Investigating methods for using genetic data to estimate the association between host factors and being an infection source with application to probing the association between HIV infection and tuberculosis transmission

Identifying host factors that influence infectious disease transmission is an important step toward developing interventions to reduce disease incidence. Recent advances in methods for reconstructing infectious disease transmission events using pathogen genomic and epidemiological data open the door for investigation of host factors that affect onward transmission. While most transmission reconstruction methods are designed to work with densely sampled outbreaks, these methods are making their way into surveillance studies, where the fraction of sampled cases with sequenced pathogens could be relatively low. Surveillance studies that use transmission event reconstruction then use the reconstructed events as response variables (i.e., infection source status of each sampled case) and use host characteristics as predictors (e.g., presence of HIV infection) in regression models. We use simulations to study estimation of the effect of a host factor on probability of being an infection source via this multi-step inferential procedure. Using TransPhylo - a widely-used method for Bayesian estimation of infectious disease transmission events - and logistic regression, we find that low sensitivity of identifying infection sources leads to dilution of the signal, biasing logistic regression coefficients toward zero. We show that increasing the proportion of sampled cases improves sensitivity and estimation of logistic regression coefficients. Application of these approaches to real world data from a population-based TB study in Botswana fails to detect an association between HIV infection and probability of being a TB infection source. We conclude that application of a pipeline, where one first uses TransPhylo and sparsely sampled surveillance data to infer transmission events and then estimates effects of host characteristics on probabilities of these events, should be accompanied by a realistic simulation study to better understand biases stemming from imprecise transmission event inference.

COVID-19 symptoms at time of testing and association with positivity among outpatients tested for SARS-CoV-2

Introduction Symptoms associated with SARS-CoV-2 infection remain incompletely understood, especially among ambulatory, non-hospitalized individuals. With host factors, symptoms predictive of SARS-CoV-2 could be used to guide testing and intervention strategies. Methods Between March 16 and September 3, 2020, we examined the characteristics and symptoms reported by individuals presenting to a large outpatient testing program in the Southeastern US for nasopharyngeal SARS-CoV-2 RNA RT-PCR testing. Using self-reported symptoms, demographic characteristics, and exposure and travel histories, we identified the variables associated with testing positive using modified Poisson regression. Results Among 20,177 tested individuals, the proportion positive was 9.4% (95% CI, 9.0–9.8) and was higher for men, younger individuals, and racial/ethnic minorities (all P<0.05); the positivity proportion was higher for Hispanics (26.9%; 95% CI. 24.9–29.0) compared to Blacks (8.6%; 95% CI, 7.6–9.7) or Whites (5.8%; 95% CI, 5.4–6.3). Individuals reporting contact with a COVID-19 case had the highest positivity proportion (22.8%; 95% CI, 21.5–24.1). Among the subset of 8,522 symptomatic adults who presented for testing after May 1, when complete symptom assessments were performed, SARS-CoV-2 RNA PCR was detected in 1,116 (13.1%). Of the reported symptoms, loss of taste or smell was most strongly associated with SARS-CoV-2 RNA detection with an adjusted risk ratio of 3.88 (95% CI, 3.46–4.35). The presence of chills, fever, cough, aches, headache, fatigue and nasal congestion also significantly increased the risk of detecting SARS-CoV-2 RNA, while diarrhea or nausea/vomiting, although not uncommon, were significantly more common in those with a negative test result. Symptom combinations were frequent with 67.9% experiencing ≥4 symptoms, including 19.8% with ≥8 symptoms; report of greater than three symptoms increased the risk of SARS-CoV-2 RNA detection. Conclusions In a large outpatient population in the Southeastern US, several symptoms, most notably loss of taste or smell, and greater symptom burden were associated with detection of SARS-CoV-2 RNA. Persons of color and those with who were a contact of a COVID-19 case were also more likely to test positive. These findings suggest that, given limited SARS-CoV-2 testing capacity, symptom presentation and host characteristics can be used to guide testing and intervention prioritization.

Diversity of Human-Associated Bifidobacterial Prophage Sequences

Members of Bifidobacterium play an important role in the development of the immature gut and are associated with positive long-term health outcomes for their human host. It has previously been shown that intestinal bacteriophages are detected within hours of birth, and that induced prophages constitute a significant source of such gut phages. The gut phageome can be vertically transmitted from mother to newborn and is believed to exert considerable selective pressure on target prokaryotic hosts affecting abundance levels, microbiota composition, and host characteristics. The objective of the current study was to investigate prophage-like elements and predicted CRISPR-Cas viral immune systems present in publicly available, human-associated Bifidobacterium genomes. Analysis of 585 fully sequenced bifidobacterial genomes identified 480 prophage-like elements with an occurrence of 0.82 prophages per genome. Interestingly, we also detected the presence of very similar bifidobacterial prophages and corresponding CRISPR spacers across different strains and species, thus providing an initial exploration of the human-associated bifidobacterial phageome. Our analyses show that closely related and likely functional prophages are commonly present across four different species of human-associated Bifidobacterium. Further comparative analysis of the CRISPR-Cas spacer arrays against the predicted prophages provided evidence of historical interactions between prophages and different strains at an intra- and inter-species level. Clear evidence of CRISPR-Cas acquired immunity against infection by bifidobacterial prophages across several bifidobacterial strains and species was obtained. Notably, a spacer representing a putative major capsid head protein was found on different genomes representing multiple strains across B. adolescentis, B. breve, and B. bifidum, suggesting that this gene is a preferred target to provide bifidobacterial phage immunity.

C-Reactive Protein Levels in Patients with Infectious Mononucleosis

Background: Plasma level of C-reactive protein (CRP) is used as a biomarker of systemic inflammation. Differential distributions of CRP levels related to different pathogens aid clinicians in the differential diagnosis of patients.Objectives: To evaluate the distribution of CRP levels in patients with Infectious Mononucleosis (IMN) and its correlation with different pathogen and host characteristics.Methods: A retrospective study conducted on electronic medical records of patients diagnosed clinically and serologically with IMN in a public regional hospital during consecutive five years.Results: CRP levels were significantly elevated in patients hospitalized with clinical diagnosis of IMN and serologic evidence of EBV (average 6.8 md/dL) or CMV (average 6.3 md/dL). However, levels of CRP were not significantly correlated with plasma levels of liver enzymes. Conclusions: Although CRP levels may aid in the differential diagnosis of respiratory syndromes, its distribution in patients infected by hepatotrophic viruses is similar to that in bacterial infections.

Ethnocultural influences for zoonoses transmission in multi-ethnic communities in Nepal

Animals contribute to a pivotal role in human societies. Occupational exposure to animals is barred in several ethnicities in Nepal. Limited studies have been found on zoonoses-related diseases and their knowledge, practices, and perception regarding ethnic groups. This study aims to identify the associated factors for human closeness to animals and their host characteristics related to ethnocultural practices. A total of 20 articles were reviewed. In addition to the review, 25 people from different ethnic groups were interviewed. The ethnomedicinal practice and host characteristics of animals for various zoonoses were reviewed from published papers and database journals. There are 1415 species identified as pathogenic to humans, 61% categorized as zoonotic, and of the 175 newly emerging pathogens, 75% are listed as zoonoses. Almost all studies among ethnic groups in Nepal revealed that people interact closely with animals for several reasons, including cultural, religious, and ethnomedical practices. Most of the domesticated animals are also possible hosts for the transmission of zoonoses. So, creating awareness about preventing zoonoses is crucial for the protection of the human race. These findings call for immediate action by government and policymakers to control prevalent zoonoses by commencing proactive activities among at-risk groups.

Environmental, Lifestyle Risk Factors and Host Characteristics Associated with Philadelphia Negative Myeloproliferative Neoplasm: A Systematic Review

Introduction: Myeloproliferative Neoplasms (MPNs) are group of clonal hematopoietic stem cell (HSC) disorders characterised by overproduction of myeloid cells and are associated with an acquired genetic mutation of JAK2V617F. The 2008 WHO MPNs classification grouped the related disorders naming them Philadelphia negative MPNs. These included polycythemia vera, essential thrombocythemia, pre-fibrotic myelofibrosis and primary myelofibrosis which are the focus of this review. The etiology of MPNs remains unknown. Epidemiological studies have indicated there are associations between environmental, lifestyle factors and host characteristic with pathogenesis of MPNs. The aim of this review is to summarize all published data investigating smoking, obesity, gender and exposure to benzene as contributing risk factors and establish their association with developing MPNs. Methods: Medline, Embase, Pubmed databases were systematically searched for relevant published articles with date restrictions of March 2003 to March 2020. The published studies using epidemiological study designs i.e. case control, cohort and cross-sectional studies were identified. Scanning of reference lists and the grey literature was also undertaken. Articles written in English language were included. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Manual review of filtered records excluded inappropriate publications. Two investigators evaluated the full text of selected articles independently analysed the content qualitatively using the Newcastle-Ottawa Scale. Results: A total of 23 published articles met the inclusion criteria, reporting data on the impact of smoking and obesity, the effects of exposure to benzene and gender on MPNs pathogenesis. A significant association was found between smoking and development of MPNs explained by the substantial increase in the levels of several proinflammatory mediators and systematic oxidative stress causing hyperstimulation of myeloid compartments. The upregulation of JAK-STAT and NF-kB signalling pathway and several transcription factors in patients with MPNs who smokers are have been confirmed. Subsequently, these changes facilitate the clonal expansion of hematopoietic stem cells with JAK2V617F mutations. The literature did not confirm any significant association between obesity and risk of developing MPNs, but it cannot be ruled out as an contributing risk factor. The consequences of obesity have been explained in terms of changes in metabolic, endocrinologic, immunologic, and inflammatory systems which may lead to increase in the cell proliferation, cell mutation rate, dysregulate gene function, disturb DNA repair or induce epigenetic changes favouring the induction of neoplastic transformation. There is some evidence in the literature that in individuals exposed to benzene, there is a stimulation of erythropoietic progenitor cells with cytokine independent growth compared to non-exposed individuals. This spontaneous growth of erythroid progenitor cells is one of the hallmarks of MPNs but evidence to prove this hypothesis is uncertain. No strong association was found between exposure of benzene and MPNs but further investigation on effects of increased levels and duration of exposure will be beneficial. Host characteristics such as gender as contributing factors associated with MPNs has been explored in several studies. Gender has been classified as an independent modifier in JAK2V617F allele burden which influences genotype and clonal expansion resulting into allele burden variability, hence, partly responsible for to the differences in the development of the disease between males and females. Conclusion: The important role of predisposing factors such as environmental, lifestyle risk factors and host characteristic in the pathogenesis of MPNs cannot be eliminated. The significant association between smoking and developing MPNs has been confirmed. Gender can be classified as an independent modifier in JAK2V617F allele burden reflecting on the phenotypic heterogeneity of MPNs. The relationship between obesity and exposure to benzene with MPNs developments has not been established yet. The results from this review proposes a large, well-designed epidemiological research exploring these contributing factors. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Literature Review: Transplacental Transmission of COVID-19 and Its Teratological Aspect

Coronavirus disease 2019 (Covid-19) pandemic affects all populations, including pregnant women. Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection in pregnancy needs to be a concern because of the risk of transplacental transmission to the fetus and the potential to interfere with fetal development. The objective of this study is to review the transplacental transmission of COVID-19 and the teratological aspects of the event. This article is a literature study. Based on the literature obtained, placental infection, vertical transmission, and fetal infection have been identified in some cases. However, there is still no consistent and enough scientific evidence to show that those condition causes fetal damage or causes congenital anomalies. Virus and host characteristics are thought to explain why SARS-Cov-2 infection has not shown a teratological effect. SARS-CoV-2, similar to severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) infection, does not indicate maternal-fetal transmission. The low-level expression of angiotensin-converting enzyme 2 (ACE2) and S protein priming proteases type II transmembrane serine protease (TMPRSS 2) in the placenta is also considered to be the factor that plays a role in inhibiting the vertical transmission of COVID-19. Adverse outcome of fetal death is more due to pathophysiological conditions of maternal health caused by SARS-CoV-2 infection during gestation.

Gut microbiome and its cofactors are linked to lipoprotein distribution profiles

Increasing evidence indicates that the gut microbiome (GM) plays an important role in the etiology of dyslipidemia. To date, however, no in depth characterization of the associations between GM and its metabolic attributes with deep profiling of lipoproteins distributions (LPD) among healthy individuals has been conducted. To determine associations and contributions of GM composition and its cofactors with distribution profiles of lipoprotein subfractions, we studied blood plasma LPD, fecal short-chain fatty acids (SCFA) and GM of 262 healthy Danish subjects aged 19-89 years. Stratification of LPD segregated subjects into three clusters of profiles that reflected differences in the lipoprotein subclasses, corresponded well with limits of recommended levels of main lipoprotein fractions and were largely explained by host characteristics such as age and body mass index. Higher levels of HDL, particularly driven by large subfractions (HDL2a and HDL2b), were associated with a higher relative abundance of Ruminococcaceae and Christensenellaceae. Increasing levels of total cholesterol and LDL, which were primarily associated with large 1 and 2 subclasses, were positively associated with Lachnospiraceae and Coriobacteriaceae, and negatively with Bacteroidaceae and Bifidobacteriaceae. Metagenome sequencing showed a higher abundance of genes involved in the biosynthesis of multiple B-vitamins and SCFA metabolism among subjects with healthier LPD profiles. Metagenomic assembled genomes (MAGs) affiliated mainly to Eggerthellaceae and Clostridiales were identified as the contributors of these genes and whose relative abundance correlated positively with larger subfractions of HDL. The results of this study demonstrate that remarkable differences in composition and metabolic traits of the GM are associated with variations in LPD among healthy subjects. Findings from this study provide evidence for GM considerations in future research aiming to shade light on mechanisms of the GM - dyslipidemia axis.