Epidemicity indices and reproduction numbers from infectious disease data in connected human populations.

We focus on distinctive data-driven measures of the fate of ongoing epidemics. The relevance of our pursuit is suggested by recent results proving that the short-term temporal evolution of infection spread is described by an epidemicity index related to the maximum instantaneous growth rate of new infections, echoing concepts and tools developed to study the reactivity of ecosystems. Suitable epidemicity indices can showcase the dynamics of infections, together with commonly employed effective reproduction numbers, especially when the latter assume values less than 1. In particular, epidemicity evaluates the short-term reactivity to perturbations of a disease-free equilibrium. Here, we show that sufficient epidemicity thresholds to prevent transient epidemic outbreaks in a spatially connected setting can be estimated by generalizing existing analogues derived when spatial effects are neglected. We specifically account for the discrete nature, in both space and time, of surveillance data of the type typically employed to estimate effective reproduction numbers that formed the bulk of the communication of the state of the COVID-19 pandemic and its controls. After analyzing the effects of spatial heterogeneity on the considered prognostic indicators, we perform a short- and long-term analysis on the COVID-19 pandemic in Italy, showing that endemic conditions were maintained throughout the duration of our simulation despite stringent control measures. Our method provides a portfolio of prognostic indices that are essential to pinpoint the ongoing pandemic in both a qualitative and quantitative manner, as our results demonstrate. We base our conclusions on extended investigations of the effects of spatial fragmentation of communities of different sizes owing to connectivity by human mobility and contact scenarios, within real geographic contexts and synthetic setups designed to test our framework.

Helminth ecological requirements shape the impact of climate change on the hazard of infection.

Outbreaks and spread of infectious diseases are often associated with seasonality and environmental changes, including global warming. Free-living stages of soil-transmitted helminths are highly susceptible to climatic drivers; however, how multiple climatic variables affect helminth species, and the long-term consequences of these interactions, is poorly understood. We used experiments on nine trichostrongylid species of herbivores to develop a temperature- and humidity-dependent model of infection hazard, which was then implemented at the European scale under climate change scenarios. Intestinal and stomach helminths exhibited contrasting climatic responses, with the former group strongly affected by temperature while the latter primarily impacted by humidity. Among the demographic traits, larval survival heavily modulated the infection hazard. According to the specific climatic responses of the two groups, climate change is expected to generate differences in the seasonal and spatial shifts of the infection hazard and group co-circulation. In the future, an intensification of these trends could create new opportunities for species range expansion and co-occurrence at European central-northern latitudes.

Epidemic Management via Imperfect Testing: A Multi-criterial Perspective.

Diagnostic testing may represent a key component in response to an ongoing epidemic, especially if coupled with containment measures, such as mandatory self-isolation, aimed to prevent infectious individuals from furthering onward transmission while allowing non-infected individuals to go about their lives. However, by its own nature as an imperfect binary classifier, testing can produce false negative or false positive results. Both types of misclassification are problematic: while the former may exacerbate the spread of disease, the latter may result in unnecessary isolation mandates and socioeconomic burden. As clearly shown by the COVID-19 pandemic, achieving adequate protection for both people and society is a crucial, yet highly challenging task that needs to be addressed in managing large-scale epidemic transmission. To explore the trade-offs imposed by diagnostic testing and mandatory isolation as tools for epidemic containment, here we present an extension of the classical Susceptible-Infected-Recovered model that accounts for an additional stratification of the population based on the results of diagnostic testing. We show that, under suitable epidemiological conditions, a careful assessment of testing and isolation protocols can contribute to epidemic containment, even in the presence of false negative/positive results. Also, using a multi-criterial framework, we identify simple, yet Pareto-efficient testing and isolation scenarios that can minimize case count, isolation time, or seek a trade-off solution for these often contrasting epidemic management objectives.

Spatially explicit effective reproduction numbers from incidence and mobility data.

Current methods for near real-time estimation of effective reproduction numbers from surveillance data overlook mobility fluxes of infectors and susceptible individuals within a spatially connected network (the metapopulation). Exchanges of infections among different communities may thus be misrepresented unless explicitly measured and accounted for in the renewal equations. Here, we first derive the equations that include spatially explicit effective reproduction numbers, ℛk(t), in an arbitrary community k. These equations embed a suitable connection matrix blending mobility among connected communities and mobility-related containment measures. Then, we propose a tool to estimate, in a Bayesian framework involving particle filtering, the values of ℛk(t) maximizing a suitable likelihood function reproducing observed patterns of infections in space and time. We validate our tools against synthetic data and apply them to real COVID-19 epidemiological records in a severely affected and carefully monitored Italian region. Differences arising between connected and disconnected reproduction numbers (the latter being calculated with existing methods, to which our formulation reduces by setting mobility to zero) suggest that current standards may be improved in their estimation of disease transmission over time.

A stratified compartmental model for the transmission of Sparicotyle chrysophrii (Platyhelminthes: Monogenea) in gilthead seabream (Sparus aurata) fish farms†.

The rapid development of intensive fish farming has been associated with the spreading of infectious diseases, pathogens and parasites. One such parasite is Sparicotyle chrysophrii (Platyhelminthes: Monogenea), which commonly infects cultured gilthead seabream (Sparus aurata)-a vital species in Mediterranean aquaculture. The parasite attaches to fish gills and can cause epizootics in sea cages with relevant consequences for fish health and associated economic losses for fish farmers. In this study, a novel stratified compartmental epidemiological model of S. chrysophrii transmission was developed and analysed. The model accounts for the temporal progression of the number of juvenile and adult parasites attached to each fish, as well as the abundance of eggs and oncomiracidia. We applied the model to data collected in a seabream farm, where the fish population and the number of adult parasites attached to fish gills were closely monitored in six different cages for 10 months. The model successfully replicated the temporal dynamics of the distribution of the parasite abundance within fish hosts and simulated the effects of environmental factors, such as water temperature, on the transmission dynamics. The findings highlight the potential of modelling tools for farming management, aiding in the prevention and control of S. chrysophrii infections in Mediterranean aquaculture.

Modeling the contribution of antibody attack rates to single and dual helminth infections in a natural system.

Within-host models of infection can provide important insights into the processes that affect parasite spread and persistence in host populations. However, modeling can be limited by the availability of empirical data, a problem commonly encountered in natural systems. Here, we used six years of immune-infection observations of two gastrointestinal helminths (Trichostrongylus retortaeformis and Graphidium strigosum) from a population of European rabbits (Oryctolagus cuniculus) to develop an age-dependent, mathematical model that explicitly included species-specific and cross-reacting antibody (IgA and IgG) responses to each helminth in hosts with single or dual infections. Different models of single infection were formally compared to test alternative mechanisms of parasite regulation. The two models that best described single infections of each helminth species were then coupled through antibody cross-immunity to examine how the presence of one species could alter the host immune response to, and the within-host dynamics of, the other species. For both single infections, model selection suggested that either IgA or IgG responses could equally explain the observed parasite intensities by host age. However, the antibody attack rate and affinity level changed between the two helminths, it was stronger against T. retortaeformis than against G. strigosum and caused contrasting age-intensity profiles. When the two helminths coinfect the same host, we found variation of the species-specific antibody response to both species together with an asymmetric cross-immune response driven by IgG. Lower attack rate and affinity of antibodies in dual than single infections contributed to the significant increase of both helminth intensities. By combining mathematical modeling with immuno-infection data, our work provides a tractable model framework for disentangling some of the complexities generated by host-parasite and parasite-parasite interactions in natural systems.

Reframing Optimal Control Problems for Infectious Disease Management in Low-Income Countries.

Optimal control theory can be a useful tool to identify the best strategies for the management of infectious diseases. In most of the applications to disease control with ordinary differential equations, the objective functional to be optimized is formulated in monetary terms as the sum of intervention costs and the cost associated with the burden of disease. We present alternate formulations that express epidemiological outcomes via health metrics and reframe the problem to include features such as budget constraints and epidemiological targets. These alternate formulations are illustrated with a compartmental cholera model. The alternate formulations permit us to better explore the sensitivity of the optimal control solutions to changes in available budget or the desired epidemiological target. We also discuss some limitations of comprehensive cost assessment in epidemiology.

A New Family of Macrocyclic Polyamino Biphenolic Ligands: Acid-Base Study, Zn(II) Coordination and Glyphosate/AMPA Binding.

In this study, the ligands 23,24-dihydroxy-3,6,9,12-tetraazatricyclo[17.3.1.1(14,18)]eicosatetra-1(23),14,16,18(24),19,21-hexaene, L1, and 26,27-dihidroxy-3,6,9,12,15-pentaazatricyclo[20.3.1.1(17,21)]eicosaepta-1(26),17,19,21(27),22,24-hexaene, L2, were synthesized: they represent a new class of molecules containing a biphenol unit inserted into a macrocyclic polyamine fragment. The previously synthesized L2 is obtained herein with a more advantageous procedure. The acid-base and Zn(II)-binding properties of L1 and L2 were investigated through potentiometric, UV-Vis, and fluorescence studies, revealing their possible use as chemosensors of H+ and Zn(II). The new peculiar design of L1 and L2 afforded the formation in an aqueous solution of stable Zn(II) mono (LogK 12.14 and 12.98 for L1 and L2, respectively) and dinuclear (LogK 10.16 for L2) complexes, which can be in turn exploited as metallo-receptors for the binding of external guests, such as the popular herbicide glyphosate (N-(phosphonomethyl)glycine, PMG) and its primary metabolite, the aminomethylphosphonic acid (AMPA). Potentiometric studies revealed that PMG forms more stable complexes than AMPA with both L1- and L2-Zn(II) complexes, moreover PMG showed higher affinity for L2 than for L1. Fluorescence studies showed instead that the L1-Zn(II) complex could signal the presence of AMPA through a partial quenching of the fluorescence emission. These studies unveiled therefore the utility of polyamino-phenolic ligands in the design of promising metallo-receptors for elusive environmental targets.

The enemy of my enemy is my friend: Immune-mediated facilitation contributes to fitness of co-infecting helminths.

The conceptual understanding of immune-mediated interactions between parasites is rooted in the theory of community ecology. One of the limitations of this approach is that most of the theory and empirical evidence has focused on resource or immune-mediated competition between parasites and yet there is ample evidence of positive interactions that could be generated by immune-mediated facilitation. We developed an immuno-epidemiological model and applied it to long-term data of two gastrointestinal helminths in two rabbit populations to investigate, through model testing, how immune-mediated mechanisms of parasite regulation could explain the higher intensities of both helminths in rabbits with dual than single infections. The model framework was selected and calibrated on rabbit population A and then validated on the nearby rabbit population B to confirm the consistency of the findings and the generality of the mechanisms. Simulations suggested that the higher intensities in rabbits with dual infections could be explained by a weakened or low species-specific IgA response and an asymmetric IgA cross-reaction. Simulations also indicated that rabbits with dual infections shed more free-living stages that survived for longer in the environment, implying greater transmission than stages from hosts with single infections. Temperature and humidity selectively affected the free-living stages of the two helminths. These patterns were comparable in the two rabbit populations and support the hypothesis that immune-mediated facilitation can contribute to greater parasite fitness and local persistence.

Optimal control of the spatial allocation of COVID-19 vaccines: Italy as a case study.

While campaigns of vaccination against SARS-CoV-2 are underway across the world, communities face the challenge of a fair and effective distribution of a limited supply of doses. Current vaccine allocation strategies are based on criteria such as age or risk. In the light of strong spatial heterogeneities in disease history and transmission, we explore spatial allocation strategies as a complement to existing approaches. Given the practical constraints and complex epidemiological dynamics, designing effective vaccination strategies at a country scale is an intricate task. We propose a novel optimal control framework to derive the best possible vaccine allocation for given disease transmission projections and constraints on vaccine supply and distribution logistics. As a proof-of-concept, we couple our framework with an existing spatially explicit compartmental COVID-19 model tailored to the Italian geographic and epidemiological context. We optimize the vaccine allocation on scenarios of unfolding disease transmission across the 107 provinces of Italy, from January to April 2021. For each scenario, the optimal solution significantly outperforms alternative strategies that prioritize provinces based on incidence, population distribution, or prevalence of susceptibles. Our results suggest that the complex interplay between the mobility network and the spatial heterogeneities implies highly non-trivial prioritization strategies for effective vaccination campaigns. Our work demonstrates the potential of optimal control for complex and heterogeneous epidemiological landscapes at country, and possibly global, scales.

Epidemicity of cholera spread and the fate of infection control measures.

The fate of ongoing infectious disease outbreaks is predicted through reproduction numbers, defining the long-term establishment of the infection, and epidemicity indices, tackling the reactivity of the infectious pool to new contagions. Prognostic metrics of unfolding outbreaks are of particular importance when designing adaptive emergency interventions facing real-time assimilation of epidemiological evidence. Our aim here is twofold. First, we propose a novel form of the epidemicity index for the characterization of cholera epidemics in spatial models of disease spread. Second, we examine in hindsight the survey of infections, treatments and containment measures carried out for the now extinct 2010-2019 Haiti cholera outbreak, to suggest that magnitude and timing of non-pharmaceutical and vaccination interventions imply epidemiological responses recapped by the evolution of epidemicity indices. Achieving negative epidemicity greatly accelerates fading of infections and thus proves a worthwhile target of containment measures. We also show that, in our model, effective reproduction numbers and epidemicity indices are explicitly related. Therefore, providing an upper bound to the effective reproduction number (significantly lower than the unit threshold) warrants negative epidemicity and, in turn, a rapidly fading outbreak preventing coalescence of sparse local sub-threshold flare-ups.

Primary orthostatic tremor and orthostatic tremor-plus in dogs: 60 cases (2003-2020).

BACKGROUND: Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the limbs while standing. OBJECTIVE: To describe the signalment, presenting complaints, phenotype, diagnostic findings, treatment, and outcome of a large sample of dogs with OT. ANIMALS: Sixty dogs diagnosed with OT based on conscious electromyography. METHODS: Multicenter retrospective case series study. Dogs were included if they had a conscious electromyography consistent with muscle discharge frequency >12 Hz while standing. RESULTS: Fifty-three cases were diagnosed with primary OT (POT). Giant breed dogs represented most cases (83%; 44/53). Most dogs (79%; 42/53) were younger than 2 years of age at onset of signs, except for Retrievers which were all older than 3.5 years of age. The most common presenting complaints were pelvic limb tremors while standing (85%; 45/53) and difficulty when rising or sitting down (45%; 24/53). Improvement of clinical signs occurred in most dogs (85%; 45/53) treated medically with phenobarbital, primidone, gabapentin, pregabalin or clonazepam, but it was mostly partial rather than complete. Orthostatic tremor-plus was seen in 7 dogs that had concurrent neurological diseases. CONCLUSIONS AND CLINICAL IMPORTANCE: Primary OT is a progressive disease of young, purebred, giant/large-breed dogs, which appears to begin later in life in Retrievers. Primary OT apparently responds partially to medications. Orthostatic tremor-plus exists in dogs and can be concomitant or associated with other neurological diseases.

Data-driven analysis of amino acid change dynamics timely reveals SARS-CoV-2 variant emergence.

Since its emergence in late 2019, the diffusion of SARS-CoV-2 is associated with the evolution of its viral genome. The co-occurrence of specific amino acid changes, collectively named 'virus variant', requires scrutiny (as variants may hugely impact the agent's transmission, pathogenesis, or antigenicity); variant evolution is studied using phylogenetics. Yet, never has this problem been tackled by digging into data with ad hoc analysis techniques. Here we show that the emergence of variants can in fact be traced through data-driven methods, further capitalizing on the value of large collections of SARS-CoV-2 sequences. For all countries with sufficient data, we compute weekly counts of amino acid changes, unveil time-varying clusters of changes with similar-rapidly growing-dynamics, and then follow their evolution. Our method succeeds in timely associating clusters to variants of interest/concern, provided their change composition is well characterized. This allows us to detect variants' emergence, rise, peak, and eventual decline under competitive pressure of another variant. Our early warning system, exclusively relying on deposited sequences, shows the power of big data in this context, and concurs to calling for the wide spreading of public SARS-CoV-2 genome sequencing for improved surveillance and control of the COVID-19 pandemic.

Intracranial meningioma in two coeval adult cats from the same litter.

CASE SUMMARY: In this report we describe the occurrence of intracranial meningioma in two adult cats from the same litter. The location of the meningioma varied: one tumour was at the level of the brainstem, and the other was affecting the temporal and piriform lobes. The cat with the brainstem meningioma was treated with radiotherapy and the littermate had a rostrotentorial craniectomy for tumour removal. Both cats had a histopathological diagnosis of grade I meningioma of a predominantly fibrous subtype. RELEVANCE AND NOVEL INFORMATION: Cases of familial meningioma in cats have not previously been described in the veterinary literature. However, familial meningioma is well described in humans and it is possible that cases are underestimated in animals. We discuss the possible genetic background and other causes, as well as challenges we may face in veterinary medicine in identifying these associations.

Exploring the potential of highly charged Ru(II)- and heteronuclear Ru(II)/Cu(II)-polypyridyl complexes as antimicrobial agents.

The antimicrobial potential of two ruthenium(II) polypyridyl complexes, [Ru(phen)2L1]2+ and [Ru(phen)2L2]2+ (phen = 1,10-phenanthroline) containing the 4,4'-(2,5,8,11,14-pentaaza[15])-2,2'-bipyridilophane (L1) and the 4,4'-bis-[methylen-(1,4,7,10-tetraazacyclododecane)]-2,2' bipyridine (L2) units, is herein investigated. These peculiar polyamine frameworks afford the formation of highly charged species in solution, influence the DNA-binding and cleavage properties of compounds, but they do not undermine their singlet oxygen sensitizing capacities, thus making these complexes attractive 1O2 generators in aqueous solution. L1 and L2 also permit to stably host Fenton -active Cu2+ ion/s, leading to the formation of mixed Ru2+/Cu2+ forms capable to further strengthen the oxidative damages to biological targets. Herein, following a characterization of the Cu2+ binding ability by [Ru(phen)2L2]2+, the water-octanol distribution coefficients, the DNA binding, cleavage and 1O2 sensitizing properties of [Ru(phen)2L2]2+ and [Cu2Ru(phen)2L2]6+ were analysed and compared with those of [Ru(phen)2L1]2+ and [CuRu(phen)2L1]4+. The antimicrobial activity of all compounds was evaluated against B. subtilis, chosen as a model for gram-positive bacteria, both under dark and upon light-activation. Our results unveil a notable phototoxicity of [Ru(phen)2L2]2+ and [Cu2Ru(phen)2L2]6+, with MIC (minimal inhibitory concentrations) values of 3.12 µM. This study highlights that the structural characteristics of polyamine ligands gathered on highly charged Ru(II)-polypyridyl complexes are versatile tools that can be exploited to achieve enhanced antibacterial strategies.

The epidemicity index of recurrent SARS-CoV-2 infections.

Several indices can predict the long-term fate of emerging infectious diseases and the effect of their containment measures, including a variety of reproduction numbers (e.g. [Formula: see text]). Other indices evaluate the potential for transient increases of epidemics eventually doomed to disappearance, based on generalized reactivity analysis. They identify conditions for perturbations to a stable disease-free equilibrium ([Formula: see text]) to grow, possibly causing significant damage. Here, we introduce the epidemicity index e0, a threshold-type indicator: if e0 > 0, initial foci may cause infection peaks even if [Formula: see text]. Therefore, effective containment measures should achieve a negative epidemicity index. We use spatially explicit models to rank containment measures for projected evolutions of the ongoing pandemic in Italy. There, we show that, while the effective reproduction number was below one for a sizable timespan, epidemicity remained positive, allowing recurrent infection flare-ups well before the major epidemic rebounding observed in the fall.

Paraneoplastic ganglioradiculoneuritis in a cat with a plasma cell tumour.

CASE SUMMARY: An 8-year-old neutered female domestic longhair cat was presented for investigation of a 48 h history of lethargy and pelvic limb ataxia. MRI of the spinal cord and vertebral column (C1 to sacrum) and brain was unremarkable. Lumbar cerebrospinal fluid analysis revealed pleocytosis and increased protein concentration. Thoracic radiographs and abdominal ultrasound were unremarkable. Anti-inflammatory doses of prednisolone were administered. Clinical deterioration occurred over the following 2 days, with the development of lower motor neuron deficits in both thoracic limbs. On repetition of the MRI, bilateral enlargement, T2-weighted hyperintensity, and marked contrast enhancement of the C7, C8 and T1 nerve roots, spinal nerves and brachial plexuses were observed. Infectious disease testing was negative. An immune-mediated inflammatory process was suspected and immunosuppressive doses of prednisolone were commenced. The clinical signs improved transiently, but marked deterioration occurred after 2 weeks. The patient was euthanased and a post-mortem examination was performed. A lymphocytic inflammatory infiltrate was detected in the C7, C8 and T1 nerve roots and dorsal root ganglia, and neoplastic plasma cells were identified in multiple organs. A diagnosis of non-cutaneous extramedullary plasmacytoma with multiorgan involvement and paraneoplastic ganglioradiculoneuritis was reached. RELEVANCE AND NOVEL INFORMATION: Paraneoplastic ganglioradiculoneuritis in association with a plasma cell neoplasia has not been previously reported in the cat and should be considered as a differential diagnosis for cats with clinical or imaging evidence of an inflammatory process affecting the nerve roots, spinal nerves or brachial plexuses.

The dynamics of microplastics and associated contaminants: Data-driven Lagrangian and Eulerian modelling approaches in the Mediterranean Sea.

Plastic pollution is widespread in the global oceans, but at the same time several other types of hydrophobic pollutants contaminate the marine environment. As more and more evidence highlights, microplastics and polluting chemicals are intertwined via adsorption/desorption processes. A thorough assessment of their total impact on marine ecosystems thus requires that these two kinds of pollution are not considered separately. Here we compare the outcomes of two complementary, data-driven modelling approaches for microplastic dispersal and for Plastic-Related Organic Pollutants (PROPs) in the marine environment. Focusing on the Mediterranean Sea, we simulate two years of Lagrangian particle tracking to map microplastic dispersion from the most impacting sources of pollution (i.e. coastal areas, the watersheds of major rivers, and fishing activities). Our particle sources are data-informed by national census data, hydrological regimes, and vessel tracking data to account for spatial and temporal variability of mismanaged plastic waste generation. These particle-based simulations are complemented with a simulation of the dynamics of primary pollutants in the sea, obtained via an advection-diffusion Eulerian model. While providing further understanding of the spatiotemporal distribution of microplastics and the dynamics of PROPs at a Mediterranean-wide scale, our results call for the development of novel integrated modelling approaches aimed at coupling the dynamics of microplastics with the chemical exchanges occurring through them, thus promoting a holistic description of marine plastic pollution.

Modelled effects of prawn aquaculture on poverty alleviation and schistosomiasis control.

Recent evidence suggests that snail predators may aid efforts to control the human parasitic disease schistosomiasis by eating aquatic snail species that serve as intermediate hosts of the parasite. Potential synergies between schistosomiasis control and aquaculture of giant prawns are evaluated using an integrated bio-economic-epidemiologic model. Combinations of stocking density and aquaculture cycle length that maximize cumulative, discounted profit are identified for two prawn species in sub-Saharan Africa: the endemic, non-domesticated Macrobrachium vollenhovenii, and the non-native, domesticated Macrobrachium rosenbergii. At profit maximizing densities, both M. rosenbergii and M. vollenhovenii may substantially reduce intermediate host snail populations and aid schistosomiasis control efforts. Control strategies drawing on both prawn aquaculture to reduce intermediate host snail populations and mass drug administration to treat infected individuals are found to be superior to either strategy alone. Integrated aquaculture-based interventions can be a win-win strategy in terms of health and sustainable development in schistosomiasis endemic regions of the world.

Within-host mechanisms of immune regulation explain the contrasting dynamics of two helminth species in both single and dual infections.

Variation in the intensity and duration of infections is often driven by variation in the network and strength of host immune responses. While many of the immune mechanisms and components are known for parasitic helminths, how these relationships change from single to multiple infections and impact helminth dynamics remains largely unclear. Here, we used laboratory data from a rabbit-helminth system and developed a within-host model of infection to investigate different scenarios of immune regulation in rabbits infected with one or two helminth species. Model selection suggests that the immunological pathways activated against Trichostrongylus retortaeformis and Graphidium strigosum are similar. However, differences in the strength of these immune signals lead to the contrasting dynamics of infections, where the first parasite is rapidly cleared and the latter persists with high intensities. In addition to the reactions identified in single infections, rabbits with both helminths also activate new pathways that asymmetrically affect the dynamics of the two species. These new signals alter the intensities but not the general trend of the infections. The type of interactions described can be expected in many other host-helminth systems. Our immune framework is flexible enough to capture different mechanisms and their complexity, and provides essential insights to the understanding of multi-helminth infections.