Observed Reductions in Schistosoma mansoni Transmission from Large-Scale Administration of Praziquantel in Uganda: A Mathematical Modelling Study

To date schistosomiasis control programmes based on chemotherapy have largely aimed at controlling morbidity in treated individuals rather than at suppressing transmission. In this study, a mathematical modelling approach was used to estimate reductions in the rate of Schistosoma mansoni reinfection following annual mass drug administration (MDA) with praziquantel in Uganda over four years (2003-2006). In doing this we aim to elucidate the benefits of MDA in reducing community transmission.Age-structured models were fitted to a longitudinal cohort followed up across successive rounds of annual treatment for four years (Baseline: 2003, TREATMENT: 2004-2006; n = 1,764). Instead of modelling contamination, infection and immunity processes separately, these functions were combined in order to estimate a composite force of infection (FOI), i.e., the rate of parasite acquisition by hosts.MDA achieved substantial and statistically significant reductions in the FOI following one round of treatment in areas of low baseline infection intensity, and following two rounds in areas with high and medium intensities. In all areas, the FOI remained suppressed following a third round of treatment.This study represents one of the first attempts to monitor reductions in the FOI within a large-scale MDA schistosomiasis morbidity control programme in sub-Saharan Africa. The results indicate that the Schistosomiasis Control Initiative, as a model for other MDA programmes, is likely exerting a significant ancillary impact on reducing transmission within the community, and may provide health benefits to those who do not receive treatment. The results obtained will have implications for evaluating the cost-effectiveness of schistosomiasis control programmes and the design of monitoring and evaluation approaches in general

A Research Agenda for Helminth Diseases of Humans: Modelling for Control and Elimination

Mathematical modelling of helminth infections has the potential to inform policy and guide research for the control and elimination of human helminthiases. However, this potential, unlike in other parasitic and infectious diseases, has yet to be realised. To place contemporary efforts in a historical context, a summary of the development of mathematical models for helminthiases is presented. These efforts are discussed according to the role that models can play in furthering our understanding of parasite population biology and transmission dynamics, and the effect on such dynamics of control interventions, as well as in enabling estimation of directly unobservable parameters, exploration of transmission breakpoints, and investigation of evolutionary outcomes of control. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A research and development agenda for helminthiasis modelling is proposed based on identified gaps that need to be addressed for models to become useful decision tools that can support research and control operations effectively. This agenda includes the use of models to estimate the impact of large-scale interventions on infection incidence; the design of sampling protocols for the monitoring and evaluation of integrated control programmes; the modelling of co-infections; the investigation of the dynamical relationship between infection and morbidity indicators; the improvement of analytical methods for the quantification of anthelmintic efficacy and resistance; the determination of programme endpoints; the linking of dynamical helminth models with helminth geostatistical mapping; and the investigation of the impact of climate change on human helminthiases. It is concluded that modelling should be embedded in helminth research, and in the planning, evaluation, and surveillance of interventions from the outset. Modellers should be essential members of interdisciplinary teams, propitiating a continuous dialogue with end users and stakeholders to reflect public health needs in the terrain, discuss the scope and limitations of models, and update biological assumptions and model outputs regularly. It is highlighted that to reach these goals, a collaborative framework must be developed for the collation, annotation, and sharing of databases from large-scale anthelmintic control programmes, and that helminth modellers should join efforts to tackle key questions in helminth epidemiology and control through the sharing of such databases, and by using diverse, yet complementary, modelling approaches

Density-Dependent Mortality of the Human Host in Onchocerciasis: Relationships between Microfilarial Load and Excess Mortality

Human onchocerciasis (River Blindness) is a parasitic disease leading to visual impairment including blindness. Blindness may lead to premature death, but infection with the parasite itself (Onchocerca volvulus) may also cause excess mortality in sighted individuals. The excess risk of mortality may not be directly (linearly) proportional to the intensity of infection (a measure of how many parasites an individual harbours). We analyze cohort data from the Onchocerciasis Control Programme in West Africa, collected between 1974 and 2001, by fitting a suite of quantitative models (including a ‘null’ model of no relationship between infection intensity and mortality, a (log-) linear function, and two plateauing curves), and choosing the one that is the most statistically adequate. The risk of human mortality initially increases with parasite density but saturates at high densities (following an S-shape curve), and such risk is greater in younger individuals for a given infection intensity. Our results have important repercussions for programmes aiming to control onchocerciasis (in terms of how the benefits of the programme are calculated), for measuring the burden of disease and mortality caused by the infection, and for a better understanding of the processes that govern the density of parasite populations among human hosts

An unconventional view of COVID-19 T cell immunity

In this issue of JEM, Jouan et al. (https://doi.org/10.1084/jem.20200872) report the activation and skewed function of unconventional T cells in severe COVID-19 patients. This may reflect a role in COVID-19 immunity or pathogenesis and potentially identifies new therapeutic targets for this disease

The evolutionary diagnosis of mental disorder

Medicalization of human behavioral diversity is a recurrent theme in the history of psychiatry, and the problem of defining what is a genuine mental disorder is an unresolved question since the origins of clinical psychopathology. Darwinian psychiatry can formulate a definition of mental disorder that is value free and based on factual criteria. From an evolutionary perspective, genuine mental disorders are maladaptive conditions. The ultimate function of an adaptation is gene propagation via maximization of survival and reproduction. It follows that a distressing and/or disabling psychological or behavioral syndrome is a psychiatric disorder only if it impacts negatively on the individual's inclusive fitness. However, in many cases, an evolutionary definition of disorder cannot be reconciled with current social values. Thus, clinicians adopting the evolutionary approach should conform to the prevailing trend of contemporary medicine and accept that their task is to be healers of the distressed, not watchdogs of biological adaptation. These pragmatic considerations do not minimize the scientific validity of the Darwinian definition of mental disorders. Probably, its major contribution to psychiatric theory is the elimination of the necessity to find a brain lesion or dysfunctional mechanism to validate the distinction between disorders and non-disorders. WIREs Cogn Sci 2015, 6:323-331. doi: 10.1002/wcs.1339 For further resources related to this article, please visit the . Conflict of interest: The author has declared no conflict of interest for this article

Diagnosis, power and certainty: Response to Davis

Lennard Davis’s “Biocultural Critique” of the alleged certainty of diagnosis (Davis Journal of Bioethical Inquiry 7:227−235, 2010) makes errors of fact concerning psychiatric diagnostic categories, misunderstands the role of power in the therapeutic relationship, and provides an unsubstantiated and vague alternative to the management of psychological distress via a conceptually outdated model of the relationships between physical and psychological disease and illness. This response demonstrates that diagnostic knowledge vouchsafes legitimate power to physicians, and via them relief to patients who suffer from psychological distress. The history of medicine and psychiatry demonstrates that psychiatric diagnosis shares many features with physical diagnosis, while there is also reason to believe that the two types will continue to be distinct in some respects. Diagnostic categories in psychological medicine, like those in physical medicine, are provisional, probabilistic, and often uncertain. These features do not detract from the dependence on diagnosis of therapeutic efficacy in both domains.© 2010 Springer Science+Business Media B.V

Butyrophilin 2A1 is essential for phosphoantigen reactivity by gamma delta T cells

Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2+ T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9+ TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell-based immunotherapies