The role of real-world evidence in health technology assessment: a case study of direct oral anticoagulants in the atrial fibrillation population

Real-World Evidence (RWE) refers to any “data used for decision-making that are not collected in conventional Randomised Controlled Trials (RCTs), and is increasingly used in Health Technology Assessment (HTA) as an adjustment to the evidence coming from Randomised Controlled Trials (RCTs). RWE can provide additional evidence concerning treatment safety and effectiveness, facilitate the identification of relevant subpopulations, and permit the inclusion and analysis of clinical endpoints not expected in RCTs but observed in real life. However, the use RWE in the context of HTA is still limited. The aim of this thesis is to explore the role of RWE in economic evaluation by exploring methods to use with observational data and the role of RWE for a case study of direct oral anticoagulants (DOACs); a class of drugs, including apixaban, dabigatran and rivaroxaban, used for the prevention of stroke in the population affected by atrial fibrillation (AF). In addition to quantifying resource use and associated healthcare expenditure for the AF population in Scotland and evaluating propensity score methods for estimating the Average Treatment Effect (ATE), specific objectives are assessing cost as well as effectiveness and safety of DOACs using Scottish linked data. Two cohorts, one consisting of patients with a diagnosis of AF or atrial flutter, and the other of patients on any oral anticoagulant (OAC) were identified from inpatient hospital records and prescribing data for the 1997 – 2015 study period. These data were complemented by outpatient attendances, the care home census and mortality records using individual patient data linkage. As a first step, this thesis assessed the predictors of costs and estimated inpatient, outpatient, prescribing and care-home costs associated with AF, using population-based individual-level linked data. Inpatient admissions accounted for the majority of total costs and these were the main cost driver across all age groups. Overall, inpatient cost contributions (~75 %) were constant across age groups.. This is offset by increasing care-home cost contributions. The inclusion of all available cost components is crucial for establishing overall costs, as these often extend beyond hospitalisation. Most importantly, the thesis found that patients’ age has a limited impact on overall AF-related cost, and therefore may not be the main driver of future growth of AF-related costs in an ageing Scottish population. In order to identify an appropriate method for the comparative-effectiveness analysis, propensity score (PS) based method, such as PS matching, covariate adjustment including PS as covariate, and a series of Inverse Probability Weighting (IPW) methods were tested. A cohort of patients were followed from their first oral anticoagulant prescription to first clinical event (stroke and major bleeding) or death, and censoring was applied to treatment switching or discontinuation. In this methodological chapter, the approach that uses propensity scores (PS) as a covariate was identified as the most robust method to be used in the more comprehensive comparative-effectiveness analysis. The comparative-effectiveness analysis, including additional clinical outcomes that were also used in the pivotal RCTs assessing the efficacy of DOACs versus warfarin in the AF population, found no statistically significant differences in risk of stroke for apixaban, dabigatran and rivaroxaban compared with warfarin. There were however, concerns over safety aspects of rivaroxaban, as it was associated with increased risk of all-cause mortality. The hazard ratios estimated from the comparative-effectiveness analysis were used to populate a Markov model to evaluate the lifetime cost- effectiveness of DOACs compared to warfarin; one-way and probabilistic sensitivity analyses were carried out to assess the uncertainty around the findings and identify key drivers. At the £20,000 threshold, apixaban and dabigatran were found to be cost-effective in AF patients who are 50 years old when starting anticoagulation. Rivaroxaban, being the least effective intervention, was dominated by warfarin, being less costly but more effective than rivaroxaban. This thesis shows the potential of RWE in general and within the Scottish healthcare setting. The findings highlight the importance of taking into account resource utilisation beyond hospital care, and assessing several comparative-effectiveness methods to understand strengths and limitation of each. Most importantly, the findings from this thesis have the potential to inform future research, prescribing patterns and provide real-world evidence for other healthcare settings, especially where rivaroxaban is the DOAC most widely prescribed. Finally, this thesis shows that RWE generated from routinely collected linked data in Scotland, may well support the reassessment of prescription drugs accepted conditionally by the Scottish Medicine Consortium (SMC), an independent organisation that advises the NHS Health Boards about medicines, and would therefore support the SMC in making the final acceptance decision

Problemas de traducción de las distintas versiones de las obras de Camilleri

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Filología, leída el 09-02-2022I testi di Camilleri oggetto di analisi del presente lavoro sono: Il cane di terracotta, La gita a Tindari, Il ladro di merendine. La scelta è ricaduta su tre libri, utili per un’analisi comparativa, e sul primo capitolo di ciascuno dei libri summenzionati vista la notevole mole di lavoro analitico che offrono. Inoltre, l’incipit di ogni libro risulta importante e indicativo dello svolgimento del libro stesso e appare già abbastanza ampia la materia racchiusa in ciascun primo capitolo per un particolareggiato lavoro scientifico.Nel capitolo intitolato “Teoria della traduzione. Traduzione a caratteri generali e linguistica” si affronterà il tema della teoria della traduzione, della traduzione delineata nei suoi caratteri generali e della linguistica; procederò, dunque, con un breve excursus sulla professione del traduttore e sulla storia della traduzione con contributi storici e sviluppi relativamente al tema della traduzione dei testi letterari e in relazione allo stile di Andrea Camilleri; disquisirò sulle analisi e sulle strategie traduttive in merito al passaggio di informazioni dal prototesto al metatesto; approfondirò l’interpretazione e la traduzione dei testi letterari; mi soffermerò sulla traduzione dei testi audiovisivi e sulla produzione televisiva del Commissario Montalbano in un’ottica internazionale; esaminerò il tema della lingua nazionale e del dialetto con la produzione mistilingue di Camilleri; concluderò con una panoramica sulle varietà linguistiche che offre il repertorio italiano contemporaneo.Nel capitolo intitolato “Andrea Camilleri” mi dedicherò al grande scrittore siciliano Andrea Camilleri; alla morte del compianto Maestro e al vuoto che ha lasciato attorno a sé; al profilo dell’autore anche attraverso i libri o le biografie a lui dedicate; mi soffermerò anche su Alberto Sironi e sulla sua dipartita, l’altro papà del Commissario Montalbano...Los textos de Camilleri objeto de análisis de este trabajo son: El perro de terracota, El ladrón de meriendas, La excursión a Tindari. La elección recayó sobre tres libros, útiles para un análisis comparativo, y en el primer capítulo de cada uno de los libros mencionados, dada la considerable cantidad de trabajo analítico que ofrecen. Además, el comienzo de cada libro es importante e indicativo del desarrollo del libro mismo y el tema contenido en cada primer capítulo ya es bastante extenso para un trabajo científico detallado. Después de la introducción, el segundo capítulo tratará el tema de la teoría de la traducción, sus características generales y lingüística; por lo tanto, procederé con un breve recorrido sobre la profesión del traductor y sobre la historia de la traducción con contribuciones históricas y desarrollos sobre el tema de la traducción de textos literarios y en relación con el estilo de Andrea Camilleri; discutiré las estrategias de análisis y traducción con respecto al paso de información del prototexto al metatexto; profundizaré en la interpretación y traducción de textos literarios; me centraré en la traducción de los textos audiovisuales y en la producción televisiva del Comisario Montalbano en una perspectiva internacional; examinaré el tema de la lengua y el dialecto nacionales con la producción en lenguas mixtas de Camilleri; concluiré con un resumen de las variedades lingüísticas que ofrece el repertorio italiano contemporáneo...Fac. de FilologíaTRUEunpu

A two-part model to estimate inpatient, outpatient, prescribing and care home costs associated with atrial fibrillation in Scotland

Objective:This study aimed to estimate global inpatient, outpatient, prescribing and care home costs for patients with atrial fibrillation using population-based, individual-level linked data. Design:A two-part model was employed to estimate the probability of resource utilisation and costs conditional on positive utilisation using individual-level linked data. Settings:Scotland, 5 years following first hospitalisation for AF between 1997 and 2015. Participants: Patients hospitalised with a known diagnosis of AF or atrial flutter. Primary and secondary outcome measures: Inpatient, outpatient, prescribing and care home costs. Results: The mean annual cost for a patient with AF was estimated at £3785 (95% CI £3767 to £3804). Inpatient admissions and outpatient visits accounted for 79% and 8% of total costs, respectively; prescriptions and care home stay accounted for 7% and 6% of total costs. Inpatient cost was the main driver across all age groups. While inpatient cost contributions (~80%) were constant between 0 and 84 years, they decreased for patients over 85 years. This is offset by increasing care home cost contributions. Mean annual costs associated with AF increased significantly with increasing number of comorbidities. Conclusion: This study used a contemporary and representative cohort, and a comprehensive approach to estimate global costs associated with AF, taking into account resource utilisation beyond hospital care. While overall costs, considerably affected by comorbidity, did not increase with increasing age, care home costs increased proportionally with age. Inpatient admission was the main contributor to the overall financial burden of AF, highlighting the need for improved mechanisms of early diagnosis to prevent hospitalisations

Chemical composition of essential oils from Pantelleria Island autochthonous and naturalized spices and evaluation of their individual and combined antimicrobial activities

In this study, the antimicrobial activity of the essential oils (EOs) from Origanum majorana L. and Rosmarinus officinalis L. growing in Pantelleria (Sicily, Italy) were tested alone and in combination against some prokaryotic and eukaryotic food-borne pathogens. The chemical composition of the EOs as well as the minimum inhibitory concentrations (MIC) against the most sensitive strains were also determined. Both EOs showed interesting antimicrobial effects against all bacteria and yeasts tested. MIC was in the range 1.25-2.50 mu l/ml. Interestingly, O. majorana was particularly rich in thymol acetate, while carvacrol was present at very low percentages. Also R. officinalis EOs composition was different from rosemary collected in different areas, as being particularly rich in caryophyllene. Furthermore, the antimicrobial activity of the combination of O. majorana and R. officinalis EOs indicated their potential as food biopreservatives

Understanding Pathways into Care homes using Data (UnPiCD study) a retrospective cohort study using national linked health and social care data: a retrospective cohort study using national linked health and social care data

Background: Pathways into care are poorly understood but important life events for individuals and their families. UK policy is to avoid moving-in to care homes from acute hospital settings. This assumes that moves from secondary care represent a system failure. However, those moving to care homes from community and hospital settings may be fundamentally different groups, each requiring differing care approaches. Objective: To characterise individuals who move-in to a care home from hospital and compare with those moving-in from the community. Design and setting: A retrospective cohort study using cross-sectoral data linkage of care home data. Methods: We included adults moving-in to care homes between 1/4/13 and 31/3/16, recorded in the Scottish Care Home Census. Care home data were linked to general and psychiatric hospital admissions, community prescribing and mortality records to ascertain comorbidities, significant diagnoses, hospital resource use, polypharmacy and frailty. Multivariate logistic regression identified predictors of moving-in from hospital compared to from community. Results: We included 23,892 individuals moving-in to a care home, 13,564 (56.8%) from hospital and 10,328 (43.2%) from the community. High frailty risk adjusted Odds Ratio (aOR) 5.11 (95% Confidence Interval (CI): 4.60–5.68), hospital discharge with diagnosis of fracture aOR 3.91 (95%CI: 3.41–4.47) or stroke aOR 8.42 (95%CI: 6.90–10.29) were associated with moving-in from hospital. Discharge from in-patient psychiatry was also a highly significant predictor aOR 19.12 (95%CI: 16.26–22.48). Conclusions: Individuals moving-in to care homes directly from hospital are clinically distinct from those from the community. Linkage of cross-sectoral data can allow exploration of pathways into care at scale

Fermented Honey and Manna Ash Products: Novel Ecological Niches of Wine Yeasts

The selection of novel strains of yeasts is still relevant to improve flavour of wines produced around the word. Several food niches have not been microbiologically investigated and they might represent important sources of microorganisms with technological aptitudes, e.g. in wine industry. To this purpose, two novel yeast communities associated with matrices rich in carbohydrates and characterized by low levels of water activity (aw), such as fermented honey by-products (FHP) and “Manna” ash products (MAP) extracted from Fraxinus angustifolia (Oleaceae), were investigated. FHP contain mainly fructose and glucose, while MAP ash is mainly characterized by high concentrations of mannitol, fructose and mannotriose. The values of aw of both matrices is around 0.5-0.6. Yeasts were isolated, subjected to the genotypic identification and then technologically characterized to evaluate their oenological potential. The species Lachancea fermentati, Pichia anomala, Pichia kudriavzevii, Saccharomyces cerevisiae, Wickerhamomyces anomalus, Zygosaccharomyces bailii and Zygosaccharomyces rouxii were genetically identified from FHP samples. During the spontaneous alcoholic fermentation, the dominating species were S. cerevisiae, Z. bailii and Z. rouxii whose feed conversion ratio of sugars into ethanol was about 53%. On the other hand, MAP was characterized by the presence of Candida aaseri, Candida lactis-condensi, Citeromyces matritensis, Lachancea thermotolerans, Saccharomyces cerevisiae and Zygosaccharomyces bailii. Interestingly, both matrices showed the presence of S. cerevisiae at consistent levels and a high number of L. thermotolerans strains were isolated from MAP. Both species have interesting eonological potential. Six strains of S. cerevisiae were tested as starters to ferment grape must from Grillo, Catarratto and Chardonnay cultivars at industrial winery-scale over two consecutive years. Interestingly, four strains isolated from FHP showed a fructophilic potential and the experimental wines were characterized by an intense floral flavour. Among non-Saccharomyces yeasts, L. thermotolerans strains showed resistance to ethanol up to 12-13 % (v/v) and ability to ferment grape must with a feed conversion ratio of sugars into ethanol of about 45-55%. Eonological potential was showed by C. lactis-condensi and C. aaseri since a high content of glycerol was produced at the end of alcoholic fermentation and a fructophilic aptitude was found. In conclusions, the present research provided novel microbiological and physicochemical insights on the alcoholic fermentation conducted by novel starters belonging to S. cerevisiae and L. thermotolerans species and, for the first time, the species C. lactis-condensi and C. aaseri were found to be of relevance for wine application