Hepatoma Tissue Culture (HTC) cells grown in the presence of 60µM arachidonic acid for 24, 36 and 48 hours became progressively more thermosensitive than control cells. However, this difference in thermal sensitivity was only detectable with the clonogenic assay and not with the colorimetric assay. Attempts were also made to manipulate cellular cholesterol levels. Firstly, some cells were incubated with phosphatidylcholine liposomes to deplete the plasma membrane of cholesterol: Secondly, another group of cells were treated with 25 hydroxycholesterol, an inhibitor of cholesterol synthesis, to lower cholesterol levels: Finally, a third group of cells were supplemented with cholesterol hemisuccinate, a hydrophilic ester of cholesterol. The first two approaches did not enhance the thermal sensitivity of HTC cells. Supplementation with cholesterol hemisuccinate, which was predicted to partition in to the plasma membrane and reduce membrane fluidity, resulted in increased thermal sensitivity of the cells. Thus, the thermal sensitivity of HTC cells could be enhanced by supplementation with either arachidonate or cholesterol hemisuccinate. A rapid plasma membrane isolation procedure was developed which generated plasma membranes in relatively high yield and purity. The plasma membrane- enriched fraction was also assayed for contaminating intracellular membranes by determining marker enzyme activities associated with these membranes. Using this method, plasma membranes were prepared from HTC cells grown m 60µM arachidonic acid for 36 hours and from cells grown in normal medium. Analysis of the plasma membrane showed that the arachidonic acid content of the phospholipid fatty acyl groups had been significantly increased in cells grown in the presence of this fatty acid. There was no change in the cholesterol/phospholipid molar ratio or cholesterol concentration relative to amount of protein in the plasma membranes from the two cell populations. The measurement of fluidity using DPH fluorescence polarisation revealed that the increase in the arachidomc acid content of the plasma membrane phospholipid acyl groups was associated with enhanced plasma membrane fluidity when compared to control plasma membranes. This increase in plasma membrane fluidity correlated with the enhanced thermal sensitivity of the cells grown in arachidonic acid-containing medium when compared to cells grown in normal medium. Furthermore, the thermal sensitivity of Na(^+), K(^+) –ATPase and alkaline phosphodiesterase I were assessed in plasma membranes derived from arachidonic acid-supplemented and control cells. The enhanced fluidity of plasma membranes derived from arachidonate-supplemented cells also correlated with increased thermosensitivity of alkaline phosphodiesterase I.

UA Open Access Publishing Fund / Background Missing outcome data is a threat to the validity of treatment effect estimates in randomized controlled trials. We aimed to evaluate the extent, handling, and sensitivity analysis of missing data and intention-to-treat (ITT) analysis of randomized controlled trials (RCTs) in top tier medical journals, and compare our findings with previous reviews related to missing data and ITT in RCTs. Methods Review of RCTs published between July and December 2013 in the BMJ, JAMA, Lancet, and New England Journal of Medicine, excluding cluster randomized trials and trials whose primary outcome was survival. Results Of the 77 identified eligible articles, 73 (95%) reported some missing outcome data. The median percentage of participants with a missing outcome was 9% (range 0 – 70%). The most commonly used method to handle missing data in the primary analysis was complete case analysis (33, 45%), while 20 (27%) performed simple imputation, 15 (19%) used model based methods, and 6 (8%) used multiple imputation. 27 (35%) trials with missing data reported a sensitivity analysis. However, most did not alter the assumptions of missing data from the primary analysis. Reports of ITT or modified ITT were found in 52 (85%) trials, with 21 (40%) of them including all randomized participants. A comparison to a review of trials reported in 2001 showed that missing data rates and approaches are similar, but the use of the term ITT has increased, as has the report of sensitivity analysis. Conclusions Missing outcome data continues to be a common problem in RCTs. Definitions of the ITT approach remain inconsistent across trials. A large gap is apparent between statistical methods research related to missing data and use of these methods in application settings, including RCTs in top medical journals.

"High strength aluminum alloys are recently widely used in aircraft, automobile and construction industry fields. Typical T6 heat treatment process can be applied to improve the heat treatable aluminum alloy in order to facilitate the formation of prime strengthening precipitate phases. Critical steps in T6 heat treatment process include solution treatment, quenching and aging. Due to high thermal gradients in quenching process and aging process, large thermal stress will remain in the matrix and may bring unexpected deformation or distortion in further machining. Therefore, in order to predict the thermal stress effects, constitutive model and precipitate hardening model are needed to simulate the mechanical properties of alloy. In this dissertation, an optimized constitutive model, which is used to describe the mechanical behavior during quenching and intermediate period of quenching and aging process, was given based on constitutive models with Zenor-Holloman parameter. Modification for constitutive model is based on the microstructure model, which is developed for the quenching and aging processes. Quench factor analysis method was applied to describe the microstructure evolution and volume fraction of primary precipitate phases during quenching process. Some experimental phenomena are discussed and explained by precipitate distributions. Classical precipitate hardening models were reviewed and two models were selected for Al-Cu-Mn alloy aging treatment. Thermal growth model and Euler algorithm were used to improve the accuracy and the selected precipitate hardening models were validated by yield stress and microstructure observations of Al-Cu-Mn aging response experiments."

Doctor of Philosophy / Department of Mechanical and Nuclear Engineering / Douglas S. McGregor / Advancements in nuclear reactor core modeling and computational capability have encouraged further development of in-core neutron sensors. Measurement of the neutron-flux distribution within the reactor core provides a more complete understanding of the operating conditions in the reactor than typical ex-core sensors. Micro-Pocket Fission Detectors (MPFDs) have been developed and tested previously but have been limited to single-node operation and have utilized highly specialized designs. The development of a widely deployable, multi-node MPFD assembly will enhance nuclear research capabilities. In-core neutron flux measurements include many challenges because of the harsh environment within the reactor core. Common methods of in-core neutron measurement are also limited by geometry and other physical constraints. MPFDs are designed to be small and robust while offering a real-time, spatial measurement of neutron flux. Improvements to the MPFD design were developed based on shortcomings of prior research in which many of the theoretical considerations for MPFDs were examined. Fabrication techniques were developed for the preparation of MPFD components and electrodeposition of fissile material. Numerous arrays of MPFDs were constructed for test deployments at the Kansas State University TRIGA Mk. II research nuclear reactor, University of Wisconsin Nuclear Reactor, Transient REActor Test facility at the Idaho National Laboratory (INL), and Advanced Test Reactor at INL. Preliminary testing of a single MPFD sensor at KSU yielded a linear response to reactor power between 10 kWth and 750 kWth and followed both positive and negative reactivity insertions in real-time. A $1.50 reactor pulse was monitored from the Intra-Reflector Irradiation System, located in reflector region of the KSU TRIGA Mk. II core with 1-ms time resolution. Improved multi-node MPFD arrays were then designed, fabricated, and deployed in flux ports between fuel rods and within an iron-wire flux port which was inserted into the central thimble of the KSU TRIGA Mk. II research nuclear reactor. Work continues to develop MPFDs for deployment at research reactors at INL and elsewhere. Results from the MPFD measurements will be useful for future validation of computational modeling and as part of advanced nuclear fuel development efforts.

<p>OBJECTIVES: The primary objective of this systematic review was to illustrate the various definitions authors of methodology articles have offered for intention to treat (ITT) in relation to loss to follow up (LTFU).</p> <p> METHODS: We searched MEDLINE® for publications appearing between 1950 to 2008. Eligible papers devoted at least one paragraph to ITT and two other paragraphs to either ITT or LTFU. Investigators independently extracted relevant information from each eligible article. Discrepancies between data extractors were adjudicated. Data was extracted and variables used during data extraction were analyzed using the Landis and Koch guidelines kappa values.</p> <p> RESULTS: The MEDLINE® search yielded 1007 articles. One-hundred and ten articles underwent full text screening yielding 66 articles. All kappa's were substantial to near perfect agreement (>0.74). Of the 66 articles, five (8%) did not define ITT, 25 (41%) mentioned LTFU but did not discuss its relationship with ITT, 36 (59%) commented on LTFU in the context of ITT. These 36 articles segregated into three distinctive definitions for ITT: "full-follow-up required" (mentioned 58%), "ITT and LTFU are separate issues" (mentioned 17%), and "ITI involves specific strategy for LTFU" (mentioned 78%). Of the 36 articles, 17 (47%) had multiple definitions for ITT. The most frequent strategies mentioned for handling LTFU were last outcome carried forward (50%), sensitivity analysis (50%), and use of available data to impute (46%). Most articles (81%) specifically excluded complete case analysis under ITI.</p> <p> CONCLUSION : The most striking finding of our systematic review is that there is no meaningful consensus on the definition of ITI. This review, considered alongside previous reviews of RCTs, demonstrates that simply stating a study employed ITT is useless at best and misleading and dangerous at worst. It is the recommendation of this thesis that trialists replace the term ITI with a clear statements about analytic strategies applied to participants who were followed and with those not followed.</p> / Thesis / Master of Science (MS)

La rectocolite hémorragique (RCH) est une maladie inflammatoire chronique de l'intestin responsable d'un handicap et d'une altération de la qualité de vie pouvant exposer les patients à des complications sévères en dépit des thérapeutiques actuelles. L'objectif de cette thèse était d'analyser les voies possibles d'amélioration de la prise en charge thérapeutique des patients à partir de données expérimentales et cliniques. Au niveau expérimentale nous nous sommes intéressés au mécanisme impliqué dans la régulation de l'expression de PPARγ, récepteur nucléaires aux propriétés anti-inflammatoires, primitivement diminuée au cours de la RCH et cible des 5-aminosalicylés. Il a été montré que son expression était d'une part sous le contrôle de la stéroidogenèse intraépithéliale, elle-même sous contrôlée par LRH-1 et d'autre part que l'hypoxie épithéliale diminuait son expression via une sur-expression de miR-27a. Par ailleurs, les effets de l'hypoxie sur l'expression de PPARγ étaient inversés en présence de sildénafil. Sur le versant clinique, l'analyse d'une nouvelle stratégie thérapeutique ciblant la cicatrisation muqueuse, c'est à dire l'abrogation de l'inflammation colique macroscopique était efficace et possible dans la pratique clinique. Cet objectif semble aujourd’hui fondamental pour diminué la morbi-mortalité induite par cette maladie. Enfin nous avons observé l'efficacité des anti-TNF dans le cas spécifique de la rectite réfractaire et l'importance de son utilisation prolongée pour éviter les rechutes de la maladie et l’obtention d’une rémission prolongée. / Ulcerative colitis (UC) is a chronic disabling and relapsing inflammatory disease of the colonic mucosa that for more than half of patients results in chronic intermittent or continuous symptoms of increased stool frequency, fecal urgency and rectal bleeding The aim of the present work was to assess experimental ways and new therapeutic strategies with current treatments to improve long-term outcomes of UC. We focused experimental work on the peroxisome proliferator-activated receptor γ (PPARγ), a key factor of gut homeostasis and a target of mesalamine. The mechanism of primary impaired expression of PPARγ in colonic epithelial cells (CEC) during UC remains unknown. We demonstrated the control of PPARγ expression by intracellular CEC production of cortisol and the lack of cortisol production during UC that may participate towards the decreased expression of PPARγ. Furthermore hypoxia, a driver of mucosal inflammation during UC, markedly decreased PPARγ expression through the over-expression of miR-27a that was reversible by the use of sildenafil. From a clinic point of view, we assessed the efficacy and feasibility of a treat to target strategy which implies treatment optimization to achieve mucosal healing a key factor of long-term outcomes. Finally we addressed the long-term outcomes of patients treated with infliximab including the case of refractory proctitis.

Background: Changing service demands require United Kingdom ambulance services to redefine their role and response strategies, in order to reduce unnecessary Emergency Department attendances. Treat and Refer guidelines have been developed with this aim in mind. However, these guidelines have been developed in the absence of reliable evidence or guiding mid-range theory. This has resulted in inconsistencies in clinical practice. One condition frequently included in Treat and Refer guidelines is hypoglycaemia. Therefore this thesis aimed to investigate prehospital hypoglycaemic emergencies in order to develop an evidence base for future interventions and guideline development. Research approach: A pragmatic and inductive applied health services research approach was employed. Multiple methods were used in a sequential explanatory design. Three linked studies were undertaken with the results of previous studies informing the development of the next. Study one: A scoping review of prehospital treatment of hypoglycaemic events. Aims: i) To describe the demographics of the patient population requiring ambulance service assistance for hypoglycaemic emergencies; ii) To determine the extent to which post-hypoglycaemic patients with diabetes, who are prescribed oral hypoglycaemic agents (OHA), experience repeat hypoglycaemic events (RHE) after being treated in the prehospital environment. Methods: A scoping literature review was conducted using an overlapping retrieval strategy that included both published and unpublished literature. Findings: Twenty-three papers and other relevant material were included. Hypoglycaemia related ambulance calls account for 1.3% to 5.2% of ambulance calls internationally. Transportation rates varied between studies (25%-73%). Repeat hypoglycaemic emergencies are experienced by 2-7% of patients within 48 hours. There was insufficient detail to determine any relationship between repeat events and OHA. The low quality of included papers means that the results should be cautiously interpreted. The safety of leaving patients on OHA at home post hypoglycaemic emergency is unknown. Consequently patients taking OHAs who experience a hypoglycaemic emergency should be transported to hospital for observation. There was a lack of knowledge about the Scottish demographics of the patient population. Study two: A retrospective cross-sectional observational study of diabetes related emergency calls. Aims: To investigate i) the patient demographics and characteristics of hypoglycaemia related emergency calls; ii) the incidence of repeat hypoglycaemic events; and iii) the factors associated with emergency calls that result in individuals being left at home. Methods: A retrospective observational cross-sectional study conducted using Medical Priority Dispatch System® call data from West of Scotland Ambulance Control Centre over a 12 month period. Data were extracted on age, gender, dispatch code, time of call, deprivation category, and immediate outcome (home or hospital). Multiple regression analysis was used to determine predictors of remaining at home. Findings: 1319 calls for hypoglycaemia were received. Patient demographics were similar to the scoping review findings. Most patients remained at home (N = 916 vs N = 380; p < .001). RHE’s were experience by 3.1% within 48 hours, and 10.6% within two weeks. The most significant independent predictor for patients remaining at home was a prior call to the ambulance service (OR of 2.4 [95%CI 1.5 to 3.7]). Patients’ reasons for remaining at home and the causes of subsequent severe events are unknown. It is likely that non-clinical factors may explain some of this behaviour. Study 3: Investigating patients’ experiences of prehospital hypoglycaemic care. Aim: To investigate the experiences of patients who are attended by ambulance clinicians for a hypoglycaemic emergency. Methods: In-depth interviews with adults with diabetes who had recently experienced a hypoglycaemic emergency treated by ambulance clinicians. Participants were recruited from Greater Glasgow and Clyde and Lanarkshire Health Board areas. Data were analysed using Framework Analysis. Findings: Twenty six patients were interviewed. Three key themes were developed. Firstly, an explanation for help seeking behaviour; patients’ impaired awareness of hypoglycaemia as well as the inability of friends and relatives to cope can contribute to an ambulance call-out. Secondly, the perceptions of ambulance service care; patients felt the service provided was good; however ambulance clinicians’ advice was inconsistent. Thirdly, the influences on uptake of follow-up care; patient preferences for follow-up care were influenced by previous experiences of home, hospital and primary care. Post-hoc analysis identified three psychological theories that may explain these findings and provide a useful basis for intervention development: Common Sense Model (Leventhal et al, 1998); Health Belief Model (Rosenstock, 1966); Ley’s cognitive hypothesis model of communication (Ley and Llewelyn, 1995; 1981). Conclusion: Most people treated for severe hypoglycaemia by ambulance clinicians remain at home and do not follow-up their care. A few experience repeat hypoglycaemic emergencies. Key causal, but modifiable factors, contributing to this include:- impaired awareness of hypoglycaemia; inconsistent delivery of ambulance clinician referral advice; and patients’ perceptions of the costs and benefits of follow-up care. Ambulance services cannot address all these factors in isolation. The studies in this thesis have generated an evidence base and identified plausible candidate theories. This will support the future development of novel interventions to improve severe hypoglycaemic emergency follow-up.

Introdução: A estratégia de tratamento baseado em metas tem sido extensamente estudada em pacientes com AR inicial. No entanto, estudos sobre os benefícios de longo prazo do controle de atividade de doença em pacientes com AR estabelecida ainda são escassos. Objetivo: Avaliar a efetividade de longo prazo da estratégia de tratamento baseado em metas em pacientes com artrite reumatoide estabelecida na prática diária. Métodos: Pacientes com AR, previamente tratados de forma convencional, iniciaram estratégia de tratamento baseado em metas, sendo incluídos de março de 2005 a fevereiro de 2007 e acompanhados até dezembro de 2014. Os pacientes eram avaliados a cada 3 meses até remissão ou baixa atividade de doença serem alcançadas, e após a cada 6 meses. O tratamento seguiu um escalonamento de acordo com as recomendações vigentes. A atividade de doença foi mensurada através do DAS28 e do CDAI e a capacidade funcional, através do HAQ-DI. As informações foram extraídas pela revisão de formulários e de tabelas padronizadas. Variações na atividade de doença e na capacidade funcional foram comparadas pelo teste de Wilcoxon e Equações de Estimativas Generalizadas (GEE) A mortalidade foi avaliada através da curva de Kaplan-Meier. Resultados: Duzentos e vinte e nove pacientes foram incluídos, com duração média de doença 10,6±7,4 anos. Dentre os pacientes em moderada e alta atividade de doença no início da coorte, houve significativa redução do DAS28 (4,6±0,1 vs. 3,1±0,1; p<0,001) e do CDAI (21,2±1,0 vs. 7,9±0,7; p<0,001). Também houve redução do HAQ-DI (1,3±0,05 vs 1,0±0,1; p<0,001). A proporção de pacientes em remissão ou em baixa atividade de doença aumentou de 20% para 62% pelo DAS28. Com a estratégia de tratamento baseado em metas, houve um aumento na proporção de pacientes em uso de biológico para 30%. A taxa de mortalidade foi de 24,2 por 1000 pacientes-ano, discretamente superior à descrita na literatura. Conclusão: A estratégia de tratamento baseado em metas com objetivo de remissão e de baixa atividade de doença é efetivo em pacientes com AR estabelecida. / Introduction: Treating RA to a target has become a landmark strategy to be pursued in every patient. Nonetheless, few studies have addressed the true long-term impact of a T2T strategy in a real-world setting with established RA patients. Objective. To examine the long-term effectiveness of a treat-to-target (T2T) strategy in patients with established rheumatoid arthritis (RA) in daily practice. Methods. Patients with RA who were previously given the standard of care were started on a T2T strategy between March 2005 and February 2007 and followed through December 2014. Participants were seen every 3 months until remission/low disease activity was achieved and every 6 months thereafter. Treatment escalation followed a step-up strategy, according to national recommendations. Disease activity was measured by the DAS28 score and Clinical Disease Activity Index (CDAI), and physical function by the Health Assessment Questionnaire (HAQ). Data were extracted with standardized forms and a chart review. Changes in disease activity and physical function were compared using Wilcoxon’s test and generalized estimating equations. Mortality was analyzed using a Kaplan–Meier survival curve. Results. Two hundred and twenty-nine patients were included, with a mean (S.D.) disease duration of 10.6 (7.4) years. Significant reductions were observed in DAS28 (4.6±0.1 vs. 3.1±0.1; p<0.001), CDAI (21.2±1.0 vs. 7.9±0.7; p<0.001), and HAQ (1.3±0.05 vs 1.0±0.1; p<0.001) scores. The proportion of participants in remission/with low disease activity according to DAS28 increased from 20% to 62%. During implementation of the T2T strategy, a gradual increase in the proportion of participants using biologics was observed, to nearly 30%. The mortality rate was 24.2 per 1000 patient-years, slightly higher than that reported in other cohorts. Conclusion. A treat-to-target strategy aiming for remission or low disease activity is effective in patients with established RA.

<p>I möten mellan människor sker samspelet på ett kommunikativt plan där den professionella förhållningen innebär att bemöta och inte bara att möta en annan person. Polisens bemötande har stor betydelse för hur ett brottsoffer bearbetar upplevelsen av brottet hon upplevt. Syftet med studien var att undersöka och beskriva polisens uppfattningar av bemötande av brottsoffer, utifrån deras personliga erfarenheter av att vara brottsoffer. Studien genomfördes med en fenomenografisk forskningsansats och kvalitativa forskningsintervjuer av sex poliser. I en fenomenografisk studie är avsikten att försöka hitta variationen i och kategorisera människors erfarenheter i det tilltänkta undersökningsområdet. Resultatet visade att polisens olika uppfattningar av bemötande av brottsoffer kunde delas in i tre kvalitativt skilda beskrivningskategorier. Naturligt-, förvärvat- och rutinmässigt bemötande. Naturligt bemötande var något som fanns med sedan uppväxten, förvärvat bemötande var något som förvärvades genom olika erfarenheter, i rutinmässigt bemötandet gick arbetsuppgiften före bemötandet av brottsoffren. Studien visade också att brottsoffrets lidande hade en avgörande betydelse för polisens bemötande. Fler studier inom ämnet är att rekommendera för att få en större inblick och förståelse för hur polisens erfarenheter kan avspegla sig i mötet med brottsoffer, samt att öka kunskapen om hur negativa följder av erfarenheter kan förebyggas inför nya möten med brottsoffer.</p>

An evaluation is reported of an alcohol prevention program that targets parents in order to decrease drinking among 13-16 year-olds. The evaluation was performed in a quasi-experimental study with a matched control group and annual assessments, directed at youths and their parents independently, in a longitudinal intention-to-treat design. The implementation of the program centered around three different schools located in inner city, public housing and small town areas. Participants in the study were 900 students entering junior high school and their parents. The intervention consisted in information and mailings directed at parents, which advised them to maintain restrictive attitudes towards underage alcohol drinking, and to encourage their youths’ involvement in organized leisure activities. The implementation successfully influenced parents’ attitudes to underage drinking, but failed to increase youth participation in organized activities. At post-test at grade 9, youths in the intervention group reported less drunkenness and delinquency. Effect sizes were 0.35 for drunkenness and 0.38 for delinquency. Two subsamples, early starters in drinking and early delinquents, were analyzed separately in addition to full sample. Results from analyses of these subsamples yielded effect sizes of .52 for drunkenness and .32 for delinquency. The findings were similar for boys and girls. The effects of the intervention were not moderated by type of community. The main results were replicated in a latent growth curve analysis, which too the clustered nature of the data into account. It is concluded that working via parents is an effective way of reducing underage drinking and delinquency.