specific Monoclonal IgM Antibodies Using Vaccinated “Human Immune System” Mice

Passive transfer of antibodies not only provides immediate short-term protection against disease, but also can be exploited as a therapeutic tool. However, the 'humanization' of murine monoclonal antibodies (mAbs) is a time-consuming and expensive process that has the inherent drawback of potentially altering antigenic specificity and/or affinity. The immortalization of human B cells represents an alternative for obtaining human mAbs, but relies on the availability of biological samples from vaccinated individuals or convalescent patients. In this work we describe a novel approach to generate fully human mAbs by combining a humanized mouse model with a new B cell immortalization technique. After transplantation with CD34+CD38⁻ human hematopoietic progenitor cells, BALB/c Rag2⁻/⁻IL-2Rγc⁻/⁻ mice acquire a human immune system and harbor B cells with a diverse IgM repertoire. "Human Immune System" mice were then immunized with two commercial vaccine antigens, tetanus toxoid and hepatitis B surface antigen. Sorted human CD19+CD27+ B cells were retrovirally transduced with the human B cell lymphoma (BCL)-6 and BCL-XL genes, and subsequently cultured in the presence of CD40-ligand and IL-21. This procedure allows generating stable B cell receptor-positive B cells that secrete immunoglobulins. We recovered stable B cell clones that produced IgM specific for tetanus toxoid and the hepatitis B surface antigen, respectively. This work provides the proof-of-concept for the usefulness of this novel method based on the immunization of humanized mice for the rapid generation of human mAbs against a wide range of antigen