Managing the risks of making the wrong diagnosis: First, do no harm

The appropriate use of diagnostics is important as misdiagnosis may have serious consequences. Confidence in a diagnostic test result depends on the test's accuracy (sensitivity and specificity) in the context of the use-case (who is tested and why) and the prevalence of the condition investigated. Here, we offer an approach to diagnostics focused on the risks and effects of making the wrong diagnosis. We propose ‘fitness brackets’ for a given test to define the range within which the test is fit-for-purpose, based on the use-case and risk-management principles. We use as exemplars tests for dengue pre-vaccination screening and tests for diagnosing Covid-19 in different settings

Drugs for neglected diseases: a failure of the market and a public health failure?

Infectious diseases cause the suffering of hundreds of millions of people, especially in tropical and subtropical areas. Effective, affordable and easy-to-use medicines to fight these diseases are nearly absent. Although science and technology are sufficiently advanced to provide the necessary medicines, very few new drugs are being developed. However, drug discovery is not the major bottleneck. Today's R&D-based pharmaceutical industry is reluctant to invest in the development of drugs to treat the major diseases of the poor, because return on investment cannot be guaranteed. With national and international politics supporting a free market-based world order, financial opportunities rather than global health needs guide the direction of new drug development. Can we accept that the dearth of effective drugs for diseases that mainly affect the poor is simply the sad but inevitable consequence of a global market economy? Or is it a massive public health failure, and a failure to direct economic development for the benefit of society? An urgent reorientation of priorities in drug development and health policy is needed. The pharmaceutical industry must contribute to this effort, but national and international policies need to direct the global economy to address the true health needs of society. This requires political will, a strong commitment to prioritize health considerations over economic interests, and the enforcement of regulations and other mechanisms to stimulate essential drug development. New and creative strategies involving both the public and the private sector are needed to ensure that affordable medicines for today's neglected diseases are developed. Priority action areas include advocating an essential medicines R&D agenda, capacity-building in and technology transfer to developing countries, elaborating an adapted legal and regulatory framework, prioritizing funding for essential drug development and securing availability, accessibility, distribution and rational use of these drugs

Comparison of otolith readability and reproducibility of counts of translucent zones using different otolith preparation methods for four endemic Labeobarbus species in Lake Tana, Ethiopia

The analysis of fish age data is vital for the successful conservation of fish. Attempts to develop optimal management strategies for effective conservation of the endemic Labeobarbus species are strongly affected by the lack of accurate age estimates. Although methodological studies are key to acquiring a good insight into the age of fishes, up to now, there have not been any studies comparing different methods for these species. Thus, this study aimed at determining the best method for the endemic Labeobarbus species. Samples were collected from May 2016 to April 2017. Asteriscus otoliths from 150 specimens each of L. intermedius, L. tsanensis, L. platydorsus, and L. megastoma were examined. Six methods were evaluated; however, only three methods resulted in readable images. The procedure in which whole otoliths were first submerged in water, and subsequently placed in glycerol to take the image (MO1), was generally best. Except for L. megastoma, this method produced the clearest image as both the coefficient of variation and average percentage error between readers were lowest. Furthermore, except for L. megastoma, MO1 had high otolith readability and no systematic bias. Therefore, we suggest that MO1 should be used as the standard otolith preparation technique for the first three species, while for L. megastoma, other preparation techniques should be evaluated. This study provides a reference for researchers from Africa, particularly Ethiopia, to develop a suitable otolith preparation method for the different tropical fish species

Genotoxicity profile of fexinidazole—a drug candidate in clinical development for human African trypanomiasis (sleeping sickness)

The parasitic disease human African trypanomiasis (HAT), also known as sleeping sickness, is a highly neglected fatal condition endemic in sub-Saharan Africa, which is poorly treated with medicines that are toxic, no longer effective or very difficult to administer. New, safe, effective and easy-to-use treatments are urgently needed. Many nitroimidazoles possess antibacterial and antiprotozoal activity and examples such as tinidazole are used to treat trichomoniasis and guardiasis, but concerns about toxicity including genotoxicity limit their usefulness. Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining of public and pharmaceutical company databases, has the potential to become a short-course, safe and effective oral treatment, curing both acute and chronic HAT. This paper describes the genotoxicity profile of fexinidazole and its two active metabolites, the sulfoxide and sulfone derivatives. All the three compounds are mutagenic in the Salmonella/Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more nitroreductase(s). It is known that these enzymes can nitroreduce compounds with low redox potentials, whereas their mammalian cell counterparts cannot, under normal conditions. Fexinidazole and its metabolites have low redox potentials and all mammalian cell assays to detect genetic toxicity, conducted for this study either in vitro (micronucleus test in human lymphocytes) or in vivo (ex vivo unscheduled DNA synthesis in rats; bone marrow micronucleus test in mice), were negative. Thus, fexinidazole does not pose a genotoxic hazard to patients and represents a promising drug candidate for HAT. Fexinidazole is expected to enter Phase II clinical trials in 201