In der Promotion wird die Entwicklung, Optimierung und Validierung einer Reversed-phase-Chromatography Methode zur Messung des Ribavirinplasmaspiegels beschrieben. Diese wurde mit einer Solid Phase Extraction zur Probenvorbereitung kombiniert. Zudem finden sich zahlreiche Auswertungen von gemessenen Patienenchromatogrammen zu ausgewählten, klinisch relevanten Fragestellungen, wie beispielsweise die Darstellung des Ribavirinplasmaspiegels im Tagesverlauf, im Verlauf der ersten sechs Therapiewochen, im Vergleich von Männern und Frauen, sowie bei einem niereninsuffizienten Patienten. Zu den erhobenen Ergebnissen wird Stellung genommen, und daraus resultierende Schlussfolgerungen bezüglich einer zukünftigen Optimierung der Hepatitis-C-Therapie kommentiert. / The doctorate program will describe the development, optimization and validation of a reversed phase chromatography method for measuring ribavirinplasma levels. This has been combined with solid phase extraction for preparing samples. In addition, numerous analyses of patients’ chromatograms are included relative to clinically relevant questions such as the depiction of ribavirinplasma levels during the course of a day, during the course of the first six weeks of therapy, in comparison to other men and women as well as patients suffering from kidney insufficiencies. The collected data will be commented on, as well as the resulting implications relative to a future optimization of hepatitis-C therapy.

Publicación a texto completo no autorizada por el autor / Determina la insulinoresistencia como marcador pronóstico en cirrosis hepática avanzada en pacientes que han acudido al consultorio externo de gastroenterología del Hospital Alberto Sabogal Sologuren, así como aquellos pacientes hospitalizados en el Servicio de Especialidades Médicas 2 a cargo de gastroenterología durante el periodo de marzo del 2013 a marzo del 2014. Estudio prospectivo, descriptivo, observacional, correlacional. Se analizaron 125 pacientes con un promedio de edad de 61,70 años (DS: 43,84). Obtiene que el 58% (73) del total de los pacientes bajo estudio fueron mujeres; el 65% (81) presentaron edades entre 61 a 80 años y el 24% (30) edades entre 51 a 60 años. El 50% (63) presentaron etiología de cirrosis hepática desconocida, el 15% (19) presentaron etiología alcohólica y hepatitis C crónica, respectivamente y el 12% (15) hepatitis crónica B; el 44% (55) presentaron como escala de Child Pugh la B y el 35% (44) la A; el 63% (79) tuvieron valores de HOMAR-IR, menor a 3,2; el 62% (78) presentaron como valores de potasio 3,7 a 5,2 mEq/l. El 77% (96) del total de pacientes bajo estudio tuvieron valores de fósforo sérico menor de 2,4 a 4,1 mg/dl, el 14% (17) mayor a 4,1 mg/dl y el 53% (10) del total de pacientes con cirrosis por alcohol tuvieron valores de fósforo sérico menor de 2,4 mg/dl y el 26% (5) mayor a 4,1 mg/dl. Existe relación y correlación moderada inversa entre los valores de HOMAR-IR y escala de Child Pugh; y, existe relación y correlación leve inversa entre los valores de potasio y escala de Child Pugh con un p=0.000, respectivamente. Concluye que la insulinoresistencia se encuentra en estadios Child Pugh avanzados, pudiéndose considerar como marcador pronóstico, La hipokalemia está presente en estadios avanzados, siendo mecanismo desencadenante en estos pacientes, la hipofosfatemia se encuentra presente en cirrosis alcohólica, siendo el mecanismo patogénico de Insulinoresistencia en estos pacientes. / Trabajo académico

People with hepatitis C (HCV) face stigma and discrimination because of the association of this disease with injecting drug use (IDU). Research has found that many instances of HCV-related discrimination occur in the health care sector. Health care workers' beliefs about their HCV positive clients are likely to influence how they relate to clients and their treatment delivery. This research assessed the implicit and explicit attitudes of both health care workers and their HCV positive injecting drug using (HCV+) clients toward each other and then established whether these affect the treatment experiences of health care workers and clients. The sample consisted of 60 health care workers (doctors and nurses), 120 HCV+ and 120 HCV- clients, recruited from the same treatment facility. Participants were given a series of attitude and treatment experiences measures to complete. Data illustrate that while health care workers' and HCV+ clients' explicit attitudes towards each other were positive, clients with HCV still rated their health care workers less highly and reported less satisfaction with their treatment than HCV- clients. Analyses also indicated that more conservative health care workers displayed greater prejudice toward their HCV+ clients because they believe that injecting drug use is controllable. This prejudice toward IDUs on the part of health care workers was associated with worry about the behaviour of IDU clients and this worry in turn predicted differences in treatment experiences reported by HCV+ and HCV- clients. These data support the contention that health care worker concerns, particularly those related to injecting drug use, underlie discriminatory treatment of people with HCV. Finally the research also addressed the impact of health care worker contact with HCV+ clients on their attitudes towards this group. Analysis revealed that while health care workers who have had more contact with people with HCV show more positive explicit attitudes, they also show less favourable implicit attitudes toward IDUs. This may reflect the difficulties and stresses associated in caring for IDUs and may provide insight into the hidden costs involved for health care workers working with a population that may be challenging and at times difficult to manage.

The use of mathematical models in studying disease epidemics can be diverse, from the focused study of the role of a single determinant of the epidemic, or to the overall estimation of morbidity and mortality. In using simple deterministic models, a balance is struck between biological and social complexities, and the high data input demands of mathematical models. This thesis aims to apply the use of deterministic mathematical models to the studies of HIV and hepatitis C epidemiology in the Asia-Pacific region. In Australia, about 85% of reported HIV cases are among homosexual men. Casual homosexual partnerships made up 40% of incident HIV cases in 1995 increasing to 65% in 2004. In the state of New South Wales, it was estimated that over 7,500 people were living with HIV/AIDS in 2005, increasing to over 10,000 by 2016 with existing levels of intervention. Intervention measures were estimated to have prevented some 44,500 cases, the majority being among injecting drug users through the Needle and Syringe Programmes. Models for the HIV epidemics in developing countries were also developed incorporating multiple routes of HIV transmission. For Papua New Guinea, it was estimated 64,000 people were living with HIV/AIDS in 2005, rising to over 500,000 by 2025 with current levels of intervention. High levels of interventions, in particular increased condom use, will be required to achieve a stabilisation or reduction in HIV prevalence. In East Timor, the HIV epidemic is still in the early stages with 138 people estimated to be living with HIV/AIDS, rising to 5,000 by 2025 with minimal intervention. For HCV, models of the epidemic in Australia showed HCV incidence peaking in 1999, followed by a decline reaching 9,700 incident cases in 2005. Of 197,000 estimated chronic HCV cases in 2005, 58% had stage F 0/1 liver disease, 15% F 2/3 liver disease, and 2% HCV-related cirrhosis. Models estimated 210 and 105 people developed HCV-related liver failure and hepatocellular carcinoma, respectively. Comparisons of modelled HCV long-term sequelae projections with linkage data showed relatively good agreement, despite discrepancies in liver-related deaths. To decrease the number of chronic HCV, at least a tripling of treatment coverage would be required. These models provide estimates of the current levels of epidemics as well as projections of future scenarios under different intervention strategies, which have an important role in the planning of strategies, as well as assessment of previous epidemic conditions.

Hintergrund: Die Datenlage zur Substitutionstherapie Opiatabhängiger ist defizitär. Vor diesem markant defizitären Erkenntnishintergrund erscheint es sinnvoll und notwendig, eine versorgungsepidemiologische Studie zur aktuellen Versorgungslage opiatabhängiger Substitutionspatienten durchzuführen, um offene Fragen zu klären. Hierfür haben wir ein mehrstufiges Forschungsprojekt unter dem Akronym COBRA initiiert. COBRA steht für "Cost-Benefit and Risk Appraisal of Substitution Treatments" und signalisiert, dass wir uns in umfassender Weise um eine Evaluation der Risiken, Vor- und Nachteile verschiedener Interventionsstrategien und Modalitäten in der Substitutions- und Versorgungspraxis Opiatabhängiger in Deutschland bemühen. Zielsetzungen des COBRA-Projekts sind: • Die Charakterisierung von bestehenden Einrichtungsformen und -modellen; • Die Charakterisierung von: – Merkmalen opiatabhängiger Patienten in diesen Einrichtungen (Schwere, Dauer/ Stadium, Komorbidität, Delinquenz, Desintegration etc.), – der Diagnostik sowie den Indikations- und Allokationsentscheidungen in der Versorgungsrealität sowie – den eingesetzten Interventionsmethoden (Substitutionsmittel, Therapie komorbider Störungen, psychotherapeutische und soziale Interventionen) • Die Ermittlung von Problemen der Substitutionstherapie bei verschiedenen Risikogruppen (z.B. Hepatitis-C- und HIVPatienten) • Die Beschreibung des Kurzzeitverlaufs und Outcomes hinsichtlich verschiedener klinischer und sozialer Kriterien Methodik: Die Studie teilt sich in einen deskriptiv-klinisch-epidemiologischen und einen analytisch-evaluativen Teil. Der deskriptive Teil soll zunächst darüber Auskunft geben, wie viele und welche Arten von Substitutionseinrichtungen in Deutschland wie viele Opiatabhängige erreichen und behandeln. Auf dieser Grundlage soll dann im evaluativen Teil an möglichst repräsentativen Einrichtungen und Patienten beurteilt werden, wie und mit welchen Methoden welche Arten von Patienten und Problemlagen versorgt werden. Durch Abgleich mit den wissenschaftlichen Bewertungsmaßstäben können daraus Defizite, Probleme und mögliche verbesserte Allokationsstrategien abgeleitet werden. Ergebnisse: Es werden erste Vorstudienbefunde und Ihre Design- Konsequenzen vorgestellt und diskutiert. / In the present paper, we will describe aims, methods, and design along with selected pre-study findings of an epidemiological study in a nationally representative sample of substitution doctors (N = 381) and their patients (n = 2500) in Germany. The project has three major components: (a) Pre-study: We sent mailed questionnaires to a sample of over 1000 substitution doctors to describe qualification and setting characteristics, treatment profiles and attitudes of substitution doctors in Germany. (b) Cross-sectional study: With a two-step epidemiological design (target day assessment of the patients, clinical appraisals by the doctors), our main aims were (1) to determine the number of opiate addicts treated by methadone or buprenorphine or other substitution drugs; (2) to find predictors and correlates for treatment, taking into account doctors, patients, and system variables; and (3) to evaluate cross-sectional differences between groups with regard to clinical presentation (comorbidity), clinical course, acceptance/compliance, critical incidences, and social integration. (c) Furthermore, the study includes a prospective-longitudinal cohort study of a total of 1000 patients sampled from this data base. The cohort will be followed-up over a period of three months to investigate whether buprenorphine patients have a more favorable course and outcome in terms of clinical, psychosocial, pharmaco-economic, and related measures. Selected pre-study findings are summarized, highlightening that current registers include a considerable proportion of doctors and a considerable heterogeneity of setting characteristics in terms of the number of patients, choice of substitution drugs and involvement in hepatitis- C treatment.

People with hepatitis C (HCV) face stigma and discrimination because of the association of this disease with injecting drug use (IDU). Research has found that many instances of HCV-related discrimination occur in the health care sector. Health care workers' beliefs about their HCV positive clients are likely to influence how they relate to clients and their treatment delivery. This research assessed the implicit and explicit attitudes of both health care workers and their HCV positive injecting drug using (HCV+) clients toward each other and then established whether these affect the treatment experiences of health care workers and clients. The sample consisted of 60 health care workers (doctors and nurses), 120 HCV+ and 120 HCV- clients, recruited from the same treatment facility. Participants were given a series of attitude and treatment experiences measures to complete. Data illustrate that while health care workers' and HCV+ clients' explicit attitudes towards each other were positive, clients with HCV still rated their health care workers less highly and reported less satisfaction with their treatment than HCV- clients. Analyses also indicated that more conservative health care workers displayed greater prejudice toward their HCV+ clients because they believe that injecting drug use is controllable. This prejudice toward IDUs on the part of health care workers was associated with worry about the behaviour of IDU clients and this worry in turn predicted differences in treatment experiences reported by HCV+ and HCV- clients. These data support the contention that health care worker concerns, particularly those related to injecting drug use, underlie discriminatory treatment of people with HCV. Finally the research also addressed the impact of health care worker contact with HCV+ clients on their attitudes towards this group. Analysis revealed that while health care workers who have had more contact with people with HCV show more positive explicit attitudes, they also show less favourable implicit attitudes toward IDUs. This may reflect the difficulties and stresses associated in caring for IDUs and may provide insight into the hidden costs involved for health care workers working with a population that may be challenging and at times difficult to manage.

The use of mathematical models in studying disease epidemics can be diverse, from the focused study of the role of a single determinant of the epidemic, or to the overall estimation of morbidity and mortality. In using simple deterministic models, a balance is struck between biological and social complexities, and the high data input demands of mathematical models. This thesis aims to apply the use of deterministic mathematical models to the studies of HIV and hepatitis C epidemiology in the Asia-Pacific region. In Australia, about 85% of reported HIV cases are among homosexual men. Casual homosexual partnerships made up 40% of incident HIV cases in 1995 increasing to 65% in 2004. In the state of New South Wales, it was estimated that over 7,500 people were living with HIV/AIDS in 2005, increasing to over 10,000 by 2016 with existing levels of intervention. Intervention measures were estimated to have prevented some 44,500 cases, the majority being among injecting drug users through the Needle and Syringe Programmes. Models for the HIV epidemics in developing countries were also developed incorporating multiple routes of HIV transmission. For Papua New Guinea, it was estimated 64,000 people were living with HIV/AIDS in 2005, rising to over 500,000 by 2025 with current levels of intervention. High levels of interventions, in particular increased condom use, will be required to achieve a stabilisation or reduction in HIV prevalence. In East Timor, the HIV epidemic is still in the early stages with 138 people estimated to be living with HIV/AIDS, rising to 5,000 by 2025 with minimal intervention. For HCV, models of the epidemic in Australia showed HCV incidence peaking in 1999, followed by a decline reaching 9,700 incident cases in 2005. Of 197,000 estimated chronic HCV cases in 2005, 58% had stage F 0/1 liver disease, 15% F 2/3 liver disease, and 2% HCV-related cirrhosis. Models estimated 210 and 105 people developed HCV-related liver failure and hepatocellular carcinoma, respectively. Comparisons of modelled HCV long-term sequelae projections with linkage data showed relatively good agreement, despite discrepancies in liver-related deaths. To decrease the number of chronic HCV, at least a tripling of treatment coverage would be required. These models provide estimates of the current levels of epidemics as well as projections of future scenarios under different intervention strategies, which have an important role in the planning of strategies, as well as assessment of previous epidemic conditions.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Thesis (Ph.D.)--Edith Cowan University, 2006. / Submitted to the Faculty of Education and Arts. Includes bibliographical references.