Dioxinas y furanos (PCDD/Fs) en la electro-oxidación de fármacos utilizados en la pandemia de COVID-19. Análisis experimental y teórico

ABSTRACT: The current situation of water resources, within the framework of the global pandemic COVID-19, centers the starting point of this doctoral thesis. The treatments applied in the fight against the SARS-CoV-2 virus, have led to intensive consumption of the drugs dexamethasone (DEX), amoxicillin (AMX), paracetamol (PAR) and sertraline (STR), which finally end in the aquatic medium as part of the group of emerging contaminants (ECs). In this context, advanced oxidation processes (AOPs) are an attractive option for their removal, standing out electrochemical oxidation (EOX) because its high effectiveness. Nevertheless, previous studies have demonstrated that under the application of some AOPs, it may be possible that intermediate and derivative compounds can be generated, possibly more toxic than the initial ones, like polychlorinated dibenzo-p-dioxin and furans (PCDD/Fs). To corroborate this hypothesis, this doctoral thesis has assessed, in an experimental and theoretical way (computational chemistry) the formation of PCDD/Fs and the final toxicity of the samples, after applying EOX to matrices containing the COVID-19 drugs, dexamethasone (DEX), amoxicillin (AMX), paracetamol (PAR) and sertraline (STR).RESUMEN: La situación actual de los recursos hídricos, en el marco de la pandemia mundial COVID-19, es el punto de partida de esta tesis doctoral. El tratamiento aplicado en la lucha contra el virus SARS-CoV-2, ha llevado al consumo intensivo de los fármacos dexametasona (DEX), amoxicilina (AMX), paracetamol (PAR) y sertralina (STR), que finalmente acaban en el medio acuático formando parte del grupo de contaminantes emergentes (CEs). En este contexto, los procesos de oxidación avanzada (POAs) se presentan como una opción atractiva para su eliminación, destacando la oxidación electroquímica (EOX) por su alta eficacia. Sin embargo, estudios previos han demostrado, que, bajo la aplicación de algunos POAs, es posible que se generen compuestos intermedios derivados, que pueden ser más tóxicos que los iniciales, como las dibenzo-p-dioxinas policloradas y los furanos (PCDD/Fs). Para corroborar esta hipótesis, esta tesis doctoral ha evaluado, experimental y teóricamente (química computacional) la formación de PCDD/Fs y la toxicidad final de las muestras, tras aplicar EOX a matrices que contienen los fármacos COVID-19, dexametasona (DEX), amoxicilina (AMX), paracetamol (PAR) y sertralina (STR).This research was financially supported by the Spanish Ministry of Science, Innovation and Universities through the Projects CTM2014-58029-R (MINECO/FEDER,UE), “Identificación y cuantificación de las variables responsables de la potencial formación de PCDD/Fs en procesos de oxidación avanzada”; CTM2017-87740-R (AEI/FEDER, UE) “Aplicación de Tecnologías Ambientales a Matrices Líquidas Conteniendo Contaminantes Orgánicos Emergentes Precursores de la Formación de Derivados Clorados (PCDD/Fs)

The Relationship Between Elevation, Connectedness, and Compassionate Love in Meaningful Films

Expanding on the research of meaningful entertainment media and its effects, this study investigated the relationship between experiences related to elevation responses to film. Whereas research thus far has focused primarily on portrayals of altruism to elicit elevation, the results of this study show that portrayals of connectedness, love, and kindness in meaningful films are also able to elicit feelings of elevation. Moreover, elevation mediated the relationship between meaningful films and feelings of connectedness towards the transcendent, close others and toward one’s family; compassionate love towards close others; and compassionate motivation to love and be good to humanity. The study demonstrates the potential of meaningful films to increase experiences of connectedness to the transcendent, which ultimately can enhance our concern about the well-being of others, and motivation to be more compassionate even to strangers. Implications for the scholarship of positive media psychology are discussed

Obstacles to returning to work with chronic pain : in-depth interviews with people who are off work due to chronic pain and employers

Background: The global burden of chronic pain is growing with implications for both an ageing workforce and employers. Many obstacles are faced by people with chronic pain in finding employment and returning to work after a period of absence. Few studies have explored obstacles to return-to-work (RTW) from workers’ and employers’ perspectives. Here we explore views of both people in pain and employers about challenges to returning to work of people who are off work with chronic pain. Methods: We did individual semi-structured interviews with people who were off work (unemployed or off sick) with chronic pain recruited from National Health Service (NHS) pain services and employment services, and employers from small, medium, and large public or private sector organisations. We analysed data using the Framework method. Results: We interviewed 15 people off work with chronic pain and 10 employers. Obstacles to RTW for people with chronic pain spanned psychological, pain related, financial and economic, educational, and work-related domains. Employers were concerned about potential attitudinal obstacles, absence, ability of people with chronic pain to fulfil the job requirements, and the implications for workplace relationships. Views on disclosure of the pain condition were conflicting with more than half employers wanting early full disclosure and two-thirds of people with chronic pain declaring they would not disclose for fear of not getting a job or losing a job. Both employers and people with chronic pain thought that lack of confidence was an important obstacle. Changes to the job or work conditions (e.g. making reasonable adjustments, phased return, working from home or redeployment) were seen by both groups as facilitators. People with chronic pain wanted help in preparing to RTW, education for managers about pain and supportive working relationships. Conclusions: People with chronic pain and employers may think differently in terms of perceptions of obstacles to RTW. Views appeared disparate in relation to disclosure of pain and when this needs to occur. They appeared to have more in common regarding opinions about how to facilitate successful RTW. Increased understanding of both perspectives may be used to inform the development of improved RTW interventions

Feeding ecology and carrying capacity of a reintroduced pack of African wild dogs in a relatively small, fenced reserve.

Thesis (M.Sc.)-University of KwaZulu-Natal, 2010.Reintroduction has been used successfully as a tool to restore declining populations of many threatened species. However, the lack of detailed evaluations of past reintroduction attempts has hindered a priori planning of management actions to achieve conservation goals. The metapopulation approach resulted in the most extensive and successful reintroduction efforts of the African wild dog (Lycaon pictus) in South Africa, but the approach was only recently evaluated by Gusset et al. (2008). For future reintroduction attempts to be successful on relatively small reserves, extensive evaluations are needed. Particular focus on feeding behaviour and impact on prey populations is essential to predict sustainability and carrying capacities in these areas for the African wild dog. A small reintroduced population of African wild dogs (pack number varying from 3 to 13 during the study period) were studied in the Karongwe Game reserve (79 km2) between January 2002 and January 2004. Fourteen prey species were identified: impala (Aepyceros melampus, 60 %) was the most dominant prey followed in descending order by bushbuck (Tragelaphus scriptus, 7.4 %), waterbuck (Kobus ellipsiprymnus, 4.9 %), warthog (Phacochoerus aethiopicus, 4.7 %), kudu (Tragelaphus strepsiceros, 4.4 %), and grey duiker (Sylvicapra grimmia, 4.4 %). Generally, prey were included in the diet in relation to abundance, and the dogs were not rate maximizing foragers but, unlike the findings of previous studies, were opportunistic feeders. The fences and angles in the fence, were used to assist hunting, but only for medium sized prey, impala and bushbuck, which were killed significantly more than expected along the fence line. A predictive prey preference model was then tested, but the model did not account for possible differences in feeding behaviours and prey preferences found in this, nor another study from the small Shambala Game Reserve. The model had limited accuracy as a predictive tool for proposed reintroductions into relatively small reserves. Models which can predict carrying capacity and minimum area requirements were also tested. Large variation and low numbers were predicted, which conflicted with social requirements needed for the survival of the population; further the models did not account for interspecific competition nor simultaneous depletion of prey by other guild predator. If the metapopulation approach is to continue to be successful and sustainable, more detailed evaluations of reintroductions of African wild dog on relatively small, fenced reserves are needed to determine the impact of these dogs on prey populations, and to determine if African wild dog feeding behaviour does differ for these areas in comparison to previously described open systems. With this information, more appropriate protocols regarding reintroduction and management can then be developed, thereby meeting one goal of management and conservation for the African wild dogs and their coexisting prey populations, and which can be used as a model for managing other large predators

Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV.

PURPOSE: To study recent trends in the incidence of anal cancer in HIV-infected patients receiving long-term combined antiretroviral treatment (cART) compared with the general population. PATIENTS AND METHODS: From the French Hospital Database on HIV, we identified 263 cases of invasive anal squamous cell carcinoma confirmed histologically between 1992 and 2008. We compared incidence rates of anal cancer across four calendar periods: 1992-1996 (pre-cART period), 1997-2000 (early cART period), and 2001-2004 and 2005-2008 (recent cART periods). Standardized incidence ratios (SIRs) were calculated by using general population incidence data from the French Network of Cancer Registries. RESULTS: In HIV-infected patients, the hazard ratio (HR) in the cART periods versus the pre-cART period was 2.5 (95% CI, 1.28 to 4.98). No difference was observed across the cART calendar periods (HR, 0.9; 95% CI, 0.6 to 1.3). In 2005-2008, HIV-infected patients compared with the general population had an excess risk of anal cancer, with SIRs of 109.8 (95% CI, 84.6 to 140.3), 49.2 (95% CI, 33.2 to 70.3), and 13.1 (95% CI, 6.8 to 22.8) for men who have sex with men (MSM), other men, and women, respectively. Among patients with CD4 cell counts above 500/μL for at least 2 years, SIRs were 67.5 (95% CI, 41.2 to 104.3) when the CD4 nadir was less than 200/μL for more than 2 years and 24.5 (95% CI, 17.1 to 34.1) when the CD4 nadir was more than 200/μL. CONCLUSION: Relative to that in the general population, the risk of anal cancer in HIV-infected patients is still extremely high, even in patients with high current CD4 cell counts. cART appears to have no preventive effect on anal cancer, particularly in MSM

Peptidyl-prolyl isomerase 1 (Pin1) preserves the phosphorylation state of tissue factor and prolongs its release within microvesicles

© 2017 Elsevier B.V. The exposure and release of TF is regulated by post-translational modifications of its cytoplasmic domain. Here, the potential of Pin1 to interact with the cytoplasmic domain of TF, and the outcome on TF function was examined. MDA-MB-231 and transfected-primary endothelial cells were incubated with either Pin1 deactivator Juglone, or its control Plumbagin, as well as transfected with Pin1-specific or control siRNA. TF release into microvesicles following activation, and also phosphorylation and ubiquitination states of cellular-TF were then assessed. Furthermore, the ability of Pin1 to bind wild-type and mutant forms of overexpressed TF-tGFP was investigated by co-immunoprecipitation. Additionally, the ability of recombinant or cellular Pin1 to bind to peptides of the C-terminus of TF, synthesised in different phosphorylation states was examined by binding assays and spectroscopically. Finally, the influence of recombinant Pin1 on the ubiquitination and dephosphorylation of the TF-peptides was examined. Pre-incubation of Pin1 with Juglone but not Plumbagin, reduced TF release as microvesicles and was also achievable following transfection with Pin1-siRNA. This was concurrent with early ubiquitination and dephosphorylation of cellular TF at Ser253. Pin1 co-immunoprecipitated with overexpressed wild-type TF-tGFP but not Ser258 → Ala or Pro259 → Ala substituted mutants. Pin1 did interact with Ser258-phosphorylated and double-phosphorylated TF-peptides, with the former having higher affinity. Finally, recombinant Pin1 was capable of interfering with the ubiquitination and dephosphorylation of TF-derived peptides. In conclusion, Pin1 is a fast-acting enzyme which may be utili sed by cells to protect the phosphorylation state of TF in activated cells prolonging TF activity and release, and therefore ensuring adequate haemostasis

Developing a complex intervention to support medication adherence in cancer

Adjuvant endocrine therapy (AET) reduces the risk of breast cancer recurrence and mortality, but up to three-quarters of women do not take AET as prescribed. Most existing interventions aiming to support AET adherence have not been effective. Guided by the Multiphase Optimisation Strategy (MOST), this PhD aimed to develop and assess the acceptability of a complex intervention to support AET adherence. Study One combined Intervention Mapping with MOST to identify barriers to adherence, and develop a conceptual model. The intervention components included; 1) text messages targeting habit formation; 2) an information leaflet targeting medication beliefs; 3) a guided self-help acceptance and commitment therapy programme targeting psychological distress (via increasing psychological flexibility); and 4) self-management website targeting side-effects. Study Two involved a series of studies using mixed-methods to develop text messages promoting habit formation to support AET adherence. A pool of 66 messages, considered acceptable to women with breast cancer and showing fidelity to intended behaviour change techniques, were developed. Study Three used a 2^5 factorial experiment to optimise the content of the information leaflet to increase necessity beliefs and reduce concerns. The leaflet comprised five components. Quotes and pictures from breast cancer survivors was the only component to have a main effect on medication beliefs. There were also four significant interaction effects between other components. A stepped decision-making process led the enhanced side-effect information to be screened out of the optimised leaflet. Study four was a mixed-methods process evaluation, nested in a pilot trial, which aimed to investigate the acceptability of the four intervention components, guided by the theoretical framework of acceptability. All four components were considered acceptable to women taking AET. A complex intervention aiming to support AET adherence was developed and considered acceptable to women with breast cancer. This intervention will now be optimised in an optimisation trial

Representations of motherhood in the media:A systematic literature review

We undertook a systematic review to understand (i) how motherhood is represented across different media, (ii) how the modalities of media domains influence the motherhood representations that they offer, (iii) the gaps in recent research on the subject. We searched 7 databases for all studies investigating the representation of motherhood in media texts, in any geographical location, published after 31 December 2016. We identified 55 studies as relevant to the search criteria and undertook a thematic analysis of their findings. Our contribution is to offer a framework that summarizes and contrasts key themes of motherhood and tensions within and between motherhood ideologies as identified in different media domains

Oligoubiquitination of tissue factor on Lys255 promotes Ser253-dephosphorylation and terminates TF release

Restriction of tissue factor (TF) activity at the cell surface and TF release are critical for prevention of excessive coagulation. This study examined the regulation of TF dephosphorylation and its release through ubiquitination. A plasmid containing the sequence to express the tandem protein TF-tGFP was mutated to include an arginine-substitution at Lys255 within TF. MDA-MB-231 cell line, and HCAEC endothelial cells were transfected and subsequently activated with PAR2-agonist peptide. The wild-type and mutant TF-tGFP were immunoprecipitated from the cell lysates and the ubiquitination and phosphorylation state of TF examined. Analysis of the proteins showed that arginine-substitution of Lys255 within TF prevented its ubiquitination while the wild-type TF-tGFP was oligoubiquitinated. The TF-associated oligoubiquitin chain was estimated to contain up to 4 ubiquitin units, with the linkage formed between Lys63 of one ubiquitin unit, and the C-terminus of the next unit. The Lys255 → Arg substitution of TF-tGFP prolonged the phosphorylation of Ser253 within TF, compared to the wild-type TF-tGFP, lengthened the presence of TF-tGFP at the cell surface and extended the duration of TF-tGFP release from cells following PAR2 activation. A biotinylated 19-mer peptide corresponding to the C-terminus of TF (TFc) was used as substrate to show that the ubiquitination of TF was mediated by the Ube2D family of E2-enzymes and involved Mdm2. Moreover, double-phosphorylation of TFc was prerequisite for ubiquitination, with subsequent dephosphorylation of Ser253 by phosphatase PP2A. In conclusion, oligoubiquitination of Lys255 within TF permits PP2A to bind and dephosphorylate Ser253 and occurs to terminate TF release and contain its activity

Harmful or helpful : perceived solicitous and facilitative partner responses are differentially associated with pain and sexual satisfaction in women with provoked vestibulodynia

Introduction.  Provoked vestibulodynia (PVD) is a highly prevalent vulvovaginal pain condition that negatively affects women's emotional, sexual, and relationship well-being. Recent studies have investigated the role of interpersonal variables, including partner responses. Aim.  We examined whether solicitous and facilitative partner responses were differentially associated with vulvovaginal pain and sexual satisfaction in women with PVD by examining each predictor while controlling for the other. Methods.  One hundred twenty-one women (M age = 30.60, SD = 10.53) with PVD or self-reported symptoms of PVD completed the solicitous subscale of the spouse response scale of the Multidimensional Pain Inventory, and the facilitative subscale of the Spouse Response Inventory. Participants also completed measures of pain, sexual function, sexual satisfaction, trait anxiety, and avoidance of pain and sexual behaviors (referred to as “avoidance”). Main Outcome Measures.  Dependent measures were the (i) Pain Rating Index of the McGill Pain Questionnaire with reference to pain during vaginal intercourse and (ii) Global Measure of Sexual Satisfaction Scale. Results.  Controlling for trait anxiety and avoidance, higher solicitous partner responses were associated with higher vulvovaginal pain intensity (β = 0.20, P = 0.03), and higher facilitative partner responses were associated with lower pain intensity (β = −0.20, P = 0.04). Controlling for sexual function, trait anxiety, and avoidance, higher facilitative partner responses were associated with higher sexual satisfaction (β = 0.15, P = 0.05). Conclusions.  Findings suggest that facilitative partner responses may aid in alleviating vulvovaginal pain and improving sexual satisfaction, whereas solicitous partner responses may contribute to greater pain