15,133 research outputs found

    The Genetics of Pain: An exploration of gene-by-environment interactions and their effects on pain

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    The findings presented in this dissertation are part of the bigger SYMBIOME project which aims to use the biopsychosocial model of pain to develop a prognostic clinical phenotype for people that experience musculoskeletal (MSK) trauma. Chapter 2 presents an exploratory analysis to assess the relationships between genetic polymorphisms and pain severity and interference. Early childhood trauma was also explored as a moderator between genetic polymorphisms and pain outcomes. For pain severity, major allele carriers (A/A and G/A) of FKBP5 rs9394314 reported significantly higher scores than minor allele carriers (G/G). Further, major allele carriers who had at least one adverse childhood experience (ACE) reported significantly higher scores than minor allele carriers with at least one ACE. For pain interference, minor allele carriers (G/G) of CNR2 rs2501431 scored significantly higher than major allele carriers (A/A and G/A). Chapter 3 presents a cluster analysis that combines genotypes of FKBP5 rs9394314 and CNR2 rs2501431 to explore meaningful relationships with pain and trauma-related distress. ACE was also explored as a moderator of these relationships. Three clusters were identified where the second cluster characterized by major allele carriers of rs9394314 and minor allele carriers of rs2501431 reported significantly higher pain-related functional interference scores. Participants in the second cluster with at least one ACE reported higher pain interference and traumatic distress scores compared to the third cluster, while participants in the first cluster with at least one ACE reported higher pain severity compared to the first cluster. Chapter 4 presents genomic structural equation models (SEM) that explore the relationships of genotypes with trauma-related distress using the traumatic injuries distress scale (TIDS), ACE, and recovery outcomes. The results demonstrate a relationship between TIDS and recovery outcomes, and an indirect relationship between FKBP5 rs9394314 and recovery outcomes exist which is mediated by TIDS. Major allele carriers of FKBP5 rs9394314 reported higher TIDS scores, which was also demonstrated for participants that had at least one ACE. Major allele carriers that scored higher on the TIDS were predicted to be in the none-recovered category. These results support the notion that gene-x-environment interactions may play an important role in pain and recovery

    The Professional Identity of Doctors who Provide Abortions: A Sociological Investigation

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    Abortion is a medicalised problem in England and Wales, where the law places doctors at the centre of legal provision and puts doctors in control of who has an abortion. However, the sex-selection abortion scandal of 2012 presented a very real threat to 'abortion doctors', when the medical profession's values and practices were questioned in the media, society and by Members of Parliament. Doctors found themselves at the centre of a series of claims that stated doctors were acting both illegally and unethically, driven by profit rather than patient needs. Yet, the perspectives of those doctors who provide abortions has been under-researched; this thesis aims to fill that gap by examining the beliefs and values of this group of doctors. Early chapters highlight the ambiguous position of the abortion provider in Britain, where doctors are seen as a collective group of professionals motivated by medical dominance and medical autonomy. They outline how this position is then questioned and contested, with doctors being presented as unethical. By studying abortion at the macro-, meso- and micro-levels, this thesis seeks to better understand the values of the 'abortion doctor', and how these levels shape the work and experiences of abortion providers in England and Wales. This thesis thus addresses the question: 'What do abortion doctors' accounts of their professional work suggest about the contemporary dynamics of the medicalisation of abortion in Britain?'. It investigates the research question using a qualitative methodological approach: face-to-face and telephone interviews were conducted with 47 doctors who provide abortions in England and Wales. The findings from this empirical study show how doctors' values are linked to how they view the 'normalisation of abortion'. At the macro-level doctors, openly resisted the medicalisation of abortion through the position ascribed to them by the legal framework, yet at the meso-level doctors construct an identity where normalising abortion is based on further medicalising services. Finally, at the micro-level, the ambiguous position of the abortion provider is further identified in terms of being both a proud provider and a stigmatised individual. This thesis shows that while the existing medicalisation literature has some utility, it has limited explanatory power when investigating the problem of abortion. The thesis thus provides some innovative insights into the relevance and value of medicalisation through a comprehensive study on doctors' values, beliefs and practices

    Understanding interactions between Ramularia collo-cygni and barley leaf physiology to target improvements in host resistance and disease control strategy

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    Ramularia Leaf Spot (RLS) is an increasingly problematic disease of barley. Control options are limited as the causal fungus, Ramularia collo-cygni, has developed resistance to several of the major fungicide groups. Developing new methods for controlling this disease is therefore a priority. R. collo-cygni can grow systemically in barley plants from infected seed, without inducing visible symptoms. In the field, visible symptoms normally only appear after flowering. The relative contribution of the latent and symptomatic stages of the fungal lifecycle to reduction in barley yield is not currently known with any certainty. Two possibilities are that the effect of asymptomatic infection on pre-flowering photosynthetic activity, and the development of grain sink capacity, plays an important role; or that reduction in photosynthetic activity during grain filling, resulting from lesion development and loss of green leaf area, is the predominant factor. This research aimed to increase our understanding of the impact of different phases of the fungal lifecycle on barley photosynthesis and yield formation, to better target host resistance and disease control strategies. Controlled environment and field experiments were used to determine the relative effects of asymptomatic and symptom-expressing phases of R. collo-cygni infection on photosynthesis and yield formation in spring barley. In controlled environment experiments leaf photosynthetic activity was measured in seedlings inoculated with suspensions of R. collo-cygni mycelia. Measurements were made before and after visible symptom development using Infra-Red Gas Analysis (IRGA), chlorophyll fluorescence analysis and chlorophyll fluorescence imaging. No reduction in photosynthetic activity was observed in leaves infected with R. collo-cygni, compared to those of non- infected leaves, during the latent phase of infection. After the appearance of visible symptoms, photosynthetic activity within lesions reduced as the lesions developed. However, this did not lead to reductions in photosynthetic activity when measured across the whole leaf area, suggesting that for there to be a significant effect of disease on whole leaf photosynthetic activity, visible symptoms must develop into mature lesions and coalesce to cover larger areas of the leaf surface. In field experiments plots were treated with a full fungicide regime, left untreated, or inoculated with R. collo-cygni and treated with fungicide to which R. collo-cygni is resistant (the latter as a precaution against lack of natural RLS disease that year and/or other diseases developing on untreated plots). RLS was the only disease of significance that developed in untreated or inoculated plots. Symptoms first appeared after flowering, around Zadoks Growth Stage 72. Fungicide-treated plots remained free of disease. Chlorophyll fluorescence analysis of field plants showed no effect of infection on the maximum quantum efficiency of Photosystem II (Fv/Fm) before visible symptom development, consistent with results from controlled environment experiments. Grain yield of untreated and fungicide-treated plots was predicted from fixed common values of radiation use efficiency (RUE) and utilisation of soluble sugar reserves, and measured values of post-flowering healthy (green) leaf area light interception. Grain yields predicted from the difference in post-flowering light interception between fungicide-treated plants and untreated or inoculated plants displaying symptoms of RLS were comparable with the measured yield response to fungicide. This suggests that yield loss to RLS is primarily associated with a reduction in light capture during grain filling, resulting from lesion development and loss of green leaf area. Results from controlled environment and field experiments suggested that symptom expression was associated with leaf senescence. Further controlled environment experiments tested this relationship by using treatments to vary the onset and rate of leaf senescence. Seedlings that were treated with cytokinin to delay senescence after inoculation with suspensions of R. collo-cygni mycelia developed fewer lesions than control plants. Fungal growth, as measured by quantification of R. collo-cygni DNA in leaves, was also restricted in plants treated with cytokinin. Collectively these results suggest that prevention of visible symptom development, rather than prevention of asymptomatic growth, is the most important target for management of this disease. Control methods targeted at delaying senescence could be a useful avenue for further investigation

    TOWARDS AN UNDERSTANDING OF EFFORTFUL FUNDRAISING EXPERIENCES: USING INTERPRETATIVE PHENOMENOLOGICAL ANALYSIS IN FUNDRAISING RESEARCH

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    Physical-activity oriented community fundraising has experienced an exponential growth in popularity over the past 15 years. The aim of this study was to explore the value of effortful fundraising experiences, from the point of view of participants, and explore the impact that these experiences have on people’s lives. This study used an IPA approach to interview 23 individuals, recognising the role of participants as proxy (nonprofessional) fundraisers for charitable organisations, and the unique organisation donor dynamic that this creates. It also bought together relevant psychological theory related to physical activity fundraising experiences (through a narrative literature review) and used primary interview data to substantiate these. Effortful fundraising experiences are examined in detail to understand their significance to participants, and how such experiences influence their connection with a charity or cause. This was done with an idiographic focus at first, before examining convergences and divergences across the sample. This study found that effortful fundraising experiences can have a profound positive impact upon community fundraisers in both the short and the long term. Additionally, it found that these experiences can be opportunities for charitable organisations to create lasting meaningful relationships with participants, and foster mutually beneficial lifetime relationships with them. Further research is needed to test specific psychological theory in this context, including self-esteem theory, self determination theory, and the martyrdom effect (among others)

    An agile development cycle of an online memory program for healthy older adults

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    Online interventions for older adults should be tailored to their unique needs to increase the efficacy of and adherence to the intervention. The agile development cycle is a dynamic model to solicit and incorporate feedback from older adults during the design process. We combined this approach with the framework of Harvard University’s clinical and translational phases that provide a clear structure for evaluating new health programs before they are offered in the community. We based our online memory program on the empirically validated in-person Memory and Aging Program. The aim of the present study was to combine the agile development cycle with the clinical and translational phases framework to develop and pilot an online memory program tailored to the unique needs of older adults. Study 1 involved piloting individual program modules on site and integrating participant feedback into the program’s design to optimize usability. Study 2 involved two sequential pilots of the program accessed remotely to evaluate preliminary clinical outcomes and obtain feedback for iterative modifications. Plans for further validation and limitations are discussed. The successful application of the agile development cycle implemented in this series of studies can be adapted by others seeking to offer online content for targeted end users. Les interventions en ligne pour les personnes âgées doivent être adaptées à leurs besoins spécifiques afin d’augmenter leur efficacité et l’adhésion des utilisateurs. Le cycle de développement agile est un modèle dynamique permettant de solliciter et d’intégrer les commentaires des personnes âgées au cours du processus de conception. Nous avons combiné cette approche avec le Cadre des phases cliniques et translationnelles de l’université Harvard qui fournit une structure claire pour évaluer les nouveaux programmes de santé avant qu’ils ne soient proposés dans la communauté. Nous avons élaboré notre programme en ligne sur la mémoire à partir du programme sur la mémoire et le vieillissement qui se donnait en présentiel, et qui avait été validé empiriquement. L’objectif de l’étude était d’associer le cycle de développement agile avec le Cadre des phases cliniques et translationnelles pour concevoir et tester un programme pilote en ligne sur la mémoire qui est adapté aux besoins uniques des personnes âgées. L’étude no 1 a permis de tester dans une phase pilote les modules individuels du programme avec des participants présents sur place, et à intégrer leurs commentaires lors du développement du programme afin d’en optimiser la convivialité. L’étude no 2 a consisté en deux pilotes séquentiels du programme accessibles à distance dans lesquels les résultats cliniques préliminaires ont été évalués et des commentaires ont été collectés pour guider les modifications itératives. Les plans pour une validation ultérieure et les limites des études sont discutés. L’application réussie du cycle de développement agile mis en œuvre dans cette série d’études pourra être adaptée par d’autres équipes souhaitant proposer un contenu en ligne à des groupes d’utilisateurs finaux plus spécifiques

    What is the importance of sperm subpopulations?

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    .The study of sperm subpopulations spans three decades. The origin, meaning, and practical significance, however, are less clear. Current technology for assessing sperm morphology (CASA-Morph) and motility (CASA-Mot) has enabled the accurate evaluation of these features, and there are many options for data classification. Subpopulations could occur as a result of the stage of development of each spermatozoon in the subpopulation. Spermatogenesis might contribute to the production of these subpopulations. Insights from evolutionary biology and recent molecular research are indicative of the diversity among male gametes that could occur from unequal sharing of transcripts and other elements through cytoplasmic bridges between spermatids. Sperm cohorts exiting the gonads would contain different RNA and protein contents, affecting the spermatozoon physiology and associations with the surrounding environmental milieu. Subsequently, these differences could affect how spermatozoa interact with the environmental milieu (maturation, mixing with seminal plasma, and interacting with the environmental milieu, or female genital tract and female gamete). The emergence of sperm subpopulations as an outcome of evolution, related to the reproductive strategies of the species, genital tract structures, and copulatory and fertilization processes. This kind of approach in determining the importance of sperm subpopulations in fertilization capacity should have a practical impact for conducting reproductive technologies, inspiring and enabling new ways for the more efficient use of spermatozoa in the medical, animal breeding, and conservation fields. This manuscript is a contribution to the Special Issue in memory of Dr. Duane GarnerS

    A productive response to legacy system petrification

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    Requirements change. The requirements of a legacy information system change, often in unanticipated ways, and at a more rapid pace than the rate at which the information system itself can be evolved to support them. The capabilities of a legacy system progressively fall further and further behind their evolving requirements, in a degrading process termed petrification. As systems petrify, they deliver diminishing business value, hamper business effectiveness, and drain organisational resources. To address legacy systems, the first challenge is to understand how to shed their resistance to tracking requirements change. The second challenge is to ensure that a newly adaptable system never again petrifies into a change resistant legacy system. This thesis addresses both challenges. The approach outlined herein is underpinned by an agile migration process - termed Productive Migration - that homes in upon the specific causes of petrification within each particular legacy system and provides guidance upon how to address them. That guidance comes in part from a personalised catalogue of petrifying patterns, which capture recurring themes underlying petrification. These steer us to the problems actually present in a given legacy system, and lead us to suitable antidote productive patterns via which we can deal with those problems one by one. To prevent newly adaptable systems from again degrading into legacy systems, we appeal to a follow-on process, termed Productive Evolution, which embraces and keeps pace with change rather than resisting and falling behind it. Productive Evolution teaches us to be vigilant against signs of system petrification and helps us to nip them in the bud. The aim is to nurture systems that remain supportive of the business, that are adaptable in step with ongoing requirements change, and that continue to retain their value as significant business assets

    The Idiosyncrasy of Involuntary Musical Imagery Repetition (IMIR) Experiences: The Role of Tempo and Lyrics

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    Involuntary musical imagery repetition (IMIR), colloquially known as “earworms,” is a form of musical imagery that arises involuntarily and repeatedly in the mind. A growing number of studies, based on retrospective reports, suggest that IMIR experiences are associated with certain musical features, such as fast tempo and the presence of lyrics, and with individual differences in music training and engagement. However, research to date has not directly assessed the effect of such musical features on IMIR and findings about individual differences in music training and engagement are mixed. Using a cross-sectional design (Study 1, n = 263), we examined IMIR content in terms of tempo (fast, slow) and presence of lyrics (instrumental, vocal), and IMIR characteristics (frequency, duration of episode and section) in relation to 1) the musical content (tempo and lyrics) individuals most commonly expose themselves to (music-listening habits), and 2) music training and engagement. We also used an experimental design (Study 2, n = 80) to test the effects of tempo (fast or slow) and the presence of lyrics (instrumental or vocal) on IMIR retrieval and duration. Results from Study 1 showed that the content of music that individuals are typically exposed to with regard to tempo and lyrics predicted and resembled their IMIR content, and that music engagement, but not music training, predicted IMIR frequency. Music training was, however, shown to predict the duration of IMIR episodes. In the experiment (Study 2), tempo did not predict IMIR retrieval, but the presence of lyrics influenced IMIR duration. Taken together, our findings suggest that IMIR is an idiosyncratic experience primed by the music-listening habits and music engagement of the individual

    Uso de las histonas circulantes y sus modificaciones post-traduccionales como biomarcadores en sepsis y shock séptico

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    La sepsis es una afección potencialmente mortal causada por una respuesta anormal del huésped a una infección, produciendo respuestas fisiológicas alteradas que dañan los propios tejidos del paciente y pueden provocar disfunción orgánica e incluso la muerte. Asimismo, algunos pacientes sépticos progresan a shock séptico, caracterizado por alteraciones circulatorias, celulares y metabólicas sustanciales que aumentan el riesgo de mortalidad. A pesar de que la sepsis se caracteriza por un mal funcionamiento del sistema inmunológico, lo que a su vez conduce a una respuesta inmune alterada e inmunosupresión, la alta complejidad de la fisiopatología de la sepsis requiere una mayor investigación para comprender las respuestas inmunes que ocurren durante la sepsis. Asimismo, las histonas extracelulares circulantes han ganado relevancia como mediadores citotóxicos en la sepsis, ya que actúan como patrones moleculares asociados a daño, que inducen estrés oxidativo y activan el inflamasoma NLRP3. Estos mecanismos median la activación de la piroptosis, un mecanismo de muerte celular programada que produce inflamación mediante la expresión de IL-18, IL-1β and IL-1α. Sin embargo, a pesar de la evidencia de activación del inflamasoma en las células inmunes durante la sepsis, se desconoce si las histonas extracelulares son capaces de activar los inflamasomas endoteliales y sus consecuencias. En este trabajo destacamos el papel previamente desconocido de las histonas extracelulares, mediando la activación del inflamasoma NLRP3 y la piroptosis en las células endoteliales, contribuyendo a la disfunción endotelial y la desregulación de la respuesta inmune mediada por el endotelio. Asimismo, también demostramos cómo la acetilación de histonas disminuye la activación de la piroptosis. Además, demostramos que la piroptosis se produce en pacientes con shock séptico y los niveles de histonas circulantes se correlacionan con la expresión de citoquinas proinflamatorias y citoquinas piroptóticas, la liberación de factores de adhesión endotelial y la gravedad de la enfermedad. Proponemos la piroptosis mediada por histonas como un nuevo objetivo para desarrollar intervenciones clínicas. De manera similar, hemos analizado las respuestas inmunorelacionadas que ocurren durante las primeras etapas de la sepsis con el objetivo de proporcionar nuevos datos comparando las cantidades de citoquinas, inmunomoduladores y otros mediadores endoteliales en pacientes críticamente enfermos no sépticos, sépticos y de shock séptico. Nuestro enfoque ayudará a caracterizar rápidamente las respuestas inmunes alteradas en pacientes sépticos y de shock séptico ingresados en la Unidad de Cuidados Intensivos. Finalmente analizamos el papel de la metilación del ADN en el control del sistema inmune séptico. Nuestros resultados demostraron el papel central de la metilación del ADN modulando la respuesta molecular en los pacientes de shock séptico y contribuyendo a la inmunosupresión, a través de la alteración de los patrones de metilación de los promotores de IL-10 y TREM-2.Sepsis is a life-threatening condition caused by an abnormal host response to an infection that produce altered physiological responses which damages own tissues of the patient and can result in organ dysfunction and in some cases death. Likewise, a subset of septic patients progresses to septic shock, characterized by substantial circulatory, cellular and metabolic abnormalities, which substantially increase the risk of mortality. Sepsis is characterized by a malfunction of the immune system and it can lead to an altered immune response and immunosuppression. Moreover, the high complexity of the pathophysiology of sepsis requires of further investigation to characterize the immune responses in sepsis and septic shock. Likewise, circulating extracellular histones have gained relevance as cytotoxic mediators in sepsis pathophysiology, since they act as damage-associated molecular patterns, which induce oxidative stress and activate NLRP3 inflammasome. Subsequently, inflammasome mediates pyroptosis activation, a programmed cell death mechanism that produces inflammation through the release of IL-18, IL-1β and IL-1α. However, despite inflammasome activation may occur in immune cells during sepsis, it is unknown if this process also takes place in endothelial cells and particularly whether extracellular histones are capable of activating endothelial inflammasomes and their consequences. In this work we highlight a previously unknown role for extracellular histones, that mediates the activation of NLRP3 inflammasome and pyroptosis in endothelial cells by contributing to endothelial dysfunction and the dysregulation of the immune response mediated by endothelium. Likewise, we demonstrated how histone acetylation decreases pyroptosis activation. Furthermore, we show how pyroptosis occurs in septic shock patients and how circulating histone levels correlate with the expression of pro-inflammatory and pyroptotic cytokines, the release of endothelial adhesion factors and septic shock severity. We propose histone-mediated pyroptosis as a new target to develop clinical interventions. Similarly, we have analyzed the immune-related responses occurring during the early stages of sepsis with the aim of providing new data by comparing the amounts of cytokines, immune modulators and other endothelial mediators in critically-ill non-septic patients, septic and septic shock patients. Our approach will help to rapidly characterize the altered immune responses in septic and septic shock patients admitted in the Intensive Care Unit. Finally, we also analyzed the role of DNA methylation in the control of septic immune system. Our results demonstrated the central role of DNA methylation modulating the molecular response in septic shock patients and contributing to immunosuppression, through the alteration of DNA methylation patterns of IL-10 and TREM2 promoters
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