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The present work comprises different projects within the scope of public health. In detail, they all aim at combating the high-burden diseases HIV/AIDS, malaria and tuberculosis more effectively. Since there was, and still is, no harmonization between the existing biowaiver guidelines, the biowaiver dissolution test conditions by WHO and FDA were compared against each other using drug products, which had already demonstrated BE to the comparator in vivo. Thereby it could be shown that the dissolution conditions proposed by the WHO are more appropriate for granting biowaivers than those of the FDA. Further, the applicability of the WHO dissolution test conditions was investigated using the APIs ethambutol, isoniazid and pyrazinamide (all BCS Class III) as model compounds. These investigations demonstrated that the concept of the biowaiver proved to work properly, i.e. leading to no false positive BE decision and an acceptable incidence of false negative BE decisions. In addition, four new biowaiver monographs were published addressing important APIs in the treatment of HIV/AIDS and malaria. Before these efforts, there were only a very few biowaiver monographs available for antiviral or antimalarial APIs, i.e. the database of biowaiver monographs has been clearly improved. The last part of the present work dealt with the extension of the biowaiver concept to related areas such as the WHO Prequalification of Medicines Programme. Investigations revealed that the biowaiver tools are generally eligible for prequalification of drug products containing ethambutol, isoniazid, pyrazinamide, or lamivudine to prove BE between an appropriate comparator and the test candidate. By contrast, some APIs are excluded from the biowaiver procedure. In conclusion, the implementation of the biowaiver tools for prequalification of biowaivable APIs is, along with BCS-based biowaiver approval of new generics, an important step towards making essential, high-quality drug products more cost-effective and, as a consequence, more accessible for a larger percentage of the population. In that way, the treatment conditions for those in need living in the developing countries can be improved enormously, so that those who are poor do not have to receive poor treatment. The quality standard of essential medicines will increase worldwide, thereby helping to combat the high-burden diseases better and, in turn, lead to an improvement of the global health status.
Observed weather and projected climate change suggest an increase in the transmission of vector-borne diseases (VBDs) in the Hindu Kush Himalayan (HKH) region. In this study, we systematically explore the literature for empiric associations between the climate variables and specific VBDs and their vectors in the HKH region. We conducted a systematic synthesis of the published literature on climate variables, VBDs and vectors in the HKH region until the 8th of December 2020. The majority of studies show significant positive associations of VBDs with climatic factors, such as temperature, precipitation, relative humidity, etc. This systematic review allowed us to identify the most significant variables to be considered for evidence-based trend estimates of the effects of climate change on VBDs and their vectors in the HKH region. This evidence-based trend was set into the context of climate change as well as the observed expansion of VBDs and disease vectors in the HKH region. The geographic range of VBDs expanded into previously considered non-endemic areas of highlands (mountains) in the HKH region. Based on scarce, but clear evidence of a positive relationship of most climate variables and VBDs and the observed climatic changes, we strongly recommend an expansion of vector control and surveillance programmes in areas of the HKH region that were previously considered to be non-endemic.
Malaria is an environmental disease, influenced not only by physical and biological environmental factors but also by socio-cultural ones. These factors affect each other, and, in turn, cause the disease in endemic areas. Some factors that cause the high morbidity rate associated with the disease include climate change, physical environment that varies geographically, socio-economic circumstances, and human behaviour in the affected areas. Other risk factors include housing conditions and poor sanitation, lack of hygiene practices, and inadequate health services in endemic areas. Efforts to eliminate malaria have been a topic at various public health meetings for decades. However, in Indonesia, malaria continues to be one of the leading causes of morbidity and mortality. The research aimed to analyse and model the critical variables associated with malaria in endemic areas of Indonesia. So, this included relationships between malaria and both socio-demographic variables and physical environments. The research is in three parts, adding value to a model that determines malaria in Indonesia.
This dissertation follows a cross-sectional design survey. The research data in this PhD dissertation is drawn from four sources: routine reporting of malaria from provincial health departments in South Sumatra; the national basic health research data (IDN acronym: Riskesdas); climate data from the Meteorology, Climatology, and Geophysics Climatological Agency (IDN acronym: BMKG); spatial data from Geospatial Information Agency (IDN acronym: BIG). This study takes a holistic approach, integrating the following univariate, bivariate, and multivariable logistic regressions, to establish a modelling determinant of malaria. Additionally, the researchers compared the performance of both Geographically Weighted Regression (GWR) and Ordinary Least Square (OLS). It also used some statistical analysis software tools for data processing, analysis, visualisation, and the development of the model as follows: Statistical Package for the Social Sciences (SPSS), Stata, Aeronautical Reconnaissance Coverage Geographic Information System (ArcGIS) 10.3, and GWR 4.0 version 4.0.90 for Windows.
The prevalence of malaria varied according to the local area, which, in turn, was related to the local physical environment that varied geographically. The determinants for malaria cases varied locally and regionally as well. Rural areas with a high percentage of households keeping livestock/pets showed a higher proportion of malaria prevalence than the national average. Other socio-demographic risk factors included gender, age, occupation, knowledge about healthcare, protection against mosquito bites, and condition of dwellings. This study reveals that the independent variables - "rainfall", "altitude", and "distance from mosquito resting sites in the forest," in global OLS analysis- are significantly associated with malaria cases in South Sumatra, Indonesia.
On the other hand, in the GWR analysis, the determinants of malaria cases at the village level vary geographically. Therefore, it is essential for the decision maker, the government, to acquire a more in-depth understanding of region-specific, ecological factors that influence confirmed malaria cases. The findings lead to the recommendation for developing sustainable regional malaria control programs and incentivising malaria elimination efforts, particularly at the village level. In another setting, the research led to the conclusion that the presence of mid-sized livestock comprised a significant risk factor for contracting malaria in rural Indonesia. The recommendation, especially for the study area, is to employ integrated vector management (IVM), for example, the simultaneous implementation of insecticide-treated bed nets (ITNs) and insecticide-treated livestock (ITL). Other factors such as socio-demographic and use of health care facilities were also crucial as they related to malaria prevalence. Further, the research leads to the recommendation for increased education and increased promotion and utilisation of the health care framework to promote knowledge and awareness of villagers on how to protect themselves from Anopheles bites. Finally, improving information concerning the availability of health care services and access to various health facilities in endemic areas is essential.
Background: Ever since it was discovered that zoophilic vectors can transmit malaria, zooprophylaxis has been used to prevent the disease. However, zoopotentiation has also been observed. Thus, the presence of livestock has been widely accepted as an important variable for the prevalence and risk of malaria, but the effectiveness of zooprophylaxis remained subject to debate. This study aims to critically analyse the effects of the presence of livestock on malaria prevalence using a large dataset from Indonesia.
Methods: This study is based on data from the Indonesia Basic Health Research ("Riskesdas") cross-sectional survey of 2007 organized by the National Institute of Health Research and Development of Indonesia’s Ministry of Health. The subset of data used in the present study included 259,885 research participants who reside in the rural areas of 176 regencies throughout the 15 provinces of Indonesia where the prevalence of malaria is higher than the national average. The variable "existence of livestock" and other independent demographic, social and behavioural variables were tested as potential determinants for malaria prevalence by multivariate logistic regressions.
Results: Raising medium-sized animals in the house was a significant predictor of malaria prevalence (OR = 2.980; 95% CI 2.348–3.782, P < 0.001) when compared to keeping such animals outside of the house (OR = 1.713; 95% CI 1.515–1.937, P < 0.001). After adjusting for gender, age, access to community health facility, sewage canal condition, use of mosquito nets and insecticide-treated bed nets, the participants who raised medium-sized animals inside their homes were 2.8 times more likely to contract malaria than respondents who did not (adjusted odds ratio = 2.809; 95% CI 2.207–3.575; P < 0.001).
Conclusions: The results of this study highlight the importance of livestock for malaria transmission, suggesting that keeping livestock in the house contributes to malaria risk rather than prophylaxis in Indonesia. Livestock-based interventions should therefore play a significant role in the implementation of malaria control programmes, and focus on households with a high proportion of medium-sized animals in rural areas. The implementation of a "One Health" strategy to eliminate malaria in Indonesia by 2030 is strongly recommended.
Background: A web-based malaria reporting information system (MRIS) has the potential to improve malaria reporting and management. The aim of this study was to evaluate the existing manual paper-based MRIS and to provide a way to overcome the obstacles by developing a web-based MRIS in Indonesia.
Methods: An exploratory study was conducted in 2012 in Lahat District, South Sumatra Province of Indonesia. We evaluated the current reporting system and identified the potential benefits of using a web-based MRIS by in-depth interviews on selected key informants. Feasibility study was then conducted to develop a prototype system. A web-based MRIS was developed, integrated and synchronized, with suitability ranging from Primary Healthcare Centres (PHCs) to the Lahat District Health Office.
Results: The paper-based reporting system was sub-optimal due to a lack of transportation, communication, and human capacity. We developed a web-based MRIS to replace the current one. Although the web-based system has the potential to improve the malaria reporting information system, there were some barriers to its implementation, including lack of skilled operators, computer availability and lack of internet access. Recommended ways to overcome the obstacles are by training operators, making the application in an offline mode and able to be operated by mobile phone text messaging for malaria reporting.
Conclusion: The web-based MRIS has the potential to be implemented as an enhanced malaria reporting information system and investment in the system to support timely management responses is essential for malaria elimination. The developed application can be cloned to other areas that have similar characteristics and MRIS with a built-in web base to aid its application in the 5G future.
Background: The recommendation of artemisinin combination therapy (ACT) as first-line treatment for uncomplicated falciparum malaria is supported by a plethora of high quality clinical trials. However, their recommendation for the treatment of mixed-species malaria and the large-scale use for the treatment of non-falciparum malaria in endemic regions is based on anecdotal rather than systematic clinical evidence.
Methods: This study prospectively observed the efficacy of artemether-lumefantrine for the treatment of uncomplicated non-falciparum or mixed-species malaria in two routine district hospitals in the Central African country of Gabon.
Results: Forty patients suffering from uncomplicated Plasmodium malariae, Plasmodium ovale or mixed-species malaria (including Plasmodium falciparum) presenting at the hospital received artemether-lumefantrine treatment and were followed up. All evaluable patients (n = 38) showed an adequate clinical and parasitological response on Day 28 after oral treatment with artemether-lumefantrine (95% confidence interval: 0.91,1). All adverse events were of mild to moderate intensity and completely resolved by the end of study.
Conclusions: This first systematic assessment of artemether-lumefantrine treatment for P. malariae, P. ovale and mixed-species malaria demonstrated a high cure rate of 100% and a favourable tolerability profile, and thus lends support to the practice of treating non-falciparum or mixed-species malaria, or all cases of malaria without definite species differentiation, with artemether-lumefantrine in Gabon.
Trial Registration: ClinicalTrials.gov Identifier: NCT00725777
In der vorliegenden Untersuchung werden 178 Kenia-Reisende vor und nach der Reise schriftlich befragt. Erfasst werden vor der Reise persönliche Daten, Vorerkrankungen, geplan-te Reisedauer, durchgeführte Impfungen und Vorhaben in Kenia. Nach der Reise wird nach gesundheitlichen Beschwerden im Zusammenhang mit der Reise, Medikamenteneinnahme, Malaria-Chemoprophylaxe und Beachtung von Ernährungsregeln gefragt. Ziel ist es, Qualität und Möglichkeiten der reisemedizinischen Beratung zu untersuchen. Fast alle Personen (98%) fahren in den Urlaub, 74% für zwei, 18% für drei Wochen. Strand-urlaub (89%) und Safaris (85%) sind die bevorzugten Beschäftigungen. 97% der Reisenden lassen sich vor der Reise medizinisch beraten. Nur 3% der Reisenden geben an, vor der Reise keine reisemedizinische Beratung vorgenommen zu haben; es handelt sich um Reisende mit Tropenerfahrung. Die Beratung erfolgt in drei Viertel der Fälle durch den Hausarzt. Nur 43% sind allen Impfempfehlungen der STIKO nachgekommen (Hepatitis A, Poliomyelitis, Tetanus und Diphtherie). Lediglich 75% der Reisenden nehmen eine für Kenia indizierte Malaria-Chemoprophylaxe ein (71% Mefloquin, 4% Atovaquon-Proquanil). 8% verzichten auf eine Chemoprophylaxe, 15% nehmen eine Prophylaxe ein, gegen die bereits Resistenzen beste-hen, zwei Personen (1%) eine homöopathische Prophylaxe. Sämtliche Personen, die auf eine Chemoprophylaxe verzichten, reisen nicht zum ersten Mal in ein tropisches Land. 44% der Reisenden leiden während der Reise an gesundheitlichen Beschwerden, wobei Durchfall mit 35% die mit Abstand häufigste Erkrankung ist. 20-29-jährige erkranken am häufigsten daran. Neben Durchfall stellen pulmonale Erkrankungen sowie Infektionen im HNO-Bereich die größte Gruppe von Erkrankungen dar. Folgende Symptome treten nur ver-einzelt auf: Sonnenbrand, Sonnenallergie, Insektenstiche, Fieber, Reizhusten, Atembeschwer-den, Schlafstörungen, Blasenentzündung, Furunkel am Unterarm, Gelenkbeschwerden, Hals-schmerzen, Herzrhythmusstörungen, Kopfschmerzen, Obstipation, Ohrgeräusche, Schüttel-frost, Sodbrennen, Übelkeit, Unruhe, Zahnentzündung, Zerrung am Fuß und geschwollene Augen. 3% benötigen wegen leichterer Beschwerden ärztliche Hilfe während der Reise. Schwerwiegende Erkrankungen oder Unfälle werden nicht genannt. Tropen-Erstreisende haben signifikant häufiger gesundheitliche Beschwerden als Reisende mit Tropenerfahrung. Keine bedeutende Rolle bei der Beschwerdehäufigkeit spielen in dieser Studie die Unterkunft am Reiseort, Organisation der Reise (durch eine Reisegesellschaft oder selbstständig), Vorerkrankungen und die Art der Malariaprophylaxe. 10% der Befragten ge-ben an, nach der Reise einen Arzt aufgesucht zu haben, 6% zur Vorsorge, 4% wegen leichter Beschwerden wie Durchfall oder Bronchitis. Während der Reise ist der Reisende zahlreichen Risiken ausgesetzt. Die Studie zeigt, dass neben impfpräventiblen Erkrankungen und Malaria auch weniger vital bedrohliche Erkran-kungen, wie Reisediarrhöe, Grippe oder ein Sonnenbrand, das Wohlbefinden der Reisenden einschränken können. Der Reisende sollte ausführlich über die bestehenden Risiken im Reise-land informiert werden, um eigenverantwortlich Risiken und Gefahren vermeiden zu können. Die reisemedizinische Beratung muss daher weit über die „klassischen“ Beratungsinhalte, wie Impfempfehlungen und Malariaprophylaxe, hinausgehen. Für die Berücksichtigung der Reisemedizin in der Aus- und Weiterbildung bestehen derzeit nur geringe Möglichkeiten, da sie als interdisziplinäres Fach weder einem Lehrgebiet noch einem Fachgebiet oder –bereich zuzuordnen ist. Durch eine Einbindung in ein Lehrgebiet wie die Allgemeinmedizin und Eingliederung in die Weiterbildungsordnung würde eine Verein-heitlichung der Aus- und Weiterbildung erreicht und damit eine Qualitätssicherung der reise-medizinischen Beratung begünstigt werden.
Background: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria.
Methods: The European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria.
Results: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate.
Conclusion: The majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.
PfEMP1 (erythrocyte membrane protein 1) adhesins play a pivotal role in the pathophysiology of falciparum malaria, by mediating sequestration of Plasmodium falciparum-infected erythrocytes in the microvasculature. PfEMP1 variants are expressed by var genes and are presented on membrane elevations, termed knobs. However, the organization of PfEMP1 on knobs is largely unclear. Here, we use super-resolution microscopy and genetically altered parasites expressing a modified var2csa gene in which the coding sequence of the photoactivatable mEOS2 was inserted to determine the number and distribution of PfEMP1 on single knobs. The data were verified by quantitative fluorescence-activated cell sorting analysis and immuno-electron microscopy together with stereology methods. We show that knobs contain 3.3 ± 1.7 and 4.3 ± 2.5 PfEMP1 molecules, predominantly placed on the knob tip, in parasitized erythrocytes containing wild type and sickle haemoglobin, respectively. The ramifications of our findings for cytoadhesion and immune evasion are discussed.