Zugl.: Frankfurt (Main), Univ., Diss., 2009

Thesis (M.S.)--Ball State University, 2009. / Title from PDF t.p. (viewed on Nov. 30, 2009). Includes bibliographical references.

Thesis (M. Med. Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 48-53).

Computational methods have become an integral part of drug development and can help bring new and better drugs to the market faster. The process of predicting the biological activity of large compound collections is known as virtual screening, and has been instrumental in the development of several drugs today in the market. Computational methods can also be used to elucidate the energies associated with chemical reactivity and predict how to improve a synthetic protocol. These two applications of computational medicinal chemistry is the focus of this thesis. In the first part of this work, quantum mechanics has been used to probe the energy surface of palladium(II)-catalyzed decarboxylative reactions in order to gain a better understating of these systems (paper I-III). These studies have mapped the reaction pathways and been able to make accurate predictions that were verified experimentally. The other focus of this work has been to develop virtual screening methodology. Our first study in the area (paper IV) investigated if the results from several virtual screening methods could be combined using data fusion techniques in order to get a more consistent result and better performance. The study showed that the results obtained from data fusion were more consistent than the results from any single method. The data fusion methods also for several target had a better performance than any of the included single methods. Next, we developed a dataset suitable for evaluating the performance of virtual screening methods when applied to large compound collection as a replacement or complement for high throughput screening (paper V). This is the first benchmark dataset of its kind. Finally, a method for using computationally derived reaction coordinates as basis for virtual screening was developed. The aim was to find inhibitors that resemble key steps in the mechanism (paper VI). This initial proof of concept study managed to locate several known and one previously not reported reaction mimetics against insulin regulated amino peptidase.

Those who misuse alcohol in the United States do not regularly seek treatment on their own to reduce use and avoid consequences of misuse. Because of the association between alcohol misuse, alcohol-related risk behaviors, and injury; alcohol misuse in the United States has serious societal and individual repercussions. To alleviate these problems, health care professionals; including doctors, nurses, and social workers; have an opportunity to screen injured patients for alcohol misuse and provide brief interventions. Although some brief intervention research has demonstrated reductions in alcohol misuse and other injury-related behaviors, other evidence indicates that brief alcohol interventions are not equally effective for all injured patients. Moreover, screening and brief alcohol interventions are not reimbursed in most states, leaving providers and medical centers uncompensated for providing services. A possible way to address these challenges is to target intervention services to patients who are most likely to make positive changes. Therefore, this dissertation used mixture modeling to identify subclasses of injured patients based on their past injury-related consequences and risks of alcohol misuse in order to describe which subgroups made the greatest reductions in drinking in the year following discharge from a Level-1 trauma center. This dissertation also identified which subclasses of patients made the greatest behavioral improvements for injury-related consequences and risks of alcohol misuse during the year following discharge from the trauma center. Patients with profiles that contained high probabilities of multiple consequences and risks and those with histories of alcohol-related accidents and injuries reported some of the largest improvements in drinking and injury-related consequences and risks following discharge. Those classes that made the fewest changes had profiles that consisted of fighting and taking foolish risks while drinking or that consisted of low probabilities of risks or consequences of alcohol misuse. This dissertation provides tentative evidence for targeting intervention services to injured patients. Further research should verify which subclasses of patients are most likely to reduce alcohol misuse and other alcohol-related risk behaviors in order to more effectively target brief alcohol interventions, increase cost savings, and improve the health and behavioral health outcomes for injured patients who misuse alcohol. / text

published_or_final_version / Public Health / Master / Master of Public Health

While a stable diagnosis of Autism Spectrum Disorders can be made as early as 2 years of age, the diagnosis of mild ASD cases are usually not made until primary school age or much later; and yet it is these milder cases that can benefit the most from early intervention. The present study aimed at pushing the identification of mild ASD children earlier to preschool age. A review of current screening tools revealed that they were not effective in identifying milder ASD variants. One reason perhaps is that the existing tools rely primarily on parental reports. Note that young children with mild ASD often function adequately interacting with an adult who knows them well; they typically face more difficulty in free play with other children. Parents as a result may not be in a good position to detect milder ASD. The present study therefore took a very different approach from existing screening tools by developing a more objective scale based on observation by of peer interaction in preschools. Considering peer interaction deficits are central for ASD, and deficits of these milder individuals might be more obvious in a setting that tax their social skills. A screening tool based on peer interaction observation in preschool, namely the Structured Classroom Observation Scale (SCOS), was thus developed. Drawing on existing screening tools and experts input, 84 items were compiled and pilot tested. An initial psychometric study of the scale was conducted using a community sample, with 304 preschoolers aged 3 and 4, from four English-language international schools in Hong Kong. The initial 84-item version was trimmed substantially to result in a user-friendly 13-item observation scale with good psychometric properties. The final SCOS includes 3 items depicting self-regulation challenges and 10 items describing difficulties in peer interaction. The initial psychometric study using a community sample indicated substantial interrater reliability (u= .76) and acceptable test-retest reliability (ICC = .72). The average agreement for individual items was less satisfactory (T = .40). Using Latent Class Analysis, the present scale delineated the children into 4 groups: Typical, Shy, Behavioral and High Risk of ASD. A subsequent validity study (n = 186) comparing the SCOS with ADOS scores showed that the class membership of the children based on SCOS predicted their ADOS results, after controlling for age and gender. Children from the High Risk group were found to have significantly higher Calibrated ADOS Severity scores than the other 3 groups; and their mean ADOS scores (i.e., 8.18) were above the cutoff for ASD on the ADOS. A 9-month follow found more reports of parental concerns in the High Risk group with ADOS scores above the cutoff. Discriminant validity of the SCOS was demonstrated between the scale and Head Start Competence Scale (parent version). In contrast to the usual portrayal of active but odd stereotypical children with Asperger Syndrome, the High Risk group identified by the SCOS consisted of children with infrequent interfering behaviors. They were relatively passive but not necessarily odd during social interactions, which might perhaps explain why early identification was difficult. The current scale also identified another two groups of children (Shy group and Behavioral group), which will require longitudinal follow up to ascertain educational or intervention implications. / published_or_final_version / Clinical Psychology / Doctoral / Doctor of Psychology

Background: Human papillomavirus (HPV) DNA test is more sensitive and can detect more high-grade cervical intraepithelial lesions than cytology test in cervical cancer screening. There are studies confirming HPV test being more effective in cervical cancer screening by detecting the persistence of HPV infection that could lead to cancer. However, the costs associated with a HPV test is higher than a cytology test. Moreover, HPV test is less specific which could subject more women to further triage tests or unnecessary invasive diagnostic procedures. Therefore healthcare costs could possibly increase if primary HPV screening is to be adopted. Study objective: The aim of the study is to systematically review the cost-effectiveness of primary HPV testing in cervical cancer screening Method: Electronic search was performed in three biomedical databases (PubMed, Medline, Cochrane Library) and one economic evaluation database to identify relevant studies. Studies were selected according to the explicit inclusion and exclusion criteria defined. Only those studies carried out in high-income countries were included so that result could be better applied to Hong Kong. Results: A total of 19 studies were included in this systematic review. Cytology-only method is generally not cost-effective. To be cost-effective, it has to be performed in a longer screening interval which would reduce not only the screening costs but also a reduction in the health outcomes. Among the different options in HPV-based primary screening, HPV testing with cytology triage is the most cost-effective strategy in many of the studies. Combined HPV/cytology co-screening could achieve the biggest health benefit but is also most costly. HPV-based screening is more cost-effective for those >30 years of age and is usually less cost-effective if applied to young women. From the result in sensitivity analysis, HPV-based screening is sensitive to an increase in the costs of the HPV test, a low HPV test sensitivity and a low screening compliance rate. Conclusion: Primary HPV screening is cost-effective and generally performs better than cytology screening. The result of this systematic review guides the future direction of developing an optimal cervical screening strategy in Hong Kong. Local context has to be considered when examining the cost-effectiveness of primary HPV testing for cervical screening. Good quality local epidemiological data on HPV infection and cervical cancer and screening would be required to aid future research on the application of HPV test for cervical cancer screening in Hong Kong. / published_or_final_version / Public Health / Master / Master of Public Health

In cervical screening programmes, Papanicolaou test (Pap test) is the key screening tool. However Pap test is difficult to implement in low-resource region. Introduction of an economic, cost-effective and less skill demanding equipment is hence a potential direction of advance in cervical screening methodology. 　　Cervical carcinogenesis involves genetic instability which leads to chromosomal aneuploidy. Evaluation of aneuploidy may hence provide information for identifying cancer and precursor cells. An automated DNA-image-cytometry system (DNA-imager) capable of quantitating the DNA content of cells has recently been developed. 　　To evaluate the efficacy of DNA-imager in cervical cancer screening, a total of 483 residual ThinPrep liquid-based cytology (LBC) samples after diagnosis were retrieved and evaluated by the DNA-imager. The high risk human papillomavirus (HPV) status of the atypical squamous cells of undetermined significance (ASC-US) samples has been tested as a parallel study. According to established criteria, 423 out of the 483 samples were satisfactory for downstream analysis. The samples were designated “Normal”, “Suspicious” or “Abnormal” according to their DNA aneuploidy and proliferation activity. 　　Significantly more high grade lesion samples (HSIL and SCC) were designated as “Abnormal” by DNA-imager than were lower grade lesion samples (Negative, ASC-US, AGC, ASC-H, and LSIL) (94.19% vs 51.04%, p<0.0001). For detecting ≥HSIL, DNA-imager achieved high sensitivity and specificity (94.19% and 48.96%) using “Abnormal” as cut off. Adopting a more stringent definition of “Suspicious” or “Abnormal” would increase the sensitivity to 100% but decreased the specificity to 24.33%. 　　 　　Regarding ASC-US triage, DNA-imager achieved a sensitivity and specificity of 80.00% and 71.29% respectively when “Abnormal” was used as test positive to predict cases with ≥HSIL follow-up in the next two year. The sensitivity increased but the specificity decreased to 90.00% and 34.65% respectively if “Suspicious or above” was used as indicator of undesirable follow-up. HR-HPV test, on the other hand, was able to identify all cases with ≥HSIL upon follow-up (sensitivity = 100%) but the specificity was only 15.84%. Among these ASC-US sample, test positivity of the two tests showed poor concordance with each other (Cohen’s κ = 0.062 and 0.074 respectively for “Suspicious or above” or “Abnormal”, respectively). 　　Our findings suggested that DNA-imager may be a useful tool for automated primary screening of cervical cancer 3 / published_or_final_version / Pathology / Master / Master of Medical Sciences

Hållbarhet och etik är ett högst aktuellt ämne i dagens samhälle som även påverkar den finansiella sektorn. Ämnen som CSR och hållbarhetsfrågor har tidigare haft fokus på företagsvärlden men under de senaste åren har även finansvärlden uppmärksammat ämnet, i och med uppkomsten av sociala och etiska investeringar.Tidigare forskning inom området etiska fonder har framförallt handlat om avkastningen och urvalsprocessen av bolag, få studier har gjorts av fondernas etiska prestanda. Den här studien syftar till att fördjupa diskussionen kring de etiska fonderna. Detta görs genom att studera hur fondbolagen bedriver urvalsprocessen och förvaltningen av dessa fonder.I studien används en abduktiv ansats. Det har inneburit att vi har fått komplettera den ursprungliga teoridelen utifrån de svar vi fick under den empiriska insamlingen. Studien är kvalitativ och empirin samlades in genom semi-strukturerade intervjuer. Vi valde att kontakta de fyra storbankernas fondbolag, två AP-fonder samt ytterligare ett fondbolag. Respondenterna som intervjuades bestod av fondförvaltare eller specialister inom hållbarhetsområdet.Resultatet av studien visar att benämningen etiska fonder är på väg bort. Branschen vill inte definiera etik istället talar man om efterträdarna, hållbara och ansvarsfulla fonder. Trots förnekelsen av etiska fonder används en liknande urvalprocess för de hållbara fonderna, därmed kvarstår den problematiken som funnits för de etiska fonderna. Den stora skillnaden idag är att fondbolagen vill agera hållbart och ansvarsfullt på alla plan, både gällande sociala- och miljömässiga aspekter.Studies resultat skiljer sig från tidigare forskning genom att den fokuserar på den etiska prestandan. Undersökningen konstaterar att etikfonderna håller på att försvinna, men ur dem har hållbara fonder fötts. Den här studien har gett ökad kunskap inom ett område som är relativt outforskat. Studien kan därför lämpligtvis användas för framtida forskning. / Sustainability and ethics are discussed all over the world. Subjects as CSR and sustainability related questions were earlier only highlighted by companies. Nowadays even the financial industry has started to focus on those questions, with the emergence of social and ethical investments.Previous research have focused on return or the selection process, very few have studied the ethical performance. This study aims to deepen the discussion about ethical funds. This is done by studying how the fund companies conduct the management of ethical funds.This study is using an abductive approach, which means that we have completed the original theory with more theory after we had done the research on the field. We have used a qualitative method and collected the empirical data by semi-structured interviews. The four largest banks fund companies of Sweden, two pension funds and one additional fund company were interviewed. The respondents were either fund managers or specialists in the area of sustainability.The results of the study show that the term ethical fund is slowly disappearing. No one of the respondents were willing to define ethics, they would rather discuss the successors sustainable- and responsible funds. Despite the denial of ethical funds, similar selection processes for sustainable funds are used as for ethical funds. The problems that have existed for the ethical funds are moving to the sustainable funds. The big difference today is that fund companies have a vision of acting responsible and sustainable at all levels, both in terms of social and environmental aspects.The results differ from previous research, since it focuses on the ethical performance. The study finds that ethical funds are disappearing as time goes by, but out of them have sustainable funds developed. This research has provided increased knowledge in an area that is relatively unexplored. The study can therefore be suitable for future research.