Priority setting: women’s health topics in multiple sclerosis

Cancer; Multiple sclerosis; Women’s healthCàncer; Esclerosi múltiple; Salut de la donaCáncer; Esclerosis múltiple; Salud de la mujerBackground: A scoping review found that most studies on women’s health in multiple sclerosis (MS) focused on pregnancy, fetal/neonatal outcomes and sexual dysfunction. Few studies addressed menopause, contraception, gynecologic cancers/cancer screening. However, the perceived relative importance of these knowledge gaps to people living with MS and other partners is unknown. We engaged a range of partners, including people living with MS, health care providers, researchers, and patient advocacy groups, to set priorities for future research in women’s health in MS. Methods: We employed a three-step global engagement process. First, we identified which broad research topics relevant to women’s health in MS were of highest priority using two surveys. Second, we developed specific research questions within these topics using focus groups. Finally, we prioritized the research questions with a third survey. Results: Overall, 5,266 individuals responded to the initial surveys [n = 1,430 global survey, mean (SD) age 50.0 (12.6), all continents; n = 3,836 North American Research Committee on Multiple Sclerosis survey, mean (SD) age 64.8 (9.6), United States]. Menopause, sexual dysfunction, pregnancy, gynecologic cancer/cancer screening, hormones and parenthood were identified as the most important topics. Focus groups generated 80 potential research questions related to these topics. In the final survey 712 individuals prioritized these questions. The highest priority questions in each research topic were: (i) How do perimenopause and menopause affect disease activity, course, response to disease-modifying treatment and quality of life in MS; (ii) What are the most effective strategies for managing issues around sexual intimacy, including related to low sexual desire, changes in physical function, and MS symptoms; (iii) Are there long-term effects of disease-modifying therapies on the children of persons with MS; (iv) What are the short and long-term effects of disease-modifying drugs on gynecologic cancer risk, particularly for high efficacy disease-modifying drugs and hematopoietic stem cell transplantation; (v) Are there hormone related treatments that can stabilize fluctuations in MS symptoms; and (vi) How does MS fatigue impact parenting strategies. Conclusion: Priorities for research relating to women’s health issues for persons with MS have been delineated using a collaborative process with key partners. Alignment of future research with these priorities should be monitored.The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The International Advisory Committee on Clinical Trials in MS is sponsored by the European Committee for Treatments and Research in MS and the National Multiple Sclerosis Society. NARCOMS is a project of the Consortium of Multiple Sclerosis Centers (CMSC). NARCOMS is funded in part by the CMSC and the Foundation of the CMSC. The study was also supported in part by the Waugh Family Chair in Multiple Sclerosis (to RM). The funding source(s) had no role in the study design, collection, analysis or interpretation of the data, nor in the decision to submit the article for publication

Maintenance of active chromatin states by HMGN2 is required for stem cell identity in a pluripotent stem cell model

Background: Members of the HMGN protein family modulate chromatin structure and influence epigenetic modifications. HMGN1 and HMGN2 are highly expressed during early development and in the neural stem/progenitor cells of the developing and adult brain. Here, we investigate whether HMGN proteins contribute to the chromatin plasticity and epigenetic regulation that is essential for maintaining pluripotency in stem cells. Results: We show that loss of Hmgn1 or Hmgn2 in pluripotent embryonal carcinoma cells leads to increased levels of spontaneous neuronal differentiation. This is accompanied by the loss of pluripotency markers Nanog and Ssea1, and increased expression of the pro-neural transcription factors Neurog1 and Ascl1. Neural stem cells derived from these Hmgn-knockout lines also show increased spontaneous neuronal differentiation and Neurog1 expression. The loss of HMGN2 leads to a global reduction in H3K9 acetylation, and disrupts the profile of H3K4me3, H3K9ac, H3K27ac and H3K122ac at the Nanog and Oct4 loci. At endodermal/mesodermal genes, Hmgn2-knockout cells show a switch from a bivalent to a repressive chromatin configuration. However, at neuronal lineage genes whose expression is increased, no epigenetic changes are observed and their bivalent states are retained following the loss of HMGN2. Conclusions: We conclude that HMGN1 and HMGN2 maintain the identity of pluripotent embryonal carcinoma cells by optimising the pluripotency transcription factor network and protecting the cells from precocious differentiation. Our evidence suggests that HMGN2 regulates active and bivalent genes by promoting an epigenetic landscape of active histone modifications at promoters and enhancers

Associations between nutritional properties of food and consumer perceptions related to weight management

Consumer perceptions of food (for example, how filling or healthy) influence eating behaviour and appetite control. Therefore approaches to understand the global nutritional attributes of foods that predict the strength of consumer perceptions are of academic and commercial interest. The current research describes the development of a flexible platform for systematically mapping the global nutritional attributes of foods (both objective and perceived) to consumer perceptions of those foods. The platform consists of a database of standardised UK food images (currently n= 300), linked to a catalogue of detailed perceptual, nutritional, sensory, cost, and psychological information ('nutritional attributes'). The platform also incorporates demographic and psychometric questionnaires to examine the importance of nutritional attributes on consumer perceptions within or between relevant target groups. In the current study, the platform was applied to a sample of dieting and non-dieting British men and women (n= 887) to examine the global attributes of a subset of foods (n= 75) and their association with successful weight management (i.e. supportive of weight loss, weight loss maintenance or prevention of weight gain). Generalised linear models identified energy density, cost (£/kcal), perceived energy content and satiating capacity as the main nutritional attributes underlying dieters' and non-dieters' perception of successful weight management food. Additionally, pleasantness, and desire not to (over) eat were uniquely associated with dieters' perception of food as good for weight management; pleasantness was positively associated with weight management and desire to eat was negatively associated with weight management. Therefore, global nutritional attributes of foods can predict and distinguish the extent consumers' perceive a food to be related to successful weight management. This platform will be extended to increase the variety of foods and specificity of nutritional attributes in the database suitable for a range of commercial, academic or clinical research applications

Australian approaches for managing ‘country’ using Indigenous and non-Indigenous knowledge

This paper synthesises the lessons learnt and challenges encountered when applying Indigenous and non-Indigenous knowledge and methods in natural and cultural resource management (NCRM) in northern and central Australia. We primarily draw on the papers within this special issue of Ecological Management & Restoration, which originated largely from the Indigenous land management symposium at the 2010 Ecological Society of Australia conference. Many of the papers and therefore this article discuss practical experiences that offer insight for enhanced on-ground cross-cultural NCRM and can inform broader thinking and theoretical critiques. A wider literature is also drawn upon to substantiate the points and broaden the scope of the synthesis. Four key themes for consideration in collaborative cross-cultural NCRM are discussed. They are as follows: 1. The differences in environmental philosophy between Indigenous and non-Indigenous cultures which profoundly shape perceptions of environmental management; 2. Cross-cultural awareness of Indigenous and non-Indigenous knowledge and methods; 3. The mechanics of two-way approaches to ecological research and managing country (NCRM as perceived by Indigenous people) and 4. Operational challenges for Indigenous NCRM organisations. To conclude, we point out five broad principles for managing country using Indigenous and non-Indigenous knowledge: (i) Recognise the validity of both Indigenous and non-Indigenous environmental philosophies; (ii) Create more opportunities for improved cross-cultural understanding, respect and collaborations; (iii) Involve Indigenous people and their knowledge and interests at all stages of the Indigenous NCRM project or research (including planning, design, implementation, communication and evaluation); (iv) Ensure that time and continuity of effort and resources are available (to undertake participatory processes and for trust-building and innovation) and (v) Establish high-level political support through legal and policy frameworks to maintain continuity of government commitment to Indigenous NCRM

Compromise Between Incommensurable Ethical Values

In this chapter I will concentrate on compromise in ethical conflict and disagreement. I will discuss compromises related to disagreement with respect to public decisions between options that represent conflicting incommensurable human values. The central question will be whether in those cases a principled compromise is possible. A ‘principled compromise’ can be defined as a rational way to achieve a trade-off or balance between conflicting values, for instance, by rational assignment of relative weights. I will argue that in some cases incommensurability will prevent a principled compromise in the defined sense. I will show why phrases used by some philosophers, such as ‘making a rational trade-off’, ‘striking the right balance’, ‘finding the Aristotelian Mean’ or ‘splitting the difference’, are based on misunderstandings about the characteristics of incommensurable values that are usually at stake in the pursuit of a compromise. I will show that incommensurable values lack an equivalence relation and how this prevents a determinate trade-off or balance between them. This is especially important with respect to the pursuit of compromises in ethical conflicts, including conflicts of justice, where we need a rational and ethical justification for the final decision. I will argue that the model of deliberative democracy presents a promising procedure for making the final decision legitimate but that, in the relevant cases, it cannot avoid an ethical deficit

Balancing selection at a premature stop mutation in the myostatin gene underlies a recessive leg weakness syndrome in pigs

Balancing selection provides a plausible explanation for the maintenance of deleterious alleles at moderate frequency in livestock, including lethal recessives exhibiting heterozygous advantage in carriers. In the current study, a leg weakness syndrome causing mortality of piglets in a commercial line showed monogenic recessive inheritance, and a region on chromosome 15 associated with the syndrome was identified by homozygosity mapping. Whole genome resequencing of cases and controls identified a mutation causing a premature stop codon within exon 3 of the porcine Myostatin (MSTN) gene, similar to those causing a double-muscling phenotype observed in several mammalian species. The MSTN mutation was in Hardy-Weinberg equilibrium in the population at birth, but significantly distorted amongst animals still in the herd at 110 kg, due to an absence of homozygous mutant genotypes. In heterozygous form, the MSTN mutation was associated with a major increase in muscle depth and decrease in fat depth, suggesting that the deleterious allele was maintained at moderate frequency due to heterozygous advantage (allele frequency, q = 0.22). Knockout of the porcine MSTN by gene editing has previously been linked to problems of low piglet survival and lameness. This MSTN mutation is an example of putative balancing selection in livestock, providing a plausible explanation for the lack of disrupting MSTN mutations in pigs despite many generations of selection for lean growth

Priority setting: women’s health topics in multiple sclerosis

BackgroundA scoping review found that most studies on women’s health in multiple sclerosis (MS) focused on pregnancy, fetal/neonatal outcomes and sexual dysfunction. Few studies addressed menopause, contraception, gynecologic cancers/cancer screening. However, the perceived relative importance of these knowledge gaps to people living with MS and other partners is unknown. We engaged a range of partners, including people living with MS, health care providers, researchers, and patient advocacy groups, to set priorities for future research in women’s health in MS.MethodsWe employed a three-step global engagement process. First, we identified which broad research topics relevant to women’s health in MS were of highest priority using two surveys. Second, we developed specific research questions within these topics using focus groups. Finally, we prioritized the research questions with a third survey.ResultsOverall, 5,266 individuals responded to the initial surveys [n = 1,430 global survey, mean (SD) age 50.0 (12.6), all continents; n = 3,836 North American Research Committee on Multiple Sclerosis survey, mean (SD) age 64.8 (9.6), United States]. Menopause, sexual dysfunction, pregnancy, gynecologic cancer/cancer screening, hormones and parenthood were identified as the most important topics. Focus groups generated 80 potential research questions related to these topics. In the final survey 712 individuals prioritized these questions. The highest priority questions in each research topic were: (i) How do perimenopause and menopause affect disease activity, course, response to disease-modifying treatment and quality of life in MS; (ii) What are the most effective strategies for managing issues around sexual intimacy, including related to low sexual desire, changes in physical function, and MS symptoms; (iii) Are there long-term effects of disease-modifying therapies on the children of persons with MS; (iv) What are the short and long-term effects of disease-modifying drugs on gynecologic cancer risk, particularly for high efficacy disease-modifying drugs and hematopoietic stem cell transplantation; (v) Are there hormone related treatments that can stabilize fluctuations in MS symptoms; and (vi) How does MS fatigue impact parenting strategies.ConclusionPriorities for research relating to women’s health issues for persons with MS have been delineated using a collaborative process with key partners. Alignment of future research with these priorities should be monitored

The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states

Constitutivism

A brief explanation and overview of constitutivism