10,622 research outputs found
Grasping nothing: a study of minimal ontologies and the sense of music
If music were to have a proper sense – one in which it is truly given – one might reasonably place this in sound and aurality. I contend, however, that no such sense exists; rather, the sense of music takes place, and it does so with the impossible. To this end, this thesis – which is a work of philosophy and music – advances an ontology of the impossible (i.e., it thinks the being of what, properly speaking, can have no being) and considers its implications for music, articulating how ontological aporias – of the event, of thinking the absolute, and of sovereignty’s dismemberment – imply senses of music that are anterior to sound. John Cage’s Silent Prayer, a nonwork he never composed, compels a rerethinking of silence on the basis of its contradictory status of existence; Florian Hecker et al.’s Speculative Solution offers a basis for thinking absolute music anew to the precise extent that it is a discourse of meaninglessness; and Manfred Werder’s [yearn] pieces exhibit exemplarily that music’s sense depends on the possibility of its counterfeiting. Inso-much as these accounts produce musical senses that take the place of sound, they are also understood to be performances of these pieces. Here, then, thought is music’s organon and its instrument
Management of valvular heart disease in patients with cancer: Multidisciplinary team, cancer-therapy related cardiotoxicity, diagnosis, transcatheter intervention, and cardiac surgery. Expert opinion of the Association on Valvular Heart Disease, Association of Cardiovascular Interventions, and Working Group on Cardiac Surgery of the Polish Cardiac Society
The Association on Valvular Heart Disease, Association of Cardiovascular Interventions, and the Working Group on CardiacSurgery of the Polish Cardiac Society have released a position statement on risk factors, diagnosis, and management of patients with cancer and valvular heart disease (VHD). VHD can occur in patients with cancer in several ways, for example, it can exist or be diagnosed before cancer treatment, after cancer treatment, be an incidental finding during imaging tests, endocarditis related to immunosuppression, prolonged intravenous catheter use, or combination treatment, and nonbacterial thrombotic endocarditis. It is recommended to employ close cardiac surveillance for patients at high risk of complications during and after cancer treatment and for cancer treatments that may be cardiotoxic to be discussed by a multidisciplinary team. Patients with cancer and pre-existing severe VHD should be managed according to the 2021 European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) guidelines for VHD management, taking into consideration cancer prognosis and patient preferences
Recommended from our members
European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.
An investigation of the relationship between perioperative characteristics and perioperative anaesthesia on the postoperative systemic inflammatory response and clinical outcome in patients undergoing surgery for colorectal cancer
In UK, colorectal cancer (CRC) is the fourth most common cancer and the second most common cause of cancer death. Until now, surgical resection remains the cornerstone for the management of CRC in all stages, however, stress response elicit from surgery may cause different changes through multiple systems in human body including neural, endocrine, metabolic, inflammatory, and immunological changes. In addition, other perioperative factors such as volatile anaesthetic and opioids may induce the immunosuppression. There is a proportional correlation between the stress response and the magnitude of the inflammatory immune response, invasiveness, and duration of surgery. The pre-operative and post-operative status of patients are important when considering the prognosis. The systemic inflammatory response (SIR) has been recognised to correlate with tumour progression and the prognosis of CRC. An exaggerated postoperative SIR is associated with postoperative infective complications and poor survival. Several predictive markers of the SIR have been used, such as the neutrophil to lymphocyte ratio (NLR), serum C-reactive protein (CRP) level, and Glasgow prognostic score (GPS). Some evidence reported that general anaesthesia (GA) combined with regional anaesthesia (RA) are better than the single use of general anaesthesia in reducing the post-operative immuno-suppression in some degrees. Furthermore, the peri-operative inflammatory process may be affected by the choice of anaesthetic technique, with propofol reported to have anti-inflammatory effect by targeting neutrophil activity. Up to now, there is insufficient evidence to recommend any specific anaesthetic or analgesic technique for patients undergoing surgery for tumour resection based on inflammatory response, recurrence, and metastasis. The work presented in this thesis further examines the relationship between the perioperative characteristics, perioperative anaesthesia, and the postoperative systemic inflammatory response following surgery for colorectal cancer. Several preoperative medications along with anaesthesia might influence the postoperative systemic inflammatory response but the question is whether the post-operative systemic inflammatory response affected by the administration of different types of anaesthesia or not following surgery for colorectal cancer. Chapter 1 discusses the epidemiology, aetiology, carcinogenesis, risk factors of colorectal cancer, pro-carcinogenic factors, anti-carcinogenic agents, inflammation and cancer, the post-operative systemic inflammatory response, tumour staging, screening, and diagnosis of colorectal cancer. Chapter 2 discusses the treatment of colorectal cancer. Chapter 3 discusses different anaesthetic techniques and agents. Chapter 4 provides summary and aims of the thesis. Chapter 5 represents findings from a systematic review and meta-analysis about the effect of anaesthesia on the postoperative systemic inflammatory response in patients undergoing surgery. The results conclude that there was some evidence that anaesthetic regimens may reduce the magnitude of the post-operative SIR. However, the studies identified in this systematic review were heterogeneous and generally of low quality. Chapter 6 represents a retrospective cohort study about the relationship between anaesthetic technique, clinicopathological characteristics and the magnitude of the postoperative systemic inflammatory response in patients undergoing elective surgery for colon cancer. The results show that the type of anaesthesia varied over time and appears to influence the magnitude of the postoperative SIR on post-operative day 2 for those patients who underwent for open surgery but not laparoscopic surgery. Chapter 7 represents a prospective cohort study about the effect of anaesthesia on the magnitude of the postoperative systemic inflammatory response in patients undergoing elective surgery for colorectal cancer in the context of an enhanced recovery pathway. The results show that there was a modest but an independent association between regional anaesthesia (RA) and a lower magnitude of the postoperative SIR. Chapter 8 represents the relationship between pre-operative medications, the type of anaesthesia and post-operative sequelae in patients undergoing surgery for colorectal cancer. The results show that there was no association between the preoperative administration of aspirin, statins and ACE inhibitors and anaesthesia. Chapter 9 represents the relationship between nutritional status, anaesthetic approach, and peri-operative characteristics of patients undergoing surgery for colorectal cancer. The results show that there was no significant association between measures of nutritional status and anaesthetic approach. Chapter 10 represents the relationship between opioid administration, type of anaesthesia and clinicopathological characteristics in patients undergoing surgery for colorectal cancer. The results show that opioid administration was independently associated with both anaesthetic and operative factors. Chapter 11 represents the main findings of the thesis and some recommendation for a future work
Hepatic and Endocrine Aspects of Heart Transplantation
End-organ dysfunction is a progression that can often develop in patients with end-stage heart failure. Hepatic abnormalities in advanced systolic heart failure may affect several aspects of the liver function. Hepatic function is dependent on age, nutrition, previous hepatic diseases, and drugs. The hepatic dysfunction can have metabolic, synthetic, and vascular consequences, which strongly influence the short- and long-term results of the transplantation. In this chapter, the diagnostic and treatment modalities of the transplanted patient will be discussed. On the other hand, endocrine abnormalities, particularly thyroid dysfunction, are also frequently detected in patients on the waiting list. Endocrine supplementation during donor management after brain death is crucial. Inappropriate management of central diabetes insipidus, hyperglycemia, or adrenal insufficiency can lead to circulatory failure and graft dysfunction during procurement. Thyroid dysfunction in donors and recipients is conversely discussed
Unraveling the effect of sex on human genetic architecture
Sex is arguably the most important differentiating characteristic in most mammalian
species, separating populations into different groups, with varying behaviors, morphologies,
and physiologies based on their complement of sex chromosomes, amongst other factors. In
humans, despite males and females sharing nearly identical genomes, there are differences
between the sexes in complex traits and in the risk of a wide array of diseases. Sex provides
the genome with a distinct hormonal milieu, differential gene expression, and environmental
pressures arising from gender societal roles. This thus poses the possibility of observing
gene by sex (GxS) interactions between the sexes that may contribute to some of the
phenotypic differences observed. In recent years, there has been growing evidence of GxS,
with common genetic variation presenting different effects on males and females. These
studies have however been limited in regards to the number of traits studied and/or
statistical power. Understanding sex differences in genetic architecture is of great
importance as this could lead to improved understanding of potential differences in
underlying biological pathways and disease etiology between the sexes and in turn help
inform personalised treatments and precision medicine.
In this thesis we provide insights into both the scope and mechanism of GxS across the
genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK
Biobank. We found small yet widespread differences in genetic architecture across traits
through the calculation of sex-specific heritability, genetic correlations, and sex-stratified
genome-wide association studies (GWAS). We further investigated whether sex-agnostic
(non-stratified) efforts could potentially be missing information of interest, including sex-specific trait-relevant loci and increased phenotype prediction accuracies. Finally, we
studied the potential functional role of sex differences in genetic architecture through sex
biased expression quantitative trait loci (eQTL) and gene-level analyses.
Overall, this study marks a broad examination of the genetics of sex differences. Our findings
parallel previous reports, suggesting the presence of sexual genetic heterogeneity across
complex traits of generally modest magnitude. Furthermore, our results suggest the need to
consider sex-stratified analyses in future studies in order to shed light into possible sex-specific molecular mechanisms
Children with Long Covid: Co-producing a specialist community public health nursing response
© 2021 MA Healthcare Ltd. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.12968/johv.2021.9.10.418Globally, children have been profoundly affected by the COVID-19 pandemic in many ways. Whilst the majority of children with acute COVID-19 infection experience mild illness and fully recover, substantial numbers go on to experience Long Covid. Long Covid is clinically identified by experience of persistent (and sometimes different) symptoms for many months after the acute infection (even in children who were asymptomatic). There is currently no agreed consensus on the case definition of Long Covid but real-world data from American health insurance firms and the UK Office for National Statistics report that children with Long Covid experience: intestinal symptoms, pain, breathlessness, cognitive dysfunction and post-exercise malaise. The current understanding of the natural history, diagnostics and treatments of Long Covid is limited, meaning the medical model in isolation is not helpful. Health visitors and school nurses are ideally placed to case-find children with Long Covid and co-produce child and family-centred care.Peer reviewedFinal Accepted Versio
Uso de las histonas circulantes y sus modificaciones post-traduccionales como biomarcadores en sepsis y shock séptico
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 fisiopatologÃa 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 clÃnicas. 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 crÃticamente 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
The applied psychology of addictive orientations : studies in a 12-step treatment context.
The clinical data for the studies was collected at The PROMIS Recovery Centre, a Minnesota Model treatmentc entre for addictions,w hich encouragesth e membership and use of the 12 step Anonymous Fellowships, and is abstinence based. The area of addiction is contextualised in a review chapter which focuses on research relating to the phenomenon of cross addiction. A study examining the concept of "addictive orientations" in male and female addicts is described, which develops a study conductedb y StephensonM, aggi, Lefever, & Morojele (1995). This presents study found a four factor solution which appeared to be subdivisions of the previously found Hedonism and Nurturance factors. Self orientated nurturance (both food dimensions, shopping and caffeine), Other orientated nurturance (both compulsive helping dimensions and work), Sensation seeking hedonism (Drugs, prescription drugs, nicotine and marginally alcohol), and Power related hedonism (Both relationship dimensions, sex and gambling. This concept of "addictive orientations" is further explored in a non-clinical population, where again a four factor solution was found, very similar to that in the clinical population. This was thought to indicate that in terms of addictive orientation a pattern already exists in this non-clinical population and that consideration should be given to why this is the case. These orientations are examined in terms of gender differences. It is suggested that the differences between genders reflect power-related role relationships between the sexes. In order to further elaborate the significance and meaning behind these orientations, the next two chapters look at the contribution of personality variables and how addictive orientations relate to psychiatric symptomatology. Personality variables were differentially, and to a considerable extent predictably involved with the four factors for both males and females.Conscientiousness as positively associated with "Other orientated Nurturance" and negatively associated with "Sensation seeking hedonism" (particularly for men). Neuroticism had a particularly strong association with the "Self orientated Nurturance" factor in the female population. More than twice the symptomatology variance was explained by the factor scores for females than it was for males. The most important factorial predictors for psychiatric symptomatology were the "Power related hedonism" factor for males, and "Self oriented nurturance" for females. The results are discussed from theoretical and treatment perspectives
Identification of new regenerative therapies in reproductive medicine and their application as a future therapeutic approach for endometrial regeneration
El útero es uno de los principales órganos internos del sistema reproductor femenino. Está compuesto de tres capas tisulares: perimetrio, miometrio y endometrio. Esta última capa recubre la cavidad intrauterina y es responsable directa de la implantación embrionaria (para la cual necesita un grosor endometrial mÃnimo).
Entre las patologÃas que afectan al endometrio pueden distinguirse, entre otras, la atrofia endometrial (insuficiente grosor endometrial) y el sÃndrome de Asherman (presencia de adhesiones intrauterinas y tejido fibrótico), las cuales conforman el hilo conductor de esta tesis, compuesta de 4 artÃculos cientÃficos. En ambos casos, el tejido endometrial se encuentra degenerado, lo que dificulta la implantación embrionaria, ocasionando problemas de fertilidad.
A dÃa de hoy, ninguna de estas patologÃas cuenta con una cura totalmente efectiva. Hasta el momento, una de las opciones terapéuticas más prometedora es la inyección de células madre. Por ello, el primer objetivo de esta tesis fue evaluar como la inyección de células madre derivadas de la médula ósea (aisladas con la detección del antÃgeno CD133), que habÃa resultado ser efectiva tanto en un modelo humano como en uno animal, estaba modificando el endometrio molecularmente. Para asÃ, intentar entender cuáles son los mecanismos paracrinos a través de los cuales llevan a cabo su acción terapéutica. Este primer estudio reveló que estas células madre parecÃan estar promoviendo la regeneración endometrial mediante la creación de un escenario inmunomodulador (sub-expresión del gen CXCL8), que darÃa paso a la sobreexpresión de genes involucrados en la regeneración tisular, como SERPINE1, IL4, y JUN.
Otro tratamiento que ha ido ganando acepción con los años es el plasma rico en plaquetas, eje central del manuscrito 2. Este manuscrito evidencia como este plasma, especialmente si proviene de sangre de cordón umbilical, es capaz de promover procesos celulares, como la migración y la proliferación de las células endometriales, asà como eventos regenerativos en un modelo animal con daño endometrial inducido.
Sea cual sea la aproximación terapéutica de elección, se ha hipotetizado que esta regeneración tisular podrÃa surgir de la estimulación del nicho de células madre presente en el endometrio. Es por ello que el objetivo 3 supuso el estudio de los trabajos publicados, tanto de modelos murinos como humanos, relativos a esta población de células madre endometriales. Esta búsqueda permitió concluir que aún quedan lagunas de conocimiento, bien sea en la definición de marcadores celulares especÃficos o en de la contribución de la médula ósea a este nicho de células madre endometriales.
Finalmente, dada la mencionada falta actual de una terapia definitiva para las pacientes con atrofia endometrial o sÃndrome de Asherman, el cuarto y último objetivo de esta tesis supuso el estudio de todas aquellas aproximaciones que se han llevado a cabo en modelos animales que simulan este tipo de patologÃas humanas. Este trabajo concluyó que si bien están emergiendo nuevas terapias muy prometedoras, como son aquellas derivadas de la bioingenierÃa (por ejemplo, uso de hidrogeles o biomoldes), todavÃa falta perfeccionar y estandarizar los modelos tanto animales como in vitro que permitan una mejor traslación clÃnica de las mismas.The uterus is one of the main internal organs of the female reproductive system. It is composed of three different tissue layers: perimetrium, myometrium, and endometrium. This last layer covers the intrauterine cavity and is directly responsible for embryo implantation (for which it needs a certain minimum endometrial thickness).
Among the pathologies affecting the endometrium, we can distinguish, among others, endometrial atrophy (characterized by an insufficient endometrial thickness) and Asherman's syndrome (a rare disease characterized by the presence of intrauterine adhesions and fibrotic tissue), which form the common thread of this thesis, composed of four original manuscripts. In both cases, the endometrial tissue is degenerated, which hinders the correct embryo implantation, causing then fertility problems.
To date, none of these pathologies has a totally effective cure. So far, one of the most promising therapeutic options is the injection of stem cells. Therefore, the first objective was to evaluate how the infusion of bone marrow-derived stem cells (isolated with the antigen CD133), which had proven effective in both a human and an animal model, was modifying the endometrium at the molecular level. Then, this work aimed to understand the paracrine mechanisms through which these cells were carrying out their therapeutic and regenerative action over the endometrial tissue. This first study revealed that these stem cells appeared to be promoting endometrial regeneration by creating an immunomodulatory scenario (down-regulation of the CXCL8 gene), which would give way to the over-expression of genes (SERPINE1, IL4, and JUN) involved in tissue regeneration.
Another treatment gaining acceptance over the years is a blood derivate, platelet-rich plasma, which was the focus of the second manuscript. This work shows how this plasma, mainly derived from umbilical cord blood rather than adult peripheral blood, can promote cellular processes, such as cell migration and proliferation of different types of endometrial cells (from primary culture and from stem cell lines). These plasmas also revealed how they triggered the over-expression of certain proteins involved in regenerative events in a mouse model with induced endometrial damage.
Whatever the therapeutic approach of choice, it has been hypothesized that regeneration could arise from stimulation of the stem cell niche present in the endometrium. That is why objective three involved studying those works, both murine and human models, concerning this population of endometrial stem cells. This search concluded that there are still gaps in knowledge, either in the definition of specific endometrial stem cell markers or in the contribution of the bone marrow to this endogenous endometrial stem cell niche.
Finally, given the aforementioned current lack of definitive therapy for patients with endometrial atrophy or Asherman's syndrome, the last objective involved studying all those approaches that have been carried out in animal models that simulate this type of human pathology. This work concluded that although new therapies are emerging, such as those derived from bioengineering (e.g. use of decellularized scaffolds or hydrogels), there is still a need to perfect and standardize both animal and in vitro models to allow a better clinical translation of these therapies
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