Improving quality, timeliness and efficacy of data collection and management in population-based surveillance of vital events

Electronic data collection (EDC), has become familiar in recent years, and has been quickly adopted in many research fields. It has become commonplace to assume that systems that entail entering data in mobile devices, connected through secure networks to central servers are of higher standard than old paper based data collection systems (PDC). Although the notion that EDC performs better than PDC seems reasonable and is widely accepted, few studies have tried to formally evaluate whether it can improve data quality, and none of these to our knowledge, are in the context of population-based longitudinal surveillance. This thesis project aims to assess the strength of OpenHDS, a system based on EDC, used in the population-based surveillance of vital events via Health and Demographic surveillance systems (HDSS). HDSS are both sources of vital event data and have the potential to support health intervention studies in the areas where they operate. Setting up and running an HDSS is operationally challenging, and a reliable and efficient platform for data collection and management is a basic part of it. There are often major shortcomings in the data collection and management processes in running HDSS, though these have not been extensively documented. Recent technological advances, specifically the use of mobile devices for data collection, and the adoption of OpenHDS software for data management, which makes use of best practices for data management, appear to have the potential to resolve many of these issues. The INDEPTH Network and others have invested substantial resources in the roll-out and support of OpenHDS, and there is anecdotal evidence that this has resulted in improvements, but there is considerable demand for compelling evidence. The Swiss Tropical and Public Health Institute (Swiss TPH) has supported some INDEPTH sites to fully migrate to OpenHDS (Ifakara and Rufiji in Tanzania, Nanoro in Burkina Faso, Manhiça in Mozambique and Cross river in Nigeria) and some are in the migration process (7 sites in Ethiopia: Arba Minch, Butajira, Dabat, Gilgel Gibe, Kersa and Kilite Awlaelo). Some other sites are at different stages of evaluating the possibility of adopting OpenHDS (Navrongo in Ghana, Niakhar in Senegal, Iganga/Mayuge in Uganda, Nouna in Burkina Faso, Birbhum in India etc.) and there is a demand from all of them for evidence of the benefits of adopting this system. Demonstration of the appropriate functioning of the OpenHDS is also highly relevant in the light of recently proposed approaches for comprehensive health and epidemiological surveillance systems. Such systems will need to satisfy requirements in terms of data availability and integration which are considerable higher than in a classical HDSS. This project assesses the benefits of OpenHDS in terms of and how the advances in data collection and management translate into improved data quality and timeliness. It asks whether the system architecture of the novel data management system can be further exploited to enable data integration approaches for near time quality control and near time response triggers. It also considers what are the main challenges in implementing such technologies in a new or an existing HDSS. This entails: • A description of the new system and of a set of conjectured data management best practices. For each of these best practices there is a literature review to assess if there is evidence to support it and if OpenHDS follow these practices, giving evidence of how this can be feasible and implemented in the field in two different real-life scenarios: the setting up of a new HDSS (Rusinga Island, Western Kenya and Majete Malaria Project, southern Malawi); and the migration of existing HDSSs (Ifakara, Tanzania and Nanoro, Burkina Faso) to OpenHDS. (Chapter 1) • Describing a novel approach for data collection and management in health and demographic surveillance designed to address the shortcomings of the traditional approach (OpenHDS) and documenting the usage of this system the establishment of a new HDSS (Rusinga) in Chapter 2 and 3. • Evaluating innovative approaches for quality control measures that are made possible by the novel data system architecture (in particular, use of satellite imagery to assess completeness of populations, using Majete HDSS as an example) in Chapter 4. • Studying the potential benefits of electronic data collection (compared with paper) in terms of quality, timeliness, and costs by comparing both in a contemporaneous comparison of different systems in 8 villages in Nanoro, Burkina Faso and using historical comparisons of data quality (as assessed by iSHARE2) before and after migration to OpenHDS for a range of INDEPTH sites in Chapter 5. A series of analyses were carried out to demonstrate that the OpenHDS data system for HDSSs can be implemented in both existing or newly established sites in low- and middle-income countries, and to test the hypothesis that the system is superior to previous approaches with regard of quality and timeliness of data and running costs of the system. This involved describing the novel approach to data collection and management enabled by OpenHDS, evaluating benefits in terms of quality and timeliness of the data using the OpenHDS mobile electronic data system, and the cost of electronic data collection (OpenHDS) vs. paper. It also involved evaluating the impact on the quality of the data of near-time availability and the potential of the OpenHDS system architecture for data integration for next-generation quality control and surveillance-response applications. This work demonstrates that OpenHDS is a system that manages data in a standard reference format, using rigorous checks on demographic events, adding the flexibility to introduce entire questionnaires, variables that a longitudinal study could require, and that OpenHDS can take over old demographic surveillance systems with this new real-time low-cost paperless technology opportunity to abandon old fashion research systems, that remain in use in developing countries.

Desenvolvimento e aplicação biológica de nanossistemas contendo o fotossensibilizante cloreto de alumínio ftalocianina

Tese (doutorado)—Universidade de Brasília, Instituto de Ciências Biológicas, Programa de Pós-Graduação em Biologia Animal, 2017.Sistemas de liberação de fármacos com base em nanossistemas tornou-se um campo de interesse nas últimas décadas devido à sua capacidade de transporte e entrega de fármacos, proteção contra a degradação do princípio ativo e redução de efeitos colaterais. Entretanto, elucidar como os componentes de nanossistemas se comportam quando expostos a sistemas biológicos, é um passo fundamental a ser dado para que possamos compreender melhor como fazer seu uso clínico. O fotossensibilizante hidrofóbico alumínio-cloro ftalocianina (AlClFt) já foi utilizado no tratamento de câncer de língua, na eliminação de cáries dentárias, câncer de pulmão, entre outros, associada a nanossistemas para superar a hidrofobicidade de AlClFt. Entretanto, pouco se sabe sobre a consequência biológica da exposição à AlClFt, tanto in vitro quanto in vivo. No presente estudo foram realizadas três abordagens visando esclarecer a dinâmica biológica de nanossistemas contendo AlClFt. Na primeira abordagem micelas de Pluronic® F-127 contendo AlClFt (F-127/AlClFt), foram preparadas, caracterizadas fotofísicamente e testadas quanto à geração de oxigênio singleto e sua eficiência terapêutica contra células de adenocarcinoma de pulmão foi confirmada. A segunda abordagem visou estudar por espectrometria de massa a molécula AlClFt antes e após exposição a tecidos biológicos, além de desenvolver e validar método de cromatografia líquida de ultra alta eficiência para detecção de AlClFt em nanossistemas e matrizes biológicas. O método foi validado quanto à seletividade, linearidade, limites de detecção e quantificação, precisão e recuperação. A massa molecular de AlClFt identificada experimentalmente por espectrometria de massa foi menor do que a massa esperada indicando a perda do átomo de cloro quando em solução e a formação de aduto com solvente eluente (metanol) quando associada a cromatografia líquida. O método bioanalítico desenvolvido apresentou aplicabilidade e robustez para uso em estudos de biodistribuição. A terceira abordagem apresentou uma nanoemulsão magnética contendo AlClFt, sua caraterização, efetividade terapêutica in vitro nas linhagens de carcinoma de pulmão de células não pequenas e em macrófagos murinos, assim como sua biodistribuição in vivo avaliada por tomografia computadorizada por emissão de fóton único, fluorescência por imagem e por cromatografia líquida de alta eficiência. A caracterização físico-química de NE-MAG indicou a presença de duas subpopulações compondo o produto final: uma nanoemulsão não-magnética e uma nanoemulsão magnética. A instabilidade decorrente do isolamento das subpopulações, levou à realização do presente trabalho com o nanossistema contendo a mistura das duas subpopulações. A terapia fotodinâmica das células expostas a NE-MAG resultou na identificação de concentração citotóxica que diminui a viabilidade em 50% mais baixa do que já descrito para outras linhagens com o mesmo fotossensibilizante. A biodistribuição de componente magnético por emissão de fóton único indicou captação majoritária pelo fígado e baço em todos os tempos estudados (até 72 horas). A análise de fluorescência por imagem de AlClFt no nanossistema, mostrou intensa captação por fígado e pulmão enquanto que a quantificação analítica de AlClFt por cromatografia líquida indicou maior quantidade de AlClFt recuperado de fígado e rins. A diversidade do encontrado nas diferentes técnicas é justificada pela complexidade do nanossistema utilizado e reforça a importância da associação de técnicas para estudos de biodistribuição devido às diversas vantagens e limitações de cada técnica. Desta forma, as três abordagens utilizadas contribuem para a elucidação da dinâmica biológica de nanossistemas contendo AlClFt.Nanosystem-based drug delivery systems have become a field of interest in recent decades due to their ability to transport and deliver drugs, avoid degradation of the active principle and prevent side effects. However, elucidating how components of a nanosystem behave once exposed to biological systems is a fundamental step to be taken so that we can understand how to use them in living beings. The hydrophobic photosensitizer aluminum-chlorine phthalocyanine (AlClFt) has already been used in the treatment of tongue cancer, against dental caries, lung cancer, among others, associated with nanosystems to overcome the hydrophobicity of AlClFt. However, little is known about the biological consequence of exposure to AlClFt, both in vitro and in vivo. In the present study three approaches were made to clarify the biological dynamics of nanosystems containing AlClFt. In the first approach, Pluronic F-127 micelles containing AlClFt (F-127/AlClFt) were produced, photophysically characterized and tested for singlet oxygen generation and their therapeutic efficacy against lung adenocarcinoma was confirmed. The second approach was to study by mass spectrometry AlClFt molecule before and after exposure to biological tissues and to develop and validate an ultra-high performance liquid chromatography method for detection of AlClFt in nanosystems and in biological matrices. The method was validated for selectivity, linearity, limits of detection and quantification, accuracy and recovery. The mass of AlClFt experimentally identified by mass spectrometry was lower than the predicted mass indicating the loss of the chlorine atom when in solution and the formation of aducts with eluting solvent (methanol) when combined with liquid chromatography. The developed bioanalytical method presented applicability and robustness for use in biodistribution studies. The third approach presented magnetic nanoemulsion containing AlClFt, its characterization, in vitro therapeutic effectiveness in non-small cell lung carcinomas and murine macrophages, as well as its in vivo biodistribution evaluated by single photon emission computed tomography, fluorescence imaging and by high performance liquid chromatography. The physico-chemical characterization indicated the presence of two subpopulations composing the final product: a non-magnetic nanoemulsion and a magnetic nanoemulsion containing AlClFt (NE-MAG-Ft). The instability resulting from the isolation of the subpopulations led to the use in the present work of nanosystem containing the mixture of the two subpopulations. Photodynamic therapy of cells with NE-MAG-Ft yielded a cytotoxic concentration that decreases viability by 50% lower than previously described for other strains with the same photosensitizer. The biodistribution of the magnetic component by single photon emission demonstrated a major uptake by the liver and spleen at all studied times (up to 72 hours). Fluorescence analysis of AlClFt in the nanosystem demonstrated intense liver and lung uptake while analytical quantification of AlClFt by liquid chromatography indicated more AlClFt in liver and kidneys. The diversity of the different techniques is justified by the complexity of the nanosystem used and reinforces the importance of the association of techniques for biodistribution studies due to the different advantages and limitations of each technique. In this way, the three approaches used contribute to the elucidation of the biological dynamics of AlClFtcontaining nanosystems