Harm–benefit analysis – what is the added value?:A review of alternative strategies for weighing harms and benefits as part of the assessment of animal research

Animal experiments are widely required to comply with the 3Rs, to minimise harm to the animals and to serve certain purposes in order to be ethically acceptable. Recently, however, there has been a drift towards adding a so-called harm-benefit analysis as an additional requirement in assessing experiments. According to this, an experiment should only be allowed if there is a positive balance when the expected harm is weighed against the expected benefits. This paper aims to assess the added value of this requirement. Two models, the discourse model and the metric model, are presented. According to the former, the weighing of harms and benefits must be conducted by a committee in which different stakeholders engage in a dialogue. Research into how this works in practice, however, shows that in the absence of an explicit and clearly defined methodology, there are issues about transparency, consistency and fairness. According to the metric model, on the other hand, several dimensions of harms and benefits are defined beforehand and integrated in an explicit weighing scheme. This model, however, has the problem that it makes no real room for ethical deliberation of the sort committees undertake, and it has therefore been criticised for being too technocratic. Also, it is unclear who is to be held accountable for built-in ethical assumptions. Ultimately, we argue that the two models are not mutually exclusive and may be combined to make the most of their advantages while reducing the disadvantages of how harm-benefit analysis in typically undertaken

Designing antifilarial drug trials using clinical trial simulators

Lymphatic filariasis and onchocerciasis are neglected tropical diseases (NTDs) targeted for elimination by mass (antifilarial) drug administration. These drugs are predominantly active against the microfilarial progeny of adult worms. New drugs or combinations are needed to improve patient therapy and to enhance the effectiveness of interventions in persistent hotspots of transmission. Several therapies and regimens are currently in (pre-)clinical testing. Clinical trial simulators (CTSs) project patient outcomes to inform the design of clinical trials but have not been widely applied to NTDs, where their resource-saving payoffs could be highly beneficial. We demonstrate the utility of CTSs using our individual-based onchocerciasis transmission model (EPIONCHO-IBM) that projects trial outcomes of a hypothetical macrofilaricidal drug. We identify key design decisions that influence the power of clinical trials, including participant eligibility criteria and post-treatment follow-up times for measuring infection indicators. We discuss how CTSs help to inform target product profiles

MR

Mass drug administration (MDA) programmes against Onchocerca volvulus use ivermectin (IVM) which targets microfilariae (MF), the worm's offspring. Most infected individuals are hyporesponsive and present regulated immune responses despite high parasite burden. Recently, with MDA programmes, the existence of amicrofilaridermic (a-MF) individuals has become apparent but little is known about their immune responses. Within this immunoepidemiological study, we compared parasitology, pathology and immune profiles in infection-free volunteers and infected individuals that were MF+ or a-MF. The latter stemmed from villages in either Central or Ashanti regions of Ghana which, at the time of the study, had received up to eight or only one round of MDA respectively. Interestingly, a-MF patients had fewer nodules and decreased IL-10 responses to all tested stimuli. On the other hand, this patient group displayed contrary IL-5 profiles following in vitro stimulation or in plasma and the dampened response in the latter correlated to reduced eosinophils and associated factors but elevated neutrophils. Furthermore, multivariable regression analysis with covariates MF, IVM or the region (Central vs. Ashanti) revealed that immune responses were associated with different covariates: whereas O. volvulus-specific IL-5 responses were primarily associated with MF, IL-10 secretion had a negative correlation with times of individual IVM therapy (IIT). All plasma parameters (eosinophil cationic protein, IL-5, eosinophils and neutrophils) were highly associated with MF. With regards to IL-17 secretion, although no differences were observed between the groups to filarial-specific or bystander stimuli, these responses were highly associated with the region. These data indicate that immune responses are affected by both, IIT and the rounds of IVM MDA within the community. Consequently, it appears that a lowered infection pressure due to IVM MDA may affect the immune profile of community members even if they have not regularly participated in the programmes

Chemotherapy of filariasis - established strategies and new developments

Lymphatic filariasis (lympoedema and hydrocoele) and onchocerciasis (dermatitis and ocular inflammation) caused by the parasitic filarial nematodes Wuchereria bancrofti , Brugia spp. and Onchocerca volvulus lead to severe morbidity in developing tropical countries. Mass drug administration (MDA) programmes use ivermectin or diethylcarbamazine, often combined with albendazole, with the aim to eliminate filarial diseases. However, these drugs primarily only kill the first stage larvae, the microfilariae. Removal of the parasites' mutualistic endosymbionts of the genus Wolbachia using anti-rickettsial drugs results in permanent worm sterility and death of the adult worms. Since it is currently not compatible with mass drug administration due to the comparatively long treatment time of 4-6 weeks, doxycycline has been recommended for physician-monitored treatment of individuals. For individuals suffering from filarial pathology, the use of doxycycline is the first drug to have the additional advantage of improving lymphoedema. However, new drugs and regimes need to be in the pipeline in order to tackle the upcoming or already existing problem areas, such as those with ivermectin resistance, areas coendemic for loiasis, or end-game scenarios. Here, we summarize current treatment options and review current research approaches for optimization of anti-helminthic therapy, including the exploration of optimized delivery strategies of ivermectin and albendazole, the discovery and development of new antibiotics for anti-wolbachial chemotherapy and macrofilaricidal antihelminthics

Optimierung der Kriterien zur Schockraumalarmierung

INTRODUCTION Severely injured patients are supposed to be admitted to hospital via the trauma room. Appropriate criteria are contained in the S3 guidelines on the treatment of patients with severe/multiple injuries (S3-GL); however, some of these criteria require scarce hospital resources while the patients then often clinically present as uninjured. There are tendencies to streamline the trauma team activation criteria (TTAC); however, additional undertriage must be avoided. A study group of the emergency, intensive care medicine and treatment of the severely injured section (NIS) is in the process of optimizing the TTAC for the German trauma system. MATERIAL AND METHODS In order to solve the objective the following multi-step approach is necessary: a) definition of patients who potentially benefit from TTA, b) verification of the definition in the TraumaRegister DGU® (TR-DGU), c) carrying out a prospective, multicenter study in order to determine overtriage and undertriage, thereby validating the activation criteria and d) revision of the current TTAC. RESULTS This article summarizes the consensus criteria of the group assumed to be capable of identifying patients who potentially benefit from TTA. These criteria are used to test if TTA was justified in a specific case; however, as the TTCA of the S3-GL are not fully incorporated into the TR-DGU dataset and because cases must also be considered which were not subject to trauma room treatment and therefore were not included in the TR-DGU, it is necessary to perform a prospective full survey of all individuals in order to be able to measure overtriage and undertriage. CONCLUSION Currently, the TR-DGU can only provide limited evidence on the quality of the TTAC recommended in Germany. This problem has been recognized and will be solved by conducting a prospective DGU-supported study, the results of which can be used to improve the TR-DGU dataset in order to enable further considerations on the quality of care (e. g. composition and size of the trauma team)