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bioRxiv2025

Direct genome sequencing of Leishmania tropica in tissues of Moroccan patients with cutaneous leishmaniasis reveals micro-focal transmission underlain by clonal and sexual reproduction modes

Leishmania tropica is causing cutaneous leishmaniasis (CL) from North Africa to India and in Ethiopia and is reported to be transmitted from humans to humans through sand fly bites. While this species is characterized by a high genetic diversity all over the area of endemicity, there is very little information on diversity at micro-epidemiological scale. Here, we zoomed on an epidemic Moroccan focus of CL - restricted in space and time - and studied transmission patterns by comparative genomics of parasites in human patients. We used a culture-independent method of genome sequencing based on Leishmania genome capture (SureSelect-sequencing, SuSL-seq), applied directly on dermal scrapings. We first compared the genome of paired samples: i.e. parasites in host tissues analyzed by SuSL-seq and derived isolates shortly maintained in culture and analyzed by whole genome sequencing (WGS). Despite the low passage number of isolates, significant differences were observed between karyotypes of 4/7 paired samples, highlighting the clinical and epidemiological relevance of direct genome sequencing. Secondly, we identified 7 groups of nearly identical genotypes, characteristic of clonal propagation as well as parasites with mixed ancestry, a signature of genetic exchange. Our results reveal a micro-focal transmission among humans, underlain by clonal and sexual reproductive modes. This study demonstrates the power of direct genome sequencing for evolutionary genetics at a micro-epidemiological scale.

genomics↗

bioRxiv2025

Fitting a lattice model with local and global transmission to spread of a plant disease

Understanding, predicting and managing the spread of plant pathogens is crucial given the economic, societal and climatic benefits of plants, including crops and trees. Mathematical models have long been used to investigate disease dynamics in plants. An important component of such models is to account for spatial structure, since plant hosts are immobile and a majority of disease spread will often be localised. Here we apply a lattice-based mathematical modelling approach, a pair approximation, to model disease spread. While this method has previously been used to develop epidemiological theory, it has not been used to predict spread in a specific pathosystem. We fit our lattice-based epidemiological model to experimental data relating to Bahia bark scaling of citrus, an economically-important disease in north-eastern Brazil, and compare its performance to a more commonly used dispersal-kernel modelling approach. We show that the lattice-based model fits the data well, predicting a significant degree of near-neighbour infections, with similar estimated values of epidemiologically-meaningful parameters to the dispersal model. We highlight the pros and cons of the lattice-based approach and discuss how it may be used to predict disease spread and optimise control of plant diseases. Author SummaryPlant diseases can have significant impacts, including reducing crop yields, limiting the availability of natural spaces, and the knock-on effects on our wellbeing. Mathematical models have long been used to understand how disease spreads through plant populations. Here we apply a form of mathematical model that has not previously been specifically applied to a real disease system that emphasises neighbour-to-neighbour spread of infection. In particular, we use the model to explore the spread of Bahia bark scaling of citrus, for which we have excellent experimental data available of its spatial spread. We show that the model fits the data best when there is significant neighbour-to-neighbour spread with very rare long-range infections. We show that this approach agrees well with a more commonly-used mathematical framework and highlight how it might be used to test disease management strategies.

ecology↗

bioRxiv2025

Per- and Polyfluoroalkyl Substances Induces Salt-Sensitive Hypertension by Upregulating Epithelial Sodium Channel - The First Experimental Evidence Supporting Causality

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals found in the plasma of 98% of Americans. Epidemiological studies associate PFAS exposure with hypertension and kidney dysfunction, but causality and mechanisms remain unclear. We examined the effects of a mixture of 4 PFAS commonly detected in humans, including PFOA, PFOS, PFHxS, and PFNA, on blood pressure, salt sensitivity, and renal injury in 129S6 mice. Exposure to a lower dose for 3 weeks produced plasma PFAS levels in mice resembling occupational and regional environmental exposures; while a upper dose achieved levels similar to PFAS production workers. PFAS induced dose-dependent pressor effects in male but not female mice on a 0.4% low salt diet. During 4% high salt feeding, PFAS induced greater salt-sensitive hypertension in male mice, accompanied by glomerulopathy, interstitial fibrosis, and a trend towards increased albuminuria. Pressor effects were independent of plasma norepinephrine. Single-cell RNA sequencing of kidneys revealed most transcriptional changes in proximal tubule, thick ascending limb, and collecting duct, with enrichment of pathways in cholesterol synthesis, mitochondria respiration, ATP production, and transmembrane transporter activity. PFAS markedly increased the mRNA and protein of the pore-forming subunit of epithelial sodium channel (ENaC), with no change in {beta}ENaC and a slight reduction in {gamma}ENaC protein. Elevated ENaC coincided with a 30% decrease in Nedd4-2 phosphorylation (Ser448), suggesting reduced ENaC ubiquitination and degradation. However, protein expression of 1 Na+-K+-ATPase and serum- and glucocorticoid-regulated kinase 1 (SGK1) as well as SGK1 phosphorylation (Ser78) were unaltered. Amiloride abolished salt-induced hypertension in lower-dose mice but only partially corrected hypertension in the upper dose group. Taken together, our results provide causal evidence that PFAS exposure promotes hypertension, salt sensitivity, and kidney injury via renal epithelial mechanisms, supporting and extending human epidemiologic observations. Translational StatementOur findings establish four PFAS as causal drivers of salt-sensitive hypertension and kidney injury through convergent effects on ENaC and other tubular sodium transporters. These results not only provide a mechanistic explanation for epidemiologic associations but also identify PFAS as environmental amplifiers of dietary sodium risk. Given the ubiquity of human exposure, reducing PFAS burden alongside salt reduction may represent a complementary strategy to curb the global epidemic of hypertension and kidney disease.

physiology↗

bioRxiv2025

Fourier transform infrared spectroscopy enables rapid species discrimination across Malassezia and strain-level typing in M. pachydermatis

1Malassezia pachydermatis is a zoophilic yeast found on the skin and in the outer ear canal of many mammals. It normally maintains a commensal lifestyle but can cause dermatitis and otitis in predisposed hosts, particularly in atopic dogs. M. pachydermatis is genetically diverse, with strains clustering into at least three phylogroups based on molecular typing, a pattern we now confirm through whole-genome sequencing (WGS). Accurate species and strain-level identification is essential for understanding its epidemiology, pathogenic potential, and response to treatment. In this study, we established Fourier Transform Infrared (FTIR) spectroscopy as a rapid, cost-effective method for distinguishing M. pachydermatis from other Malassezia species, including M. globosa, M. furfur, M. restricta, and M. sympodialis. Within M. pachydermatis, FTIR spectroscopy resolved even closely related strains with high accuracy producing clusters congruent with WGS-based phylogeny. The incorporation of an Artificial Neural Network classifier further enhanced the discriminatory power, enabling robust and automated strain assignment. These findings demonstrate the potential of FTIR spectroscopy as a practical tool for large-scale epidemiological surveillance of M. pachydermatis and for clinical and veterinary applications where strain-level identification could inform treatment and management of Malassezia-associated diseases. ImportanceMalassezia pachydermatis is a yeast that commonly inhabits the skin and ear canals of mammals but can cause dermatitis and otitis in predisposed hosts, especially dogs with allergies. This species displays substantial genetic diversity, with strains falling into distinct phylogroups that may differ in their biology and clinical significance. Determining these differences has typically required advanced molecular or genomic methods, which can be costly and time-consuming. In this study, we demonstrate that Fourier transform infrared spectroscopy can rapidly and accurately distinguish M. pachydermatis from other Malassezia species and resolve genetic groups within the species in a way that reflects whole-genome relationships. This capability offers a practical tool for investigating the epidemiology and inter-/intraspecies diversity of M. pachydermatis and for guiding targeted management of Malassezia-associated diseases in both veterinary and, potentially, human medicine.

microbiology↗

bioRxiv2025

Comprehensive public health surveillance identifies novel human cryptosporidiosis subtypes and genetic diversity associated with swimming pool outbreaks in Australia, Victoria (2018-2024)

Cryptosporidium and Giardia are major causes of gastrointestinal illness globally. In Australia, cryptosporidiosis is a nationally notifiable disease, yet molecular characterisation of clinical cases is rarely performed, limiting the capacity to identify outbreaks, trace sources and assess zoonotic risk. During 2024 there was a 273% cases increase in Australia, the third country with the highest increase. We present the first comprehensive molecular investigation of human Cryptosporidium and Giardia infections in the state of Victoria, Australia. We analysed faecal samples collected between 2018 and 2024. Positive samples were subtyped and parasite load was estimated. Of the 2,330 samples tested, 225 were positive for Cryptosporidium and nine for Giardia. Seven Cryptosporidium species and 24 subtypes were identified, including multiple novel or regionally unique subtypes. C. hominis was the predominant species (85%), and three subtypes associated with 11 recreational water outbreaks in 2024. Based on spatiotemporal overlap and subtypes, 52 cases were inferred to represent undetected outbreak-associated infections. Several C. parvum subtypes reflected probable zoonotic transmission, two subtypes were associated with a childcare and camp outbreak. Six C. hominis subtypes and eight subtypes overall were reported for the first time in Australia. Globally novel subtypes of C. occultus, C. fayeri and C. meleagridis in human hosts is reported. The study reveals high diversity of Cryptosporidium subtypes in human infections in Victoria. This study demonstrates the potential for molecular surveillance to inform public health interventions when integrated with epidemiological data. These findings support One Health approaches to outbreak detection and source attribution. IMPORTANCECryptosporidium is a nationally notifiable pathogen in Australia, yet routine genotyping is not performed, limiting outbreak detection and source attribution. This study represents the first large-scale molecular surveillance of human Cryptosporidium and Giardia infections in southern Australia. By integrating species- and subtype-level typing with epidemiological metadata, we demonstrate the substantial diversity of infective lineages, including several novel or zoonotic genotypes. Our findings highlight the critical role of molecular tools in tracking transmission pathways, supporting outbreak investigation and informing public health responses. These data provide a foundation for incorporating routine genotyping into national surveillance strategies for parasitic enteropathogens. This study presents the first epidemiological study of the 2024 outbreaks in Australia. The global comparison of cases during this period also highlights potential large-scale disease dynamic of public health importance.

molecular biology↗

bioRxiv2025

Simulated sample splitting approach to address biases due to instrument selection and participant overlap in two-sample Mendelian Randomization studies

Mendelian randomization (MR) is a popular statistical technique that uses genetic variants to explore causal relationships in observational epidemiology. Summary-level MR, the most common form, relies on published GWAS summary statistics to estimate causal effects between exposures and outcomes. However, empirical analyses tend to ignore issues relating to Winners Curse of instrument effects, weak instrument bias and sample overlap. Our simulations and empirical examinations using the UK Biobank indicate that such mechanisms can induce substantial bias in routine MR approaches. We propose MR Simulated Sample Splitting (MR-SimSS), a novel method that corrects this bias requiring no additional data beyond the exposure and outcome GWAS summary statistics under examination. It operates by simulating statistically independent sets of summary statistics, analogous to what would be produced by splitting the individual-level data into independent subsets, which can then be plugged into existing pleiotropy-robust MR methods. With sufficient instrument variants, MR-SimSS is robust to a range of sample overlap scenarios, providing a practical and modular solution to Winners Curse and weak instrument bias. Author summaryA central challenge in epidemiology is determining whether an observed association reflects a true cause- and-effect relationship. Mendelian randomization (MR) addresses this by using genetic variants as natural experiments to test whether a particular trait or exposure genuinely influences disease risk. However, when the same genetic data are used both to select and to estimate genetic instruments, MR results can become biased due to a phenomenon known as the Winners Curse. This problem, along with weak instruments and sample overlap between datasets, can distort causal estimates even in large studies. We introduce MR Simulated Sample Splitting (MR-SimSS), a new framework that overcomes these issues using only publicly available genome-wide association study (GWAS) summary statistics. MR-SimSS works by statistically simulating independent subsets of the data, without requiring access to individual-level information, allowing existing MR methods to be applied without bias. Through extensive simulations and analyses using UK Biobank data, we show that MR-SimSS provides more accurate and reliable causal estimates, offering a practical tool for robust causal inference in modern genetic epidemiology.

genetics↗

bioRxiv2018

Anti-CRISPR phages cooperate to overcome CRISPR-Cas immunity

Some phages encode anti-CRISPR (acr) genes, which antagonize bacterial CRISPR-Cas immune systems by binding components of its machinery, but it is less clear how deployment of these acr genes impacts phage replication and epidemiology. Here we demonstrate that bacteria with CRISPR-Cas resistance are still partially immune to Acr-encoding phage. As a consequence, Acr-phages often need to cooperate in order to overcome CRISPR resistance, with a first phage taking down the host CRISPR-Cas immune system to allow a second Acr- phage to successfully replicate. This cooperation leads to epidemiological tipping points in which the initial density of Acr-phage tips the balance from phage extinction to a phage epidemic. Furthermore, both higher levels of CRISPR-Cas immunity and weaker Acr activities shift the tipping points towards higher phage densities. Collectively these data help to understand how interactions between phage-encoded immune suppressors and the CRISPR systems they target shape bacteria-phage population dynamics.\n\nHighlightsO_LIBacteria with CRISPR immunity remain partially resistant to Acr-phage\nC_LIO_LISequentially infecting Acr phages cooperate to overcome CRISPR resistance\nC_LIO_LIAcr-phage epidemiology depends on the initial phage density\nC_LIO_LICRISPR resistant bacteria can drive Acr phages extinct\nC_LI\n\neTOC blurbSome phages encode Acr proteins that block bacterial CRISPR-Cas immune systems. Although CRISPR-Cas can clear the first infection, this Acr-phage still suppresses the host immune system, which can be exploited by other Acr-phages. This is critical for Acr-phage amplification, but this \"cooperation\" only works beyond a critical Acr-phage density threshold.

microbiology↗

bioRxiv2018

Global emergence and population dynamics of divergent serotype 3 CC180 pneumococci

Streptococcus pneumoniae serotype 3 remains a significant cause of morbidity and mortality worldwide, despite inclusion in the 13-valent pneumococcal conjugate vaccine (PCV13). Serotype 3 increased in carriage since the implementation of PCV13 in the United States, while invasive disease rates remain unchanged. We investigated the persistence of serotype 3 in carriage and disease, through genomic analyses of a global sample of 301 serotype 3 isolates of the Netherlands3-31 (PMEN31) clone CC180, combined with associated patient data and PCV utilization among countries of isolate collection. We assessed phenotypic variation between dominant clades in capsule charge (zeta potential), capsular polysaccharide shedding, and susceptibility to opsonophagocytic killing, which have previously been associated with carriage duration, invasiveness, and vaccine escape. We identify a recent shift in the CC180 population attributed to a lineage termed Clade II, which was estimated by Bayesian coalescent analysis to have first appeared in 1968 [95% HPD: 1939-1989] and increased in prevalence and effective population size thereafter. Clade II isolates are divergent from the pre-PCV13 serotype 3 population in non-capsular antigenic composition, competence, and antibiotic susceptibility, the last resulting from the acquisition of a Tn916-like conjugative transposon. Differences in recombination rates among clades correlated with variations in the ATP-binding subunit of Clp protease as well as amino acid substitutions in the comCDE operon. Opsonophagocytic killing assays elucidated the low observed efficacy of PCV13 against serotype 3. Variation in PCV13 use among sampled countries was not independently correlated with the CC180 population shift; therefore, genotypic and phenotypic differences in protein antigens and, in particular, antibiotic resistance may have contributed to the increase of Clade II. Our analysis emphasizes the need for routine, representative sampling of isolates from disperse geographic regions, including historically under-sampled areas. We also highlight the value of genomics in resolving antigenic and epidemiological variations within a serotype, which may have implications for future vaccine development.\n\nAuthor SummaryStreptococcus pneumoniae is a leading cause of bacterial pneumoniae, meningitis, and otitis media. Despite inclusion in the most recent pneumococcal conjugate vaccine, PCV13, serotype 3 remains epidemiologically important globally. We investigated the persistence of serotype 3 using whole-genome sequencing data form 301 isolates collected among 24 countries from 1993-2014. Through phylogenetic analysis, we identified three distinct lineages within a single clonal complex, CC180, and found one has recently emerged and grown in prevalence. We then compared genomic difference among lineages as well as variations in pneumococcal vaccine use among sampled countries. We found that the recently emerged lineage, termed Clade II, has a higher prevalence of antibiotic resistance compared to other lineages, diverse surface protein antigens, and a higher rate of recombination, a process by which bacteria can uptake and incorporate genetic material from its surroundings. Differences in vaccine use among sampled countries did not appear to be associated with the emergence of Clade II. We highlight the need to routine, representative sampling of bacterial isolates from diverse geographic areas and show the utility of genomic data in resolving epidemiological differences within a pathogen population.

evolutionary biology↗

bioRxiv2018

Contemporary circulating enterovirus D68 strains show differential viral entry and replication in human neuronal cells

Historically, enterovirus D68 (EV-D68) has primarily been associated with respiratory illnesses. However, in the summers of 2014 and 2016 EV-D68 outbreaks coincided with a spike in polio-like acute flaccid myelitis/paralysis (AFM/AFP) cases. This raised concerns that the EV-D68 virus could be the causative agent of AFM during these recent outbreaks. To assess the neurotropic capacity of EV-D68, we explored the use of the neuroblastoma-derived neuronal cell line, SH-SY5Y, as a tissue culture model to determine if differential infection permissibility is observed for different EV-D68 strains. In contrast to HeLa and A549 cells, which support viral infection of all EV-D68 strains tested, SH-SY5Y cells only supported infection by a subset of contemporary EV-D68 strains, including members from the 2014 outbreak. Viral replication and infectivity in SH-SY5Y was assessed using four different assays - infectious virus production, cytopathic effects, cellular ATP release, and VP1 capsid protein production - with similar results. Similar differential neurotropism was also observed in differentiated SH-SY5Y cells, primary human neuron cultures, and a mouse paralysis model. Using the SH-SY5Y cell culture model, we determined that barriers to viral entry was at least partly responsible for the differential infectivity phenotype, since transfection of genomic RNA into SH-SY5Y generated virions for all EV-D68 isolates, but only a single round of replication was observed from strains which could not directly infect SH-SY5Y. In addition to supporting virus replication and other functional studies, this cell culture model may help confirm epidemiological associations between EV-D68 strains and AFM and allow for the rapid identification of emerging neurotropic strains.\n\nAuthor SummarySince the outbreak during the summer of 2014, EV-D68 has been linked to a type of limb paralysis referred to as acute flaccid myelitis (AFM), with evidence mounting for the causal link of EV-D68 to AFM. Among these AFM cases, concurrent EV-D68 infection was confirmed in several independent epidemiological clusters in four continents. In this report, we describe a neuronal cell culture model (SH-SY5Y cells) where only a subset of contemporary 2014 outbreak strains of EV-D68 show infectivity in neuronal cells, or neurotropism, based on four different assays of viral replication and infection. We further confirmed the observed difference in neurotropism in vitro using primary human neuron cell cultures and in vivo with a mouse paralysis model. Using the SH-SY5Y cell model, we determined that a barrier to viral entry is at least partly responsible for neurotropism. SH-SY5Y cells may be useful in determining if specific EV-D68 genetic determinants are associated with neuropathogenesis, and replication in this cell line could be used as rapid screening tool for identifying neurotropic EV-D68 strains. This may assist with better understanding of pathogenesis and epidemiology, and with the development of potential therapies.

microbiology↗

bioRxiv2018

Competition for hosts modulates vast antigenic diversity to generate persistent strain structure in Plasmodium falciparum

In their competition for hosts, parasites with antigens that are novel to host immunity will be at a competitive advantage. The resulting frequency-dependent selection can structure parasite populations into strains of limited genetic overlap. For Plasmodium falciparum-the causative agent of malaria-in endemic regions, the high recombination rates and associated vast diversity of its highly antigenic and multicopy var genes preclude such clear clustering; this undermines the definition of strains as specific, temporally-persisting gene variant combinations. We use temporal multilayer networks to analyze the genetic similarity of parasites in both simulated data and in an extensively and longitudinally sampled population in Ghana. When viewed over time, populations are structured into modules (i.e., groups) of parasite genomes whose var gene combinations are more similar within, than between, the modules, and whose persistence is much longer than that of the individual genomes that compose them. Comparison to neutral models that retain parasite population dynamics but lack competition reveals that the selection imposed by host immunity promotes the persistence of these modules. The modular structure is in turn associated with a slower acquisition of immunity by individual hosts. Modules thus represent dynamically generated niches in host immune space, which can be interpreted as strains. Negative frequency-dependent selection therefore shapes the organization of the var diversity into parasite genomes, leaving a persistence signature over ecological time scales. Multilayer networks extend the scope of phylodynamics analyses by allowing quantification of temporal genetic structure in organisms that generate variation via recombination or other non-bifurcating processes. A strain structure similar to the one described here should apply to other pathogens with large antigenic spaces that evolve via recombination. For malaria, the temporal modular structure should enable the formulation of tractable epidemiological models that account for parasite antigenic diversity and its influence on intervention outcomes.\n\nSignificanceMany pathogens, including the causative agent of malaria Plasmodium falciparum, use antigenic variation, obtained via recombination, as a strategy to evade the human immune system. The vast diversity and multiplicity of genes encoding antigenic variation in high transmission regions challenge the notion of the existence of distinct strains: temporally-persistent and specific combinations of genes relevant to epidemiology. We examine the role of human immune selection in generating such genetic population structure in the major blood-stage antigen of Plasmodium falciparum. We show, using simulated and empirical data, that immune selection generates and maintains modules of genomes with higher genetic similarity within, than between, these groups. Selection further promotes the persistence of these modules for much longer times than those of their constituent genomes. Simulations show that the temporal modular structure reduces the speed at which hosts acquire immunity to the parasite. We argue that in P. falciparum modules can be viewed as dynamic strains occupying different niches in human immune space; they are thus relevant to formulating transmission models that encompass the antigenic diversity of the parasite. Our analyses may prove useful to understand the interplay between temporal genetic structure and epidemiology in other pathogens of human and wildlife importance.

ecology↗

bioRxiv2018

Genetic association of photoplethysmography-derived arterial stiffness index with blood pressure and coronary artery disease

BackgroundArterial stiffness index (ASI) is independently associated with blood pressure and coronary artery disease (CAD) in epidemiologic studies. However, it is unknown whether these associations represent causal relationships.\n\nObjectivesHere, we assess whether genetic predisposition to increased ASI is associated with elevated blood pressure and CAD risk.\n\nMethodsGenome-wide association analysis (GWAS) of finger photoplethysmography-derived ASI was performed in 131,686 participants from the UK Biobank. Across UK Biobank participants not in the ASI GWAS, a 6-variant ASI polygenic risk score was calculated. The ASI polygenic score was associated with systolic and diastolic blood pressures (SBP, DBP, N=208,897), and with incident CAD over 10 years follow-up (N=223,061; 7,534 cases). The lack of CAD association observed was replicated among 184,305 participants (60,810 cases) from the Coronary Artery Disease Genetics Consortium (CARDIOGRAMplusC4D).\n\nResultsWe replicated prior reports of the epidemiologic association of ASI with SBP (Beta 0.55mmHg, [95% CI, 0.45-0.65], P=5.77x10-24), DBP (Beta 1.05mmHg, [95% CI, 0.99-1.11], P=7.27x10-272), and incident CAD (HR 1.08 [95% CI, 1.04-1.11], P=1.5x10-6) in multivariable models. While each SD increase in genetic predisposition to elevated ASI was highly associated with SBP (Beta 4.63 mmHg [95% CI, 2.1-7.2]; P=3.37x10-4), and DBP (Beta 2.61 mmHg [95% CI, 1.2-4.0]; P=2.85x10-4), no association was observed with incident CAD in UK Biobank (HR 1.12 [95% CI, 0.55-2.3]; P=0.75), or with prevalent CAD in CARDIOGRAMplusC4D (OR 0.56 [95% CI, 0.26-1.24]; P=0.15).\n\nConclusionsA genetic predisposition to higher ASI was associated with elevated blood pressure but not with increased risk of developing CAD.\n\nCondensed AbstractArterial stiffness index (ASI) is proposed by some as a surrogate of blood pressure and coronary artery disease (CAD) risk based on epidemiologic analyses. We tested whether genetic predisposition to increased ASI is associated with elevated blood pressure and CAD risk to assess whether these represent causal relationships. We find that a genetic predisposition to higher ASI is associated with elevated systolic (Beta 4.63 mmHg [95% CI, 2.1-7.2]) and diastolic blood pressures (Beta 2.61 mmHg [95% CI, 1.2-4.0]) in the UK Biobank, but not associated with incident CAD in the UK Biobank (P=0.75) or with prevalent CAD in CARDIOGRAMplusC4D (P=0.15). These data support a causal relationship of ASI with blood pressure but do not support the notion that ASI is a suitable surrogate for CAD risk.

bioinformatics↗

bioRxiv2018

What is known about modified insects for disease prevention?: a systematic review

The modification and release of insects to suppress or replace natural insect vectors constitutes a promising tool for vector control and disease prevention, facing the unprecedented global emergence of vector-borne diseases. Little is known regarding these innovative modification strategies and available evidence is not standardized turning it difficult to reflect on their actual efficacy and eventual effects.\n\nThis work conducted a systematic review, gathering and analyzing research articles from PubMed and Biblioteca Virtual em Saude databases whose results directly report efficacy and effects of the use of modified insects for disease prevention until 2016. Within more than 1500 publications that were screened a total of 349 where analyzed.\n\nA total of 12/3.4% reported field-based evidence, and 41/11.7% covered modification stretagies efficacy after insects release, their epidemiology impact or its long-term efficacy. Examples of successful results were the replacement of natural field populations by wolbachia-infected mosquitoes in 5 weeks, and the elimination of a population in laboratory cages after transgenic mosquitoes release over 10-20 weeks. Variability in the effective results were described (90/25.7%) questioning its reproducibility in different settings. We also found 38/10.9% publications reporting reversal outcomes, such as an increase of vector population after release. Ecological effects such as horizontal transfer events to non-target species (54/15.5%), and wolbachia-induced worsening pathogenesis on mammal filarial diseases (10/2.9%) were also reported.\n\nPresent work revealed promising outcomes of both suppressing and replacing approaches. However, it also revealed a need of field-based evidence mainly regarding epidemiologic and long-term impact of insect modification strategies. It pointed out some eventual irreversible and important effects that must not be ignored when considering open-field releases, and that may constitute constraints to generate the missing field evidence. Moreover, the level of variability of existing evidence suggests the need of local/specific evidence in each setting of an eventual release.\n\nAuthor summaryInnovative strategies are needed to arrest the unprecedented increase of vector-borne disease incidence, distribution and severity. Several modification techniques are being tried all over the world. However this is still an emergent topic with scarce available information and of complex understanding.\n\nPresent work is the unique structured review regarding the use of modified insects for vector-borne disease prevention, bringing neutral and robust evidence that will contribute with critical insights regarding these approaches.\n\nHere we explored more than 1200 publications and analyzed 349 publications on this subject, describing the actual efficacy and reported effects of several modification strategies. More than 30 categories were reported such as, the type of modification, the year of the publication, the species were results were tested, the type of study, and also type of Efficacy Outcome (from modification to long-term) and/or the type of Effects Outcome (from physiologic to ecologic effects). Analysis revealed promising outcomes regarding vector-control and disease prevention. However insects modification strategies still lack field-based evidence mainly regarding epidemiological and long-term efficacy. Eventual reversal outcomes on disease transmission, or irreversible biological effects (including horizontal transfer to non-target species or worsening pathogenesis in particular diseases in mammals), were also described. These effects need to be explored, dispelled or resolved before field trials occur in human residential areas. Some of these questions could only have a robust answer if these strategies would be implemented, needing to take the risk to observe reversal outcomes and/or irreversible effects. These findings reflect the big dilemma that is under the use of modified insects to prevent vector-borne diseases. Findings could support health authorities in decision-making and regulatory committees during advisory processes, by evaluating the pros/cons of each modifying technique for a particular setting. Moreover they could also summarize what is crucial to inform to communities if planning open field releases in residential areas.

ecology↗

bioRxiv2019

Vitamin D: marker, cause or consequence of depression? An exploration using genomics

BackgroundTrials testing the effect of vitamin D or omega-3 fatty acids (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were boosted by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. Observational associations may emerge from unresolved confounding, shared genetic risk, or direct causal relationships. We explored the nature of these associations exploiting data and statistical tools from genomics. MethodsResults from GWAS on 25-OH-D (N = 79366), n3-PUFA (N = 24925) and MDD (135458 cases, 344901 controls) were applied to individual-level data (>2,000 subjects with measures of genotype, DSM-IV lifetime MDD diagnoses and circulating 25-OH-D and n3-PUFA) and summary-level data analyses. Shared genetic risk between traits was tested by polygenic risk scores (PRS). Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between traits. OutcomeIn individual-level data, PRS were associated with the phenotype of the same trait (PRS 25-OH-D p = 1.4e-20, PRS N3-PUFA p = 9.3e-6, PRS MDD p = 1.4e-4), but not with the other phenotypes, suggesting a lack of shared genetic effects. In summary-level data, 2SMR analyses provided no evidence of a causal role on MDD of 25-OH-D (p = 0.50) or n3-PUFA (p = 0.16), or for a causal role of MDD on 25-OH-D (p = 0.25) or n3-PUFA (p = 0.66). ConclusionsApplying genomics tools indicated that that shared genetic risk or direct causality between 25-OH-D, n3-PUFA and MDD is unlikely: unresolved confounding may explain the associations reported in observational studies. These findings represent a cautionary tale for testing supplementation of these compounds in preventing or treating MDD. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSMeta-analyses of trials testing the effect of vitamin D or omega-3 fatty acids (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings, including small clinical effect or no effect. These trials were boosted by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. However, observational associations may emerge from different scenarios, including unresolved confounding, shared genetic risk, or direct causal relationships. Added value of this studyGenomics provides unique opportunities to investigate shared risk and causality between traits applying new statistical tools and results from genome-wide association studies (GWAS). In the present study we examined the nature of the association of 25-OH-D and n3-PUFA with MDD using the latest data and tools from genomics. We found no significant evidence of shared genetic risk or direct causality between vitamin D or n-3 PUFA and MDD; at this stage, unresolved confounding should be considered the most likely explanation for the association reported by observational studies. Implications of all the available evidenceFindings from the present study, in conjunction with previous conflicting evidence from clinical studies, represent a cautionary tale for further research testing the potential therapeutic effect of vitamin D and n3-PUFA supplementation on depression, as the expectations of a direct causal effect of these compounds on mood should be substantially reconsidered. Genomic tools could be efficiently employed to examine the nature of observational associations emerging in epidemiology, providing some indications on the most promising associations to be prioritized in subsequent intervention studies.

genomics↗

bioRxiv2019

Reproducible data management and analysis using R

BackgroundStandardizing and documenting computational analyses are necessary to ensure reproducible results. It is especially important for large and complex projects where data collection, analysis, and interpretation may span decades. Our objective is therefore to provide methods, tools, and best practice guidelines adapted for analyses in epidemiological studies that use -omics data.\n\nResultsWe describe an R-based implementation of data management and preprocessing. The method is well-integrated with the analysis tools typically used for statistical analysis of -omics data. We document all datasets thoroughly and use version control to track changes to both datasets and code over time. We provide a web application to perform the standardized preprocessing steps for gene expression datasets. We provide best practices for reporting data analysis results and sharing analyses.\n\nConclusionWe have used these tools to organize data storage and documentation, and to standardize the analysis of gene expression data, in the Norwegian Women and Cancer (NOWAC) system epidemiology study. We believe our approach and lessons learned are applicable to analyses in other large and complex epidemiology projects.

bioinformatics↗

bioRxiv2019

Pyrenophora teres and Rhynchosporium secalis infections in malt barley as influenced by genotype, spatial and temporal effects and nitrogen fertilization

Net form net blotch (NFNB) and barley leaf scald are among the most important barley diseases worldwide and particularly in Greece. Their occurrence in malt barley can exert a significant negative effect on malt barley grain yield and quality. An experimental trial across two growing seasons was implemented in Greece in order i) to assess the epidemiology of NFNB and leaf scald in a barley disease free area when the initial inoculation of field occurs through infected seeds, and ii) to further explore the relationship among nitrogen rate, grain yield, quality variables (i.e. grain protein content and grain size) and disease severity and epidemiology. It was demonstrated that both NFNB and leaf scald can be carried over from one season to the next on infected seed under Mediterranean conditions. However, disease severity was more pronounced after barley tillering phase when soil had been successfully inoculated first. When nitrogen rate and genotype were the main sources of variation the epidemiology assessment was implemented with hotspot and Anselin Local Morans I analysis. It was found that the location of hotspots was modified during growing season. Soil and plant variables were assessed for the explanation of this variability. According to commonality analysis the effect of distance from the locations with the highest disease infections was a better predictor of disease severity (for both diseases) compared to nitrogen rate during pre-anthesis period. However, disease severity after anthesis was best explained by nitrogen rate only for the most susceptible cultivars to NFNB. The effect of disease infections on yield, grain size and grain protein content varied in relation to genotype, pathogen and stage of crop development. The importance of crop residues on the evolution of both diseases was also highlighted.

plant biology↗

bioRxiv2019

The probability distribution of the reconstructed phylogenetic tree with occurrence data

We consider a homogeneous birth-death process with incomplete sampling. Three successive sampling schemes are considered. First, individuals can be sampled through time and included in the tree. Second, they can be occurrences which are sampled through time and not included in the tree. Third, individuals reaching present day can be sampled and included in the tree. Upon sampling, individuals are removed (i.e. die).\n\nThe outcome of the process is thus composed of the reconstructed evolutionary tree spanning all individuals sampled and included in the tree, and a timeline of occurrence events which are not placed along the tree. We derive a formula allowing one to compute the joint probability density of these, which can readily be used to perform maximum likelihood or Bayesian estimation of the parameters of the model.\n\nIn the context of epidemiology, our probability density allows us to estimate transmission rates through a joint analysis of epidemiological case count data and phylogenetic trees reconstructed from pathogen sequences. Within macroevolution, our equations are the basis for taking into account fossil occurrences from paleontological databases together with extant species phylogenies for estimating speciation and extinction rates. Thus, we provide the theoretical framework for bridging not only the gap between phylogenetics and epidemiology, but also the gap between phylogenetics and paleontology.

evolutionary biology↗

bioRxiv2019

Identification of 2CS-CHXT operon signature of chlorhexidine tolerance among Enterococcus faecium

Chlorhexidine (CHX) is a broad-spectrum antiseptic widely used in community and clinical contexts for many years, recently acquiring higher relevance in nosocomial infections control worldwide. Despite of this, CHX tolerance has been poorly understood among Enterococcus faecium, one of the leading agents causing nosocomial infections. This study provides new phenotypic and molecular data for a better identification of CHX tolerant E. faecium subpopulations in community and clinical contexts. MICCHX distribution of 106 E. faecium suggested the occurrence of tolerant subpopulations in diverse sources (human, animal, food, environment) and phylogenomic backgrounds (clades A1/A2/B), with predominance in clade A1. They carried a specific variant of 2CS-CHXT operon, here identified. It encodes a glucose and an amino-acid-polyamine-organocation family transporters, besides the DNA-binding-response-regulator ChtR with a P102H mutation previously described in only CHX tolerant clade A1 E. faecium, and the ChtS sensor. Combined data from normal MIC distribution and 2CS-CHXT operon characterization supports a tentative epidemiological cut-off (ECOFF) of 8 mg/L to CHX, useful to detect tolerant E. faecium populations in future surveillance studies. The spread of tolerant E. faecium in diverse epidemiological backgrounds alerts for a prudent use of CHX in multiple contexts.\n\nImportanceChlorhexidine is one of the substances included in the World Health Organizations List of Essential Medicines which comprises the safest and most effective medicines needed in global health systems. Although it has been widely applied as a disinfectant and antiseptic since the 1950s in healthcare (skin, hands, mouthwashes, eye drops), its use in hospitals to prevent nosocomial infections has increased worldwide in recent years. Here we provide a comprehensive study on chlorhexidine tolerance among Enterococcus faecium, one of the leading nosocomial agents worldwide, and identified a novel 2CS-CHXT operon as a signature of tolerant strains occurring in diverse phylogenomic groups. Finally, our data allowed to propose a tentative epidemiological cut-off of 8 mg/L, useful to detect tolerant E. faecium populations in future surveillance studies in community and clinical contexts.

microbiology↗

bioRxiv2019

Howler monkeys are the reservoir of malaria parasites causing zoonotic infections in the Atlantic forest of Rio de Janeiro

BackgroundAlthough malaria transmission was eradicated from southeast Brazil, a significant increase in the number of Plasmodium vivax-like autochthonous human cases has been reported in remote areas of the Atlantic Forest in the last decades in Rio de Janeiro (RJ) state, including an outbreak in 2015-2016. The singular clinical and epidemiological aspects of several human cases combined with molecular and genetic data revealed that they were due to the non-human primate (NHP) parasite P. simium. The full understanding of the epidemiology of the autochthonous malaria in southeastern Brazil depends, however, upon the knowledge on the circulation of NHP Plasmodium in the foci and the determination of its reservoirs.\n\nMethodologyA large sampling effort was carried out in the Atlantic forest of RJ and its bordering states (Minas Gerais, Sao Paulo, Espirito Santo) for capture and examination of free-living NHPs. Blood and/or viscera were analyzed for Plasmodia infections through molecular and microscopic techniques.\n\nPrincipal findingsIn total, 146 NHPs of six species, from 30 counties in four states were tested. Howler monkeys (A. guariba clamitans) were the only NHP species found infected. In RJ, 26% of howlers were positive, among them 17% were found to be infected with P. simium. Importantly, specific single nucleotide polymorphisms were detected in all P. simium infected howlers regardless geographical origin of malaria foci. Interestingly, 71% of P. simium infected NHP were from the coastal slope of a mountain chain (Serra do Mar), where most human cases have been occurring. P. brasilianum/malariae was detected for the first time in 14% free-living howlers in RJ as well as in 25% of those from the Espirito Santo state. Moreover, malarial pigment was detected in spleen fragments of 50% of a subsample composed of howler monkeys found dead in both RJ and ES. All NHPs were negative for P. falciparum.\n\nConclusions/SignificanceOur data indicate the howler monkeys as the main reservoir of the Atlantic forest human malaria in RJ and other sites in Southeast Brazil and reinforce its zoonotic nature.\n\nAuthor summaryThe present work consists of an unprecedented capture effort and large-scale field survey of plasmodial species in Non-human primates (NHPs) in RJ, a state recording a three-decade history of autochthonous human cases of benign tertian malaria pending epidemiological clarification of their origin. For the first time, we describe infection rates by Plasmodium sp.in free-living NHP, match the spatial distribution of P. simium in NHP with that of local human cases of benign tertian malaria due to this parasite, disclose howler monkeys as the only confirmed reservoir of this zoonotic malaria in the state and showed that specific single nucleotide polymorphisms were present in all P. simium infected howlers, regardless of the geographical origin of malaria foci. It is also the first time that P. brasilianum/malariae is recorded in free-living NHPs from Rio de Janeiro and the widespread distribution of this quartan-malaria parasite of zoonotic potential in the state is illustrated. Together, these findings increase the understanding about the simian malaria parasites in Atlantic Forests, as well as on the zoonotic character of autochthonous human malaria in Rio de Janeiro, providing subsidies for shaping surveillance and control.

ecology↗