Secondary attack rates and determinants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) household transmission in Pakistan: A case-ascertained prospective, longitudinal study.

BACKGROUND: Households are considered ideal settings for studying the transmission dynamics of an infectious disease. METHODS: A prospective study was conducted, based on the World Health Organization FFX protocol from October 2020 to January,2021. Household contacts of laboratory-confirmed index cases were followed up for their symptomatic history, nasal swabs for RT-PCR,and blood samples for anti-SARS CoV-2 antibodies were collected at enrollment and days 7, 14 and 28. We estimated secondary attack rate (SAR), effective household case cluster size and determinants of secondary infection among susceptible household contacts using multivariable logistic regression. RESULTS: We enrolled 77 index cases and their 543 contacts. Out of these, 252 contacts were susceptible at the time of enrollment. There were 77 household clusters, out of which, transmission took place in 20 (25.9%) giving rise to 34 cases. The acquired secondary attack rate (SAR) was 14.0% (95% CI 9.0-18.0). The effective household case cluster size was 0.46 (95%CI 0.33,0.56). Reported symptoms of nausea and vomiting (aOR, 7.9; 95% CI, 1.4-45.5) and fatigue (aOR, 9.3; 95% CI, 3.8-22.7) were associated with SARS-CoV-2 transmission. CONCLUSIONS: We observed a low SARS-CoV-2 secondary attack rate in the backdrop of high seroprevalence and asymptomatic transmission among households in Karachi, Pakistan.

The impact of within-host coinfection interactions on between-host parasite transmission dynamics varies with spatial scale.

Within-host interactions among coinfecting parasites can have major consequences for individual infection risk and disease severity. However, the impact of these within-host interactions on between-host parasite transmission, and the spatial scales over which they occur, remain unknown. We developed and apply a novel spatially explicit analysis to parasite infection data from a wild wood mouse (Apodemus sylvaticus) population. We previously demonstrated a strong within-host negative interaction between two wood mouse gastrointestinal parasites, the nematode Heligmosomoides polygyrus and the coccidian Eimeria hungaryensis, using drug-treatment experiments. Here, we show this negative within-host interaction can significantly alter the between-host transmission dynamics of E. hungaryensis, but only within spatially restricted neighbourhoods around each host. However, for the closely related species E. apionodes, which experiments show does not interact strongly with H. polygyrus, we did not find any effect on transmission over any spatial scale. Our results demonstrate that the effects of within-host coinfection interactions can ripple out beyond each host to alter the transmission dynamics of the parasites, but only over local scales that likely reflect the spatial dimension of transmission. Hence there may be knock-on consequences of drug treatments impacting the transmission of non-target parasites, altering infection risks even for non-treated individuals in the wider neighbourhood.

Heterogeneous risk attitudes and waves of infection.

Many countries have experienced multiple waves of infection during the COVID-19 pandemic. We propose a novel but parsimonious extension of the SIR model, a CSIR model, that can endogenously generate waves. In the model, cautious individuals take appropriate prevention measures against the virus and are not exposed to infection risk. Incautious individuals do not take any measures and are susceptible to the risk of infection. Depending on the size of incautious and susceptible population, some cautious people lower their guard and become incautious-thus susceptible to the virus. When the virus spreads sufficiently, the population reaches "temporary" herd immunity and infection subsides thereafter. Yet, the inflow from the cautious to the susceptible eventually expands the susceptible population and leads to the next wave. We also show that the CSIR model is isomorphic to the SIR model with time-varying parameters.

Susceptibility to stress and nature exposure: Unveiling differential susceptibility to physical environments; a randomized controlled trial.

BACKGROUND: Emerging epidemiological evidence indicates nature exposure could be associated with greater health benefits among groups in lower versus higher socioeconomic positions. One possible mechanism underpinning this evidence is described by our framework: (susceptibility) adults in low socioeconomic positions face higher exposure to persistent psychosocial stressors in early life, inducing a pro-inflammatory phenotype as a lifelong susceptibility to stress; (differential susceptibility) susceptible adults are more sensitive to the health risks of adverse (stress-promoting) environments, but also to the health benefits of protective (stress-buffering) environments. OBJECTIVE: Experimental investigation of a pro-inflammatory phenotype as a mechanism facilitating greater stress recovery from nature exposure. METHODS: We determined differences in stress recovery (via heart rate variability) caused by exposure to a nature or office virtual reality environment (10 min) after an acute stressor among 64 healthy college-age males with varying levels of susceptibility (socioeconomic status, early life stress, and a pro-inflammatory state [inflammatory reactivity and glucocorticoid resistance to an in vitro bacterial challenge]). RESULTS: Findings for inflammatory reactivity and glucocorticoid resistance were modest but consistently trended towards better recovery in the nature condition. Differences in recovery were not observed for socioeconomic status or early life stress. DISCUSSION: Among healthy college-age males, we observed expected trends according to their differential susceptibility when assessed as inflammatory reactivity and glucocorticoid resistance, suggesting these biological correlates of susceptibility could be more proximal indicators than self-reported assessments of socioeconomic status and early life stress. If future research in more diverse populations aligns with these trends, this could support an alternative conceptualization of susceptibility as increased environmental sensitivity, reflecting heightened responses to adverse, but also protective environments. With this knowledge, future investigators could examine how individual differences in environmental sensitivity could provide an opportunity for those who are the most susceptible to experience the greatest health benefits from nature exposure.

Concurrent Supra-Postural Auditory-Hand Coordination Task Affects Postural Control: Using Sonification to Explore Environmental Unpredictability in Factors Affecting Fall Risk.

Clinical screening tests for balance and mobility often fall short of predicting fall risk. Cognitive distractors and unpredictable external stimuli, common in busy natural environments, contribute to this risk, especially in older adults. Less is known about the effects of upper sensory-motor coordination, such as coordinating one's hand with an external stimulus. We combined movement sonification and affordable inertial motion sensors to develop a task for the precise measurement and manipulation of full-body interaction with stimuli in the environment. In a double-task design, we studied how a supra-postural activity affected quiet stance. The supra-postural task consisted of rhythmic synchronization with a repetitive auditory stimulus. The stimulus was attentionally demanding because it was being modulated continuously. The participant's hand movement was sonified in real time, and their goal was to synchronize their hand movement with the stimulus. In the unpredictable condition, the tempo changed at random points in the trial. A separate sensor recorded postural fluctuations. Young healthy adults were compared to older adult (OA) participants without known risk of falling. The results supported the hypothesis that supra-postural coordination would entrain postural control. The effect was stronger in OAs, supporting the idea that diminished reserve capacities reduce the ability to isolate postural control from sensory-motor and cognitive activity.

A novel multi-variate immunological approach, reveals immune variation associated with environmental conditions, and co-infection in the koala (Phascolarctos cinereus).

External signs of disease are frequently used as indicators of disease susceptibility. However, immune profiling can be a more effective indicator to understand how host responses to infection may be shaped by host, pathogen and environmental factors. To better inform wildlife health assessment and research directions, we investigated the utility of a novel multivariate immunophenotyping approach examining innate and adaptive immune responses in differing climatic, pathogen co-infection and demographic contexts across two koala (Phascolarctos cinereus) populations in New South Wales: the Liverpool Plains (LP), and Southern Highlands to South-west Sydney (SHSWS). Relative to the comparatively healthy SHSWS, the LP had greater and more variable innate immune gene expression (IL-1ß, IL-6), and KoRV transcription. During extreme heat and drought, koalas from the LP displayed upregulation of a stress pathway gene and reduced adaptive immune genes expression, haematocrit and plasma protein, suggesting the possibility of environmental impacts through multiple pathways. In those koalas, KoRV transcription status, Chlamydia pecorum infection loads, and visible urogenital inflammation were not associated with immune variation, suggesting that immune markers were more sensitive indicators of real-time impacts than observed disease outcomes.

An Association between OXPHOS-Related Gene Expression and Malignant Hyperthermia Susceptibility in Human Skeletal Muscle Biopsies.

Malignant hyperthermia (MH) is a pharmacogenetic condition of skeletal muscle that manifests in hypermetabolic responses upon exposure to volatile anaesthetics. This condition is caused primarily by pathogenic variants in the calcium-release channel RYR1, which disrupts calcium signalling in skeletal muscle. However, our understanding of MH genetics is incomplete, with no variant identified in a significant number of cases and considerable phenotype diversity. In this study, we applied a transcriptomic approach to investigate the genome-wide gene expression in MH-susceptible cases using muscle biopsies taken for diagnostic testing. Baseline comparisons between muscle from MH-susceptible individuals (MHS, n = 8) and non-susceptible controls (MHN, n = 4) identified 822 differentially expressed genes (203 upregulated and 619 downregulated) with significant enrichment in genes associated with oxidative phosphorylation (OXPHOS) and fatty acid metabolism. Investigations of 10 OXPHOS target genes in a larger cohort (MHN: n = 36; MHS: n = 36) validated the reduced expression of ATP5MD and COQ6 in MHS samples, but the remaining 8 selected were not statistically significant. Further analysis also identified evidence of a sex-linked effect in SDHB and UQCC3 expression, and a difference in ATP5MD expression across individuals with MH sub-phenotypes (trigger from in vitro halothane exposure only, MHSh (n = 4); trigger to both in vitro halothane and caffeine exposure, MHShc (n = 4)). Our data support a link between MH-susceptibility and dysregulated gene expression associated with mitochondrial bioenergetics, which we speculate plays a role in the phenotypic variability observed within MH.

Stability analysis of a SAIR epidemic model on scale-free community networks.

The presence of asymptomatic carriers, often unrecognized as infectious disease vectors, complicates epidemic management, particularly when inter-community migrations are involved. We introduced a SAIR (susceptible-asymptomatic-infected-recovered) infectious disease model within a network framework to explore the dynamics of disease transmission amid asymptomatic carriers. This model facilitated an in-depth analysis of outbreak control strategies in scenarios with active community migrations. Key contributions included determining the basic reproduction number, $ R_0 $, and analyzing two equilibrium states. Local asymptotic stability of the disease-free equilibrium is confirmed through characteristic equation analysis, while its global asymptotic stability is investigated using the decomposition theorem. Additionally, the global stability of the endemic equilibrium is established using the Lyapunov functional theory.

TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model.

Introduction: The incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on many cells, including dendritic cells (DCs), which are potent antigen-presenting cells (APCs). TLR5 modulates susceptibility to obesity and alters metabolism through gut microbiota; however, little is known about the role TLR5 plays in autoimmunity, especially in T1D. Methods: To fill this knowledge gap, we generated a TLR5-deficient non-obese diabetic (NOD) mouse, an animal model of human T1D, for study. Results: We found that TLR5-deficiency led to a reduction in CD11c+ DC development in utero, prior to microbial colonization, which was maintained into adulthood. This was associated with a bias in the DC populations expressing CD103, with or without CD8α co-expression, and hyper-secretion of different cytokines, both in vitro (after stimulation) and directly ex vivo. We also found that TLR5-deficient DCs were able to promote polyclonal and islet antigen-specific CD4+ T cell proliferation and proinflammatory cytokine secretion. Interestingly, only older TLR5-deficient NOD mice had a greater risk of developing spontaneous T1D compared to wild-type mice. Discussion: In summary, our data show that TLR5 modulates DC development and enhances cytokine secretion and diabetogenic CD4+ T cell responses. Further investigation into the role of TLR5 in DC development and autoimmune diabetes may give additional insights into the pathogenesis of Type 1 diabetes.

IL-4 regulates neutrophilic pulmonary inflammation in a mouse model of bronchial asthma.

Neutrophilic pulmonary inflammation in asthmatics substantially exacerbates the severity of the disease leading to resistance to conventional corticosteroid therapy. Many studies established the involvement of Th1- and Th17-cells and cytokines produced by them (IFNg, IL-17A, IL-17F etc.) in neutrophilic pulmonary inflammation. Recent studies revealed that IL-4 - a Th2-cytokine regulates neutrophil effector functions and migration. It was showed that IL-4 substantially reduces neutrophilic inflammation of the skin in a mouse model of cutaneous bacterial infection and blood neutrophilia in a mouse model systemic bacterial infection. However, there are no data available regarding the influence of IL-4 on non-infectious pulmonary inflammation. In the current study we investigated the effects of IL-4 in a previously developed mouse model of neutrophilic bronchial asthma. We showed that systemic administration of IL-4 significantly restricts neutrophilic inflammation of the respiratory tract probably through the suppression of Th1-/Th17-immune responses and downregulation of CXCR2. Additionally, pulmonary neutrophilic inflammation could be alleviated by IL-4-dependant polarization of N2 neutrophils and M2 macrophages, expressing anti-inflammatory TGFß. Considering these, IL-4 might be used for reduction of exaggerated pulmonary neutrophilic inflammation and overcoming corticosteroid insensitivity of asthma patients.

Unique and interactive effects of emotion regulation difficulties and perceived stress on COVID-19 traumatic stress, anxiety, and safety behavior use: A four-year prospective study.

Given that emotion regulation difficulties confer risk for poor responses to stress, they may predict who is at risk for adverse psychological reactions to major, chronic stressors such as the COVID-19 pandemic. Specific adverse reactions to the pandemic may include more severe traumatic stress, anxiety, and excessive safety behavior use (i.e., hand washing). While emotion regulation difficulties may be a diathesis for adverse reactions to chronic stressors, the context(s) by which they may confer elevated risk is unclear. Accordingly, the present longitudinal study examined the interaction between pre-pandemic emotion regulation difficulties and early pandemic perceived stress in predicting subsequent COVID-related traumatic stress, anxiety, and safety behavior use over 32 weeks of the pandemic. Community adults (N = 145) who completed a measure of emotion regulation in 2016 as part of a larger study were recontacted at the start of the pandemic (March 2020) and assessed every two weeks for 32 weeks. Consistent with a diathesis-stress model, the interaction between difficulties in emotion regulation and perceived stress was significant in predicting COVID-19 anxiety (p = 0.003, d = 0.52) such that at high, but not low, levels of perceived stress, difficulties in emotion regulation in 2016 significantly predicted higher COVID-19 anxiety in 2020. The interaction between difficulties in emotion regulation in 2016 and perceived stress early in 2020 approached significance in predicting COVID-19 traumatic stress (p = 0.073, d = 0.31) and safety behavior use (p = 0.069, d = 0.31). These findings highlight that current perceived stress is an important context that potentiates the effects of preexisting emotion regulation difficulties on the emergence of anxiety-related symptoms during COVID-19, which has important implications for diathesis-stress models of adverse reactions to chronic stressors.

Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications.

BACKGROUND: Genetic variation underly inter-individual variation in host immune responses to infectious diseases, and may affect susceptibility or the course of signs and symptoms. METHODS: We performed genome-wide association studies in a prospective cohort of 1138 patients with physician-confirmed Lyme borreliosis (LB), the most common tick-borne disease in the Northern hemisphere caused by the bacterium Borrelia burgdorferi sensu lato. Genome-wide variants in LB patients-divided into a discovery and validation cohort-were compared to two healthy cohorts. Additionally, ex vivo monocyte-derived cytokine responses of peripheral blood mononuclear cells to several stimuli including Borrelia burgdorferi were performed in both LB patient and healthy control samples, as were stimulation experiments using mechanistic/mammalian target of rapamycin (mTOR) inhibitors. In addition, for LB patients, anti-Borrelia antibody responses were measured. Finally, in a subset of LB patients, gene expression was analysed using RNA-sequencing data from the ex vivo stimulation experiments. RESULTS: We identified a previously unknown genetic variant, rs1061632, that was associated with enhanced LB susceptibility. This polymorphism was an eQTL for KCTD20 and ETV7 genes, and its major risk allele was associated with upregulation of the mTOR pathway and cytokine responses, and lower anti-Borrelia antibody production. In addition, we replicated the recently reported SCGB1D2 locus that was suggested to have a protective effect on B. burgdorferi infection, and associated this locus with higher Borrelia burgdorferi antibody indexes and lower IL-10 responses. CONCLUSIONS: Susceptibility for LB was associated with higher anti-inflammatory responses and reduced anti-Borrelia antibody production, which in turn may negatively impact bacterial clearance. These findings provide important insights into the immunogenetic susceptibility for LB and may guide future studies on development of preventive or therapeutic measures. TRIAL REGISTRATION: The LymeProspect study was registered with the International Clinical Trials Registry Platform (NTR4998, registration date 2015-02-13).

Single locus HLA sequencing with the nanopore technology for HLA disease association diagnosis.

Associations between HLA genotype and disease susceptibility encompass almost all the classic HLA loci. The level of typing resolution enabling a correct identification of an HLA disease susceptibility gene depends on the disease itself and/or on the accumulated knowledge about the molecular involvement of the HLA allele(s) engaged. Therefore, the application of Next Generation Sequencing technologies to HLA disease association, which would improve typing resolution, could prove useful to better understand disease severity. In the present study, we tested a nanopore sequencing approach developed by Omixon Biocomputing Ltd, dedicated to on-demand locus typing for HLA and disease, as an alternative to the conventional widely used sequence specific oligoprobe (SSO) approach. A total of 145 DNA samples used in routine diagnosis by SSO were retrospectively analyzed with nanopore technology, for HLA-A*02 immunotherapy decision for A*29, B*27, B*51, B*57 identification in class I, and DRB1, DQA1, and DQB1 for bullous dermatosis, rheumatoid arthritis, diabetes, and celiac disease requests in class II. Each locus was typed in a separate experiment, except for DQB1 and DQA1, which were analyzed together. Concordance between typings reached 100% for all the loci tested. Ambiguities by nanopore were only found for missing exon coverage. This approach was found to be very well adapted to the routine flow imposed by the SSO technique. This study illustrates the use of the new NanoTYPE MONO kit for single locus HLA sequencing for HLA and disease association diagnosis.

Final epidemic size of a two-community SIR model with asymmetric coupling.

Communities are commonly not isolated but interact asymmetrically with each other, allowing the propagation of infectious diseases within the same community and between different communities. To reveal the impact of asymmetrical interactions and contact heterogeneity on disease transmission, we formulate a two-community SIR epidemic model, in which each community has its contact structure while communication between communities occurs through temporary commuters. We derive an explicit formula for the basic reproduction number R 0 , give an implicit equation for the final epidemic size z, and analyze the relationship between them. Unlike the typical positive correlation between R 0 and z in the classic SIR model, we find a negatively correlated relationship between counterparts of our model deviating from homogeneous populations. Moreover, we investigate the impact of asymmetric coupling mechanisms on R 0 . The results suggest that, in scenarios with restricted movement of susceptible individuals within a community, R 0 does not follow a simple monotonous relationship, indicating that an unbending decrease in the movement of susceptible individuals may increase R 0 . We further demonstrate that network contacts within communities have a greater effect on R 0 than casual contacts between communities. Finally, we develop an epidemic model without restriction on the movement of susceptible individuals, and the numerical simulations suggest that the increase in human flow between communities leads to a larger R 0 .

Waning immunity can drive repeated waves of infections.

In infectious disease models, it is known that mechanisms such as births, seasonality in transmission and pathogen evolution can generate oscillations in infection numbers. We show how waning immunity is also a mechanism that is sufficient on its own to enable sustained oscillations. When previously infected or vaccinated individuals lose full protective immunity, they become partially susceptible to reinfections. This partial immunity subsequently wanes over time, making individuals more susceptible to reinfections and potentially more infectious if infected. Losses of full and partial immunity lead to a surge in infections, which is the precursor of oscillations. We present a discrete-time Susceptible-Infectious-Immune-Waned-Infectious (SIRWY) model that features the waning of fully immune individuals (as a distribution of time at which individuals lose fully immunity) and the gradual loss of partial immunity (as increases in susceptibility and potential infectiousness over time). A special case of SIRWY is the discrete-time SIRS model with geometric distributions for waning and recovery. Its continuous-time analogue is the classic SIRS with exponential distributions, which does not produce sustained oscillations for any choice of parameters. We show that the discrete-time version can produce sustained oscillations and that the oscillatory regime disappears as discrete-time tends to continuous-time. A different special case of SIRWY is one with fixed times for waning and recovery. We show that this simpler model can also produce sustained oscillations. In conclusion, under certain feature and parameter choices relating to how exactly immunity wanes, fluctuations in infection numbers can be sustained without the need for any additional mechanisms.

Detection of Pathogenesis-Related (PR) Genes in Susceptible Tomato Plants Infected by Meloidogyne spp.

Meloidogyne species, as infective second-stage juveniles (J2s) larvae, are parasites able to attack host of relevant agronomic interest such as tomato plants. The identification of gene expression markers, useful to investigate the levels of root-knot nematode infection in the roots, is a fundamental tool in plant-pathogen interaction. The laboratory methods for analyzing the differential expression of pathogenesis-related (PR) genes constitute powerful tools for detecting the induced systemic acquired resistance defense response to M. incognita in infected plants and can be extended to all pathogen infection markers to obtain an early and sustainable control.

Multi-feature SEIR model for epidemic analysis and vaccine prioritization.

The SEIR (susceptible-exposed-infected-recovered) model has become a valuable tool for studying infectious disease dynamics and predicting the spread of diseases, particularly concerning the COVID pandemic. However, existing models often oversimplify population characteristics and fail to account for differences in disease sensitivity and social contact rates that can vary significantly among individuals. To address these limitations, we have developed a new multi-feature SEIR model that considers the heterogeneity of health conditions (disease sensitivity) and social activity levels (contact rates) among populations affected by infectious diseases. Our model has been validated using the data of the confirmed COVID cases in Allegheny County (Pennsylvania, USA) and Hamilton County (Ohio, USA). The results demonstrate that our model outperforms traditional SEIR models regarding predictive accuracy. In addition, we have used our multi-feature SEIR model to propose and evaluate different vaccine prioritization strategies tailored to the characteristics of heterogeneous populations. We have formulated optimization problems to determine effective vaccine distribution strategies. We have designed extensive numerical simulations to compare vaccine distribution strategies in different scenarios. Overall, our multi-feature SEIR model enhances the existing models and provides a more accurate picture of disease dynamics. It can help to inform public health interventions during pandemics/epidemics.