Chemotherapy against human African trypanosomiasis: Is there a road to success?

For over fifty years, human African trypanosomiasis (HAT, sleeping sickness) has been treated with suramin, pentamidine and the very toxic organo-arsenical melarsoprol that was the only drug available for effective treatment of the second stage of the disease. Recently there have been significant efforts using molecular and biochemical approaches to drug design, including high-throughput screening, but the number of lead compounds with promising activity against T. brucei spp. and an acceptable toxicity index has remained astonishingly small. Clinical research continues to be difficult due to the economic constraints and the complexity of trials on a low prevalence disease in remote and impoverished African regions. Despite those limitations the situation for the patients is improving thanks to the combination of a number of critical factors. By the late 1990s the disease had reached epidemic levels that triggered political support. WHO would sign a donation agreement with the manufacturers for all drugs to treat HAT. A result of this agreement was that eflornithine which is much safer than melarsoprol became available and widely used by non-governmental organizations. The Impamel I and II programmes demonstrated that against all odds the conduct of clinical trials on HAT was feasible. This allowed the initiation of trials on combination therapies which eventually resulted in the nifurtimox-eflornithine combination treatment (NECT). This combination is currently being introduced as first line treatment, and there is even the prospect of having a new compound, fexinidazole, in the development pipeline. This review summarizes the key information about the existing drugs and gives a comprehensive summary about the recent and currently ongoing efforts towards new drug

"You can save time if…" - a qualitative study on internal factors slowing down clinical trials in Sub-Saharan Africa

The costs, complexity, legal requirements and number of amendments associated with clinical trials are rising constantly, which negatively affects the efficient conduct of trials. In Sub-Saharan Africa, this situation is exacerbated by capacity and funding limitations, which further increase the workload of clinical trialists. At the same time, trials are critically important for improving public health in these settings. The aim of this study was to identify the internal factors that slow down clinical trials in Sub-Saharan Africa. Here, factors are limited to those that exclusively relate to clinical trial teams and sponsors. These factors may be influenced independently of external conditions and may significantly increase trial efficiency if addressed by the respective teams.; We conducted sixty key informant interviews with clinical trial staff working in different positions in two clinical research centres in Kenya, Ghana, Burkina Faso and Senegal. The study covered English- and French-speaking, and Eastern and Western parts of Sub-Saharan Africa. We performed thematic analysis of the interview transcripts.; We found various internal factors associated with slowing down clinical trials; these were summarised into two broad themes, "planning" and "site organisation". These themes were consistently mentioned across positions and countries. "Planning" factors related to budget feasibility, clear project ideas, realistic deadlines, understanding of trial processes, adaptation to the local context and involvement of site staff in planning. "Site organisation" factors covered staff turnover, employment conditions, career paths, workload, delegation and management.; We found that internal factors slowing down clinical trials are of high importance to trial staff. Our data suggest that adequate and coherent planning, careful assessment of the setting, clear task allocation and management capacity strengthening may help to overcome the identified internal factors and allow clinical trials to proceed more efficiently

A Primer on the Differential Calculus of 3D Orientations

The proper handling of 3D orientations is a central element in many optimization problems in engineering. Unfortunately many researchers and engineers struggle with the formulation of such problems and often fall back to suboptimal solutions. The existence of many different conventions further complicates this issue, especially when interfacing multiple differing implementations. This document discusses an alternative approach which makes use of a more abstract notion of 3D orientations. The relative orientation between two coordinate systems is primarily identified by the coordinate mapping it induces. This is combined with the standard exponential map in order to introduce representation-independent and minimal differentials, which are very convenient in optimization based methods

Methodological approaches for conducting follow-up research with clinical trial participants: a scoping review and expert interviews

Evidence-based establishment and implementation of best principles, laws and ordinances that regulate clinical research depend on the consultation and involvement of trial participants. Yet, guidance on methodological approaches to obtain trial participants' perspectives is currently missing. This scoping review therefore aimed at identifying, describing and evaluating research approaches to obtain trial participants' feedback on their views and experiences.; We searched the electronic databases Medline and PsycInfo via Ovid and the Web of Science Core Collection. Clinical trials were included that involved adult participants that were conducted in selected high-income countries and that were published in peer-reviewed journals between 1985 and 2018. In addition, 29 expert interviews were conducted between March and May 2019.; Out of 5994 identified records, 23 articles were included in this review. Twelve studies used a qualitative approach, 10 were quantitative and one study used a mixed-method design. More than 75% of all work was conducted in the USA and the UK. The scoping review and the expert interviews highlighted that recruitment of participants was generally done through direct contact by principal investigators and/or study nurses or through searches in de-identified patient databases. Authors used surveys, interviews or focus group discussions. The tools used were either based on existing validated ones or developed and verified de novo with the support of experts and/or patient representatives.; To our knowledge, this is the first methodological literature review of approaches to researching experiences of clinical trial participants where findings were triangulated with expert interviews. Covering a range of indications, trial phases and study settings, it demonstrates that clinical trial participant perspectives and experience is heavily under-researched. This casts doubt on the overall robustness of available insight into trial participants' views and experiences. Our results demonstrate that the methodology for studying participant opinion, perception and experience should be adapted to the measure of interest and conform to the study population. Using valid patient experience data is the basis to evaluate existing legal and regulatory human subject research frameworks for their appropriateness from a patient perspective. Such an evaluation will be critical to empower research participants

Defining clinical trial quality from the perspective of resource-limited settings: A qualitative study based on interviews with investigators, sponsors, and monitors conducting clinical trials in sub-Saharan Africa

Background Increasing clinical trial cost and complexity, as well as a high waste of clinical trial investment over the past decades, have changed the way clinical trial quality is managed. Recent evidence has highlighted that the lack of a clear clinical trial quality definition may have contributed to previous inefficiencies. This study aims to support the understanding of what clinical trial quality entails from the perspective of resource-limited settings. Methodology/Principal findings We conducted 46 semi-structured interviews involving investigators, sponsors, and monitors with experience in conducting clinical trials in 27 countries in sub-Saharan Africa. The questionnaire addressed the overall meaning of clinical trial quality and a conclusive clinical trial quality definition, as well as specific aspects of resource-limited settings across the clinical trial process. We held the interviews either in person, via Skype or by phone. They were recorded and transcribed verbatim, and we performed the analysis using The Framework Method. The analysis of clinical trial quality definitions resulted in 11 elements, which were summarised into a clinical trial quality concept consisting of two components: 1) clinical trial quality building factors (Scientific factors and Moral factors) and 2) promoting factors (Context adaptation; Infrastructure; Partnership; Operational excellence; Quality system). 12 resource-limited settings specific themes were identified. These themes were all categorised under the promoting factors "Context adaptation", "Infrastructure", and "Partnership". Conclusions/Significance We found that in order to enable comprehensive clinical trial quality management, clinical trial quality should be defined by a multidimensional concept that includes not only scientific and ethical, but also quality-promoting factors. Such a concept is of general relevance and not limited to clinical trials in resource-limited settings, where it naturally carries particular weight. In addition, from the perspective of sub-Saharan Africa, we identified specific categories that appear to be critical for the conduct of clinical trials in resource-limited settings, and we propose respective changes to a particular existing clinical trial quality framework (i.e., INQUIRE)

Defining clinical trial quality from the perspective of resource-limited settings: a qualitative study based on interviews with investigators, sponsors, and monitors conducting clinical trials in sub-Saharan Africa

In recent decades, the quality management of clinical trials has been criticised for being inefficient and ineffective. This has led to a waste of clinical trial investment and has made it particularly difficult to conduct clinical trials in settings with limited resources. The lack of a universally accepted comprehensive definition of clinical trial quality was suggested as one of the possible causes of inadequate quality management. However, resource-limited countries were not considered in the attempt to create such a definition. In our study, we developed a quality concept based on qualitative interviews from the perspective of investigators, sponsors, and monitors with experience in conducting clinical trials in sub-Saharan Africa. The analysis of these stakeholders' definitions of clinical trial quality has produced a Clinical Trial Quality Concept that includes quality promoting factors (i.e., Context adaptation; Infrastructure; Partnership; Operational excellence; Quality system) in addition to conventional scientific and ethical factors. The results thus support the need for a multidimensional quality concept to reflect clinical trial quality more comprehensively. We recommend the term "Comprehensive Quality Management (CQM)" for this concept. CQM has the potential to serve as a basis for the current revision of quality management principles in international clinical trial guidelines. Furthermore, the sub-Saharan African perspective has highlighted additional considerations compared to the existing comprehensive INQUIRE clinical trial quality framework. Therefore, we propose including the following three points relevant to resource-limited settings in the framework: 1) Communicating potential infrastructural disadvantages to funders, sponsors, and auditors. 2) Preventing potential exploitation of research populations and workforce in low- and middle-income countries by following existing ethical frameworks. 3) Including "Context adaptation" as an additional framework category (i.e., promoting factor)

Optical Coherence Tomography Navigated Laser Retinopexy for Retinal Breaks

The prevalent cause of retinal detachment is a full-thickness retinal break, which allows fluid to enter the subretinal space from the vitreous cavity. To prevent progression of the detachment, laser photocoagulation (LPC) lesions are placed around the break in clinical practice to seal the tissue. The treatment is usually performed under indirect ophthalmoscopy. Therefore, the subretinal damage can be difficult to delineate and an experienced operator is required for a successful outcome. In this work, optical coherence tomography (OCT) is used for optimal treatment planning, and LPC is subsequently applied in a navigated and user-friendly procedure. The novel method was integrated in a modified OCT diagnostic system (SPECTRALIS OCT, Heidelberg Engineering, Heidelberg, Germany) with integrated treatment laser (Merilas 532 shortpulse, Meridian, Thun, Switzerland). To reliably seal the break, LPC lesions must be applied in regions of still attached retina. Therefore, OCT B-scans were used to manually mark the boundary of the surrounding detachment, which allowed to compute an optimally placed elliptical treatment area. To evaluate the method, artificially provoked retinal breaks were treated accordingly in 10 ex-vivo porcine eyes and the outcome was assessed by fundus photography and OCT imaging. Ex-vivo experiments showed that OCT-based laser treatment is feasible and the visibility of the subretinal space allows precise treatment planning. A total of 99 to 227 automatically applied lesions per eye at 200 ms and 200 mW were evident as coagulation in color fundus photography. Furthermore, OCT cross-sectional scans showed the required ruptures of the retina at the LPC application sites (Figure 1). The results indicate the potential of OCT navigated laser retinopexy to achieve high treatment accuracy, efficiency, and safety. Future studies should address treatment of peripheral breaks and the integration of the existing tracking and follow-up functionalities to further enhance and facilitate the treatment. This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually. Retinal break treatment outcome in an ex-vivo porcine eye. Fundus photographs before (A) and after (B) treatment, infrared scanning laser ophthalmoscope images before (C) and after (E) treatment with the corresponding OCT B-scans (D)(F). The effect of LPC treatment is visible in (B)(E) as spots of whitened tissue and in (F) as ruptures in the retina at the treatment sites (marked in red)

Sleeping hearts: 12 years after a follow up study on cardiac findings due to sleeping sickness

Both American Trypanosomiasis (Chagas disease) and Human African Trypanosomiasis (HAT) are diseases caused by single-celled flagellate protozoan parasites. While cardiac complications such as conduction problems and heart failure are very common in Chagas disease there is little known about the long-term effects of Human African Trypanosomiasis (HAT) on cardiac sequelae in Sub-Saharan Africa, where heart failure has become an increasing problem and growing burden. In the context of clinical trials conducted between 2004 and 2005 in the Democratic Republic of the Congo (DRC), the prevalence of HAT related signs and symptoms and an ECG were evaluated prior to the initiation of treatment. The object of this follow-up study in 2017 was to assess the prevalence of cardiac sequelae in the same 51 first stage and 18 second stage HAT patients 12-13 years after their treatment by conducting a clinical examination and an ECG. A control group matched by age (± 5 years), sex and whenever possible form the same village was enrolled. There were no significant differences in the prevalence of cardiac symptoms and in ECG findings between patients and their controls at the time of the follow-up evaluation. Repolarization changes disappeared or improved in 24.7% of HAT patients and were even less frequent than in the control group. Peripheral low voltage was the only parameter that increased over time in HAT patients and in three patients, new conduction problems in the ECG (ventricular bigeminy, RBBB, and bifascicular block) could be found, although none of these findings was clinically significant. However, the appearance of these conduction problems might represent an early indication of a HAT related cardiomyopathy or ongoing subclinical infection. This hypothesis would be supported by the findings of an older study in which antibodies (IFAT) against trypanosomiasis in 27% of Cameroonian patients with dilated cardiomyopathy compared to 2% in normal controls had been observed

High-Precision Optical Coherence Tomography Navigated Laser Retinopexy for Retinal Breaks

The prevalent cause of retinal detachment is a full-thickness retinal break and the ingress of fluid into the subretinal space. To prevent progression of the detachment, laser photocoagulation (LPC) lesions are placed around the break in clinical practice to seal the tissue. Unlike the usual application under indirect ophthalmoscopy, we developed a semi-automatic treatment planning software based on a sequence of optical coherence tomography (OCT) scans to perform navigated LPC treatment. The depth information allows demarcation of the border where the neurosensory retina is still attached to the retinal pigment epithelium (RPE), which is critical for prevention of detachment progression. To evaluate the method, artificially provoked retinal breaks were treated in seven ex-vivo porcine eyes. Treatment outcome was assessed by fundus photography and OCT imaging. The automatically applied lesions surrounding each detachment (4.4–39.6 mm2) could be identified as highly scattering coagulation regions in color fundus photography and OCT. Between the planned and applied pattern, a mean offset of 68 µm (SD ± 16.5 µm) and a mean lesion spacing error of 5 µm (SD ± 10 µm) was achieved. The results demonstrate the potential of navigated OCT-guided laser retinopexy to improve overall treatment accuracy, efficiency, and safety

Ethical, Legal and Social Issues of Big Data - A Comprehensive Overview

The ELSI White Paper is the final achievement of the ELSI Task Force for the National Research Programme “Big Data” (NRP 75). It is an informational document that provides an overview of the key ethical, legal, and social challenges of big data and provides guidance for the collection, use, and sharing of big data. The document aims to bring together the expertise of the ELSI Task Force members rather than exhaustively covering all topics in big data relating to ethical, legal, and social issues (ELSI). The white paper comprises two parts: main articles and commentaries on it. The main articles give an overview of the major concerns associated with the use of big data, based on the assessment of the participating researchers. The commentary articles either examine in depth one or more of the issues that are presented in the main articles or highlight other issues that are considered relevant by their authors but are not covered in the main articles. The main articles are divided into three sections corresponding to the three ELSI levels of analysis. In the section on ethics, Marcello Ienca explores the threat of big data to ethics commissions, privacy rights, personal autonomy, and equality in the healthcare sector and biomedical research. Bernice Elger focuses on the need to address informed consent differently and complement it with additional mechanisms in the big data context. In the legal section, Christophe Schneble explores whether current Swiss data protection laws adequately regulate and protect individuals’ data. Eleonora Viganò analyses the threat of big data to state sovereignty and explore the two contrasting acceptations of the term “digital sovereignty” in the context of big data. In the section on social issues, Markus Christen addresses the big data divide, namely, the uneven distribution of benefits and harms from big data and the connected issue of the transparency asymmetry between data givers and data owners. Michele Loi delves into the debate on fair algorithms, presenting the risks of discriminating against certain groups when adopting big data-based predictive algorithms, such as those for predicting inmates’ recidivism. The second part of the ELSI White Paper contains three commentaries. In the first, Mira Burri focuses on the viability of new approaches to global trade governance that seek to address big data issues and makes recommendations for a better informed and more proactive Swiss approach. In the second commentary, David Shaw explores the lack of protection for vulnerable groups in big data research and the temporospatial and moral distance between researchers and participants that increases the risk of exploitation. In the third commentary, Christian Hauser tackles big data from the perspective of business ethics and provides guidance to companies employing big data. Keywords: Big data, informed consent, data protection law, big data divide, digital sovereignty, health data, discrimination, big data research, big data in industry JEL Classification: O3, F1