Genetics of vasculitis.

Systemic vasculitis encompasses a wide range of conditions characterized by varying degrees of inflammation in blood vessels. Although the etiology of vasculitis remains unclear, accumulated data suggest that it is triggered in genetically predisposed individuals by the concurrence of certain environmental factors. The importance of the genetic component has been consistently supported by evidence of familial aggregation, differential prevalence by ethnicity, and multiple genetic associations with disease susceptibility and severity reported in recent years. The strongest association signals in most vasculitides correspond to genetic variants within the HLA region, suggesting an important role of the immune system in its pathophysiology. However, each type of vasculitis has distinct defining HLA association markers, likely due to disease-specific differences in antigenic drivers. Furthermore, other genetic polymorphisms located outside the HLA region play an important role in susceptibility to different vasculitides. More recent research has assessed the shared genetic susceptibility evident across different vasculitides. Future studies should focus on the identification of genetic markers that can serve as reliable biomarkers for early diagnosis, prognosis, and treatment response in systemic vasculitis.

Multi-biomarker approach reveals the effects of heavy metal bioaccumulation in the foundation species Prosopis laevigata (Fabaceae).

Mining is a major economic activity in many developing countries. However, it disturbs the environment, producing enormous quantities of waste, known as mine tailings, which can have deleterious environmental impact, due to their high heavy metals (HM) content. Often, foundation species that establish on mine tailings are good candidates to study the effects of HM bioaccumulation at different levels of biological organization. Prosopis laevigata is considered a HM hyperaccumulator which presents attributes of a foundation species (FS) and establishes naturally on mine tailings. We evaluated the bioaccumulation of Cu, Pb, and Zn in P. laevigata foliar tissue, the leaf micro- and macro-morphological characters, DNA damage, and population genetic effects. In total, 80 P. laevigata individuals (20/site) belonging to four populations: The individuals from both sites (exposed and reference) bioaccumulated HMs (Pb > Cu > Zn). However, in the exposed individuals, Pb and Cu bioaccumulation was significantly higher. Also, a significant effect of macro- and micro-morphological characters was registered, showing significantly lower values in individuals from the exposed sites. In addition, we found significant differences in genotoxic damage in P. laevigata individuals, between the exposed and reference sites. In contrast, for the micro-morphological characters, none of the analyzed metals had any influence. P. laevigata did not show significant differences in the genetic structure and diversity between exposed and reference populations. However, four haplotypes and four private alleles were found in the exposed populations. Since P. laevigata is a species that establishes naturally in polluted sites and bioaccumulates HM in its foliar tissues, the resulting genetic, individual and population effects have not been severe enough to show detrimental effects; hence, P. laevigata can be a useful tool in phytoremediation strategies for soils polluted with Pb and Cu, maintaining its important ecological functions.

Combining ranger records and biogeographical models to identify the current and potential distribution of an expanding mesocarnivore in southern Europe.

Human-wildlife conflicts (HWC) are increasing and are potentially harmful to both people and wildlife. Understanding the current and potential distribution of wildlife species involved in HWC, such as carnivores, is essential for implementing management and conservation measures for such species. In this study, we assessed both the current distribution and potential distribution (forecast) of the Egyptian mongoose (Herpestes ichneumon) in the central part of the Iberian Peninsula. We acquired data concerning mongoose occurrences through an online questionnaire sent to environmental rangers. We used the municipality level as the sampling unit because all municipalities within the study area were covered at least by one ranger. Using the information provided by rangers (i.e. occurrences in their municipalities), we constructed environmental favourability distribution models to assess current and potential mongoose distribution through current distribution models (CDM) and ecological models (EM), respectively. >300 rangers participated in the survey and mongooses were reported in a total of 181 of 921 municipalities studied. The CDM model showed a current distribution mainly concentrated on the western part of the study area, where intermediate-high favourability values predominated. The EM model revealed a wider potential distribution, including the south-east part of the study area, which was also characterised by intermediate-high favourability values. Our predictions were verified using independent data, including confirmation of mongoose reproduction by rangers, reports by other experts, and field sampling in some areas. Our innovative approach based on an online survey to rangers coupled with environmental favourability models is shown to be a useful methodology for assessing the current distribution of cryptic but expanding wildlife species, while also enabling estimations of future steps in their expansion. The approach proposed may help policy decision-makers seeking to ensure the conservation of expanding wildlife species, for example, by designing awareness campaigns in areas where the target species is expected to arrive.

Assessment of genotoxic damage induced by exposure to binary mixtures of polycyclic aromatic hydrocarbons and three heavy metals in male mice.

INTRODUCTION: Heavy metals (HM) and polycyclic aromatic hydrocarbons (PAHs) exposition has been associated with health problems. Therefore, this research evaluated genotoxicity induced in male mice strain CD-1 exposed to benzo[a]anthracene (B[a]A) and benzo[a]pyrene (B[a]P) and their interaction with Fe, Pb, and Al. METHODS: Groups of animals were exposed intraperitoneally to HM, PAHs, and mixtures of both. Peripheral blood samples were taken from 0 to 96 h at 24 h intervals; genotoxicity was determined by micronucleus tests and comet assay. Additionally, toxicity and viability were evaluated. RESULTS: HM and PAHs individually were genotoxic. About toxicity, only Al altered polychromatic erythrocytes number and did not change leukocytes viability. Concerning mixtures, Fe + B[a]P, Fe + B[a]A, Pb + B[a]P increased genotoxicity. There were no changes with Pb + B[a]A. Finally, Al mixtures with both PAHs damage was decreased. CONCLUSIONS: Exposure to HM and PAH caused genetic damage. Fe, Al, and B[a]A, established a genotoxic potential. Every metal can interact with PAHs in different ways. Also, the micronucleus test and the comet assay demonstrated their high capacity and reliability to determine the genotoxic potential of the compounds evaluated in this work.

Early-life infection depletes preleukemic cells in a mouse model of hyperdiploid B-cell acute lymphoblastic leukemia.

Epidemiological studies report opposing influences of infection on childhood B cell acute lymphoblastic leukemia (B-ALL). Although infections in the first year of life appear to exert the largest impact on leukemia risk, the effect of early pathogen exposure on the fetal preleukemia cells (PLC) that lead to B-ALL has yet to be reported. Using cytomegalovirus as a model early-life infection, we show that virus exposure within one week of birth induces profound depletion of transplanted B-ALL cells in two mouse models and of in situ-generated PLC in Eu-ret mice. The age-dependent depletion of PLC results from an elevated STAT4-mediated cytokine response in neonates, with high levels of IL-12p40-driven IFN-g production inducing PLC death. Similar PLC depletion can be achieved in adult mice by impairing viral clearance. These findings provide mechanistic support for an inhibitory effect of early-life infection on B-ALL progression and could inform development of therapeutic or preventative approaches.

Decoding CD4+ T cell transcriptome in giant cell arteritis: Novel pathways and altered cross-talk with monocytes.

BACKGROUND: Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4+ T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4+ T cells will yield new insights into its pathogenesis. METHODS: Transcriptome analysis was conducted on CD4+ T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14+ monocytes. RESULTS: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4+ T cells in GCA. Specifically, CD4+ T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4+ T cells and monocytes that could have pathogenic relevance in GCA. CONCLUSIONS: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis.

Adaptive immune responses to two-dose COVID-19 vaccine series in healthy Canadian adults ≥ 50 years: a prospective, observational cohort study.

To evaluate immune responses to COVID-19 vaccines in adults aged 50 years and older, spike protein (S)-specific antibody concentration, avidity, and function (via angiotensin-converting enzyme 2 (ACE2) inhibition surrogate neutralization and antibody dependent cellular phagocytosis (ADCP)), as well as S-specific T cells were quantified via activation induced marker (AIM) assay in response to two-dose series. Eighty-four adults were vaccinated with either: mRNA/mRNA (mRNA-1273 and/or BNT162b2); ChAdOx1-S/mRNA; or ChAdOx1-S/ChAdOx1-S. Anti-S IgG concentrations, ADCP scores and ACE2 inhibiting antibody concentrations were highest at one-month post-second dose and declined by four-months post-second dose for all groups. mRNA/mRNA and ChAdOx1-S/mRNA schedules had significantly higher antibody responses than ChAdOx1-S/ChAdOx1-S. CD8+ T-cell responses one-month post-second dose were associated with increased ACE2 surrogate neutralization. Antibody avidity (total relative avidity index) did not change between one-month and four-months post-second dose and did not significantly differ between groups by four-months post-second dose. In determining COVID-19 correlates of protection, a measure that considers both antibody concentration and avidity should be considered.

Factors associated with SARS-CoV-2 infection in unvaccinated children and young adults.

BACKGROUND AND OBJECTIVES: Pediatric COVID-19 cases are often mild or asymptomatic, which has complicated estimations of disease burden using existing testing practices. We aimed to determine the age-specific population seropositivity and risk factors of SARS-CoV-2 seropositivity among children and young adults during the pandemic in British Columbia (BC). METHODS: We conducted two cross-sectional serosurveys: phase 1 enrolled children and adults < 25 years between November 2020-May 2021 and phase 2 enrolled children < 10 years between June 2021-May 2022 in BC. Participants completed electronic surveys and self-collected finger-prick dried blood spot (DBS) samples. Samples were tested for immunoglobulin G antibodies against ancestral spike protein (S). Descriptive statistics from survey data were reported and two multivariable analyses were conducted to evaluate factors associated with seropositivity. RESULTS: A total of 2864 participants were enrolled, of which 95/2167 (4.4%) participants were S-seropositive in phase 1 across all ages, and 61/697 (8.8%) unvaccinated children aged under ten years were S-seropositive in phase 2. Overall, South Asian participants had a higher seropositivity than other ethnicities (13.5% vs. 5.2%). Of 156 seropositive participants in both phases, 120 had no prior positive SARS-CoV-2 test. Young infants and young adults had the highest reported seropositivity rates (7.0% and 7.2% respectively vs. 3.0-5.6% across other age groups). CONCLUSIONS: SARS-CoV-2 seropositivity among unvaccinated children and young adults was low in May 2022, and South Asians were disproportionately infected. This work demonstrates the need for improved diagnostics and reporting strategies that account for age-specific differences in pandemic dynamics and acceptability of testing mechanisms.

Single-cell transcriptomic profiling reveals a pathogenic role of cytotoxic CD4+ T cells in giant cell arteritis.

Giant cell arteritis (GCA) is a systemic vasculitis mediated by an aberrant immunological response against the blood vessel wall. Although the pathogenic mechanisms that drive GCA have not yet been elucidated, there is strong evidence that CD4+ T cells are key drivers of the inflammatory process occurring in this vasculitis. The aim of this study was to further delineate the role of CD4+ T cells in GCA by applying single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling to 114.799 circulating CD4+ T cells from eight GCA patients in two different clinical states, active and in remission, and eight healthy controls. Our results revealed an expansion of cytotoxic CD4+ T lymphocytes (CTLs) in active GCA patients, which expressed higher levels of cytotoxic and chemotactic genes when compared to patients in remission and controls. Accordingly, differentially expressed genes in CTLs of active patients were enriched in pathways related to granzyme-mediated apoptosis, inflammation, and the recruitment of different immune cells, suggesting a role of this cell type in the inflammatory and vascular remodelling processes occurring in GCA. CTLs also exhibited a higher clonal expansion in active patients with respect to those in remission. Drug repurposing analysis prioritized maraviroc, which targeted CTLs, as potentially repositionable for this vasculitis. In addition, effector regulatory T cells (Tregs) were decreased in GCA and showed lower expression of genes involved in their suppressive activity. These findings provide further insights into the pathogenic role of CD4+ T cells in GCA and suggest targeting CTLs as a potential therapeutic option.

Genome-Wide Association Study Identifies the First Germline Genetic Variant Associated With Erdheim-Chester Disease.

OBJECTIVE: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. METHODS: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. RESULTS: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. CONCLUSION: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.

Eleven-month SARS-CoV-2 binding antibody decay, and associated factors, among mRNA vaccinees: implications for booster vaccination.

Background: We examined the 11 month longitudinal antibody decay among two-dose mRNA vaccinees, and identified factors associated with faster decay. Methods: The study included samples from the COVID-19 Occupational Risk, Seroprevalence and Immunity among Paramedics (CORSIP) longitudinal observational study of paramedics in Canada. Participants were included if they had received two mRNA vaccines without prior SARS-CoV-2 infection and provided two blood samples post-vaccination. The outcomes of interest were quantitative SARS-CoV-2 antibody concentrations. We employed spaghetti and scatter plots (with kernel-weighted local polynomial smoothing curve) to describe the trend of the antibody decay over 11 months post-vaccine and fit a mixed effect exponential decay model to examine the loss of immunogenicity and factors associated with antibody waning over time. Results: This analysis included 652 blood samples from 326 adult paramedics. Total anti-spike antibody levels peaked on the twenty-first day (antibody level 9042 U ml-1) after the second mRNA vaccine dose. Total anti-spike antibody levels declined thereafter, with a half-life of 94 [95 % CI: 70, 143] days, with levels plateauing at 295 days (antibody level 1021 U ml-1). Older age, vaccine dosing interval <35 days, and the BNT162b2 vaccine (compared to mRNA-1273 vaccine) were associated with faster antibody decay. Conclusion: Antibody levels declined after the initial mRNA series with a half-life of 94 days, plateauing at 295 days. These findings may inform the timing of booster vaccine doses and identifying individuals with faster antibody decay.

Exposición al Dicloro Difenil Tricloroetano y perfil tiroideo durante el embarazo: revisión sistemática y meta-análisis / Dichlorodiphenyltrichloroethane pesticide exposure and thyroid profile during pregnancy: systematic review and meta-analysis

Resumen Objetivo: Evaluar la asociación entre la exposición al p,p´-DDT y p,p´-DDE con la disrupción tiroidea durante el embarazo a través de un metaanálisis. Material y métodos: Se realizó una revisión sistemática y un meta-análisis basado en la declaración PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalysis). El protocolo de esta revisión se registró ante el International Prospective Register of Systematic Reviews (PROSPERO) con el folio de identificación: CRD42022324797. Se llevó a cabo una búsqueda en las bases de datos electrónicas PubMed y Web of Science para identificar los estudios elegibles publicados en inglés y español hasta el 2 de enero de 2022. Mediante meta-análisis de efectos aleatorios, se estimó un coeficiente de regresión beta (β) combinado, por cada hormona del perfil tiroideo, a partir de los β publicados de cada estudio y sus intervalos de confianza del 95% (IC del 95%). Resultados: Se incluyeron ocho estudios de los cuales solamente tres reportaron biomarcadores de exposición a p,p'-DDT, por lo que no fue posible conducir metaanálisis para evaluar la relación entre este compuesto y las hormonas del perfil tiroideo. La exposición a p,p'-DDE se asoció con un ligero incremento en los niveles de TSH (β combinada= 0.05; IC95%= -0.01. 0.12) y T3 total (β combinada= 0.02; IC95%= -0.05, 0.09), pero inversamente con los niveles de la T4 total (β combinada= -0.003; IC 95%= -0.05, 0.05) y T4 libre (β combinada= -0.01; IC95%= -0.03, 0.01), aunque ninguno de estos hallazgos fue estadísticamente significativo. Conclusiones: La evidencia disponible a la fecha aún es limitada como para emitir una conclusión sobre la asociación entre las variables de interés. Dado que pequeños cambios en la homeóstasis tiroidea de mujeres embarazadas podrían tener consecuencias en el desarrollo fetal, es necesario seguir generando evidencia al respecto.

Abstract Objective: Evaluate the association between p,p´-DDT and p,p´-DDE exposure with thyroid disruption during pregnancy through meta-analysis. Material and methods: We performed a systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The protocol of this review was registered in PROSPERO with the identification sheet: CRD42022324797. We conduct systematic searches in PubMed and Web of Science electronic databases to identify eligible studies published in English and Spanish up to January 2, 2022. Using random-effects meta-analysis, a beta regression coefficient was estimated (β) pooled, for each hormone of the thyroid profile, from the β published in each study and their 95% confidence intervals (95% CI). Results: Eight studies were included, of which only three reported biomarkers of exposure to p,p'-DDT, so it was not possible to conduct a meta-analysis to assess the relationship between this compound and hormones in the thyroid profile. Exposure to p,p'-DDE was associated with a slight increase in TSH (pooled β= 0.05; 95% CI= -0.01, 0.12) and total T3 (pooled β= 0.02; 95% CI= -0.05, 0.09) levels , but inversely with total T4 (β pooled= -0.003; 95% CI= -0.05, 0.05) and free T4 (β pooled= -0.01; 95% CI= -0.03, 0.01) levels, although neither of these findings was statistically significant. Conclusions: The evidence available to date is still limited to draw a conclusion on the association between the variables of interest. Since small changes in thyroid homeostasis in pregnant women could have consequences on fetal development, it is necessary to continue generating evidence in this regard.

Interaction between Akkermansia muciniphila and Diet Is Associated with Proinflammatory Index in School-Aged Children.

BACKGROUND: Imbalance in the intestinal microbiota can lead to chronic low-grade inflammation. Diet may influence this association. In this study, we aimed to evaluate the interaction between Akkermansia muciniphila (A. muciniphila) and dietary patterns using a proinflammatory index. METHODS: We conducted a cross-sectional study with school-aged children. We quantified the relative abundance (RA) of A. muciniphila in feces using a polymerase chain reaction. We collected dietary information through employing a food frequency questionnaire and generated dietary patterns using principal component analysis. We generated a proinflammatory index from serum levels of interleukin-6, interleukin-10, tumor necrosis factor alpha, and adiponectin validated by receptor operating characteristic curves. We evaluated the association between A. muciniphila and the proinflammatory index using logistic regression, including an interaction term with dietary patterns. RESULTS: We found that children with a low RA of A. muciniphila and a high intake of simple carbohydrates and saturated fats had increased odds of being high on the proinflammatory index. However, when the consumption of this dietary pattern is low, children with a low RA of A. muciniphila had decreased odds of being high on the proinflammatory index. CONCLUSIONS: Our results suggest that the simultaneous presence of A. muciniphila and diet have a more significant impact on the presence of being high on the proinflammatory index compared to both factors separately.

Two-phase Bayesian latent class analysis to assess diagnostic test performance in the absence of a gold standard: COVID-19 serological assays as a proof of concept.

BACKGROUND AND OBJECTIVES: In this proof-of-concept study, which included blood donor samples, we aimed to demonstrate how Bayesian latent class models (BLCMs) could be used to estimate SARS-CoV-2 seroprevalence in the absence of a gold standard assay under a two-phase sampling design. MATERIALS AND METHODS: To this end, 6810 plasma samples from blood donors who resided in Québec (Canada) were collected from May to July 2020 and tested for anti-SARS-CoV-2 antibodies using seven serological assays (five commercial and two non-commercial). RESULTS: SARS-CoV-2 seroprevalence was estimated at 0.71% (95% credible interval [CrI] = 0.53%-0.92%). The cPass assay had the lowest sensitivity estimate (88.7%; 95% CrI = 80.6%-94.7%), while the Héma-Québec assay had the highest (98.7%; 95% CrI = 97.0%-99.6%). CONCLUSION: The estimated low seroprevalence (which indicates a relatively limited spread of SARS-CoV-2 in Quebec) might change rapidly-and this tool, developed using blood donors, could enable a rapid update of the prevalence estimate in the absence of a gold standard. Further, the present analysis illustrates how a two-stage BLCM sampling design, along with blood donor samples, can be used to estimate the performance of new diagnostic tests and inform public health decisions regarding a new or emerging disease for which a perfect reference standard does not exist.

Uptake of SARS-CoV-2 vaccination among structurally-marginalized people who use drugs in Vancouver, Canada.

We sought to evaluate the rates and predictors of SARS-CoV-2 vaccination among members of a structurally-marginalized population of people who use drugs (PWUD) during a targeted, community-wide, vaccination campaign in Vancouver, Canada. Interviewer-administered data were collected from study participants between June 2021 and March 2022. Generalized estimating equation analysis was used to identify factors associated with SARS-CoV-2 vaccine uptake, ascertained through a province-wide vaccine registry. Among 223 PWUD, 107 (48.0%) reported receipt of at least two SARS-CoV-2 vaccine doses at baseline and this increased to 151 (67.7%) by the end of the study period. Using social media as a source of vaccine information was negatively associated with SARS-CoV-2 vaccine uptake (Adjusted odds ratio [AOR] 0.27, 95% confidence interval [CI] 0.09-0.81) and HIV seropositivity (AOR 2.68, 95% CI 1.12-6.39) and older age (AOR 1.27, 95% CI 1.07-1.51) were positively associated with SARS-CoV-2 vaccine uptake. These findings suggest that the targeted vaccination campaign in Vancouver may be an effective model to promote SARS-CoV-2 vaccination in other jurisdictions. However, using social media as a source of vaccine information likely reduced SARS-CoV-2 vaccine uptake in PWUD arguing for further efforts to promote accessible and evidence-based vaccine information among marginalized populations.

Mucosal Immune Defence Gene Polymorphisms as Relevant Players in the Pathogenesis of IgA Vasculitis?

ITGAM-ITGAX (rs11150612, rs11574637), VAV3 rs17019602, CARD9 rs4077515, DEFA (rs2738048, rs10086568), and HORMAD2 rs2412971 are mucosal immune defence polymorphisms, that have an impact on IgA production, described as risk loci for IgA nephropathy (IgAN). Since IgAN and Immunoglobulin-A vasculitis (IgAV) share molecular mechanisms, with the aberrant deposit of IgA1 being the main pathophysiologic feature of both entities, we assessed the potential influence of the seven abovementioned polymorphisms on IgAV pathogenesis. These seven variants were genotyped in 381 Caucasian IgAV patients and 997 matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of these seven polymorphisms when the whole cohort of IgAV patients and those with nephritis were compared to controls. Similar genotype and allele frequencies of all polymorphisms were disclosed when IgAV patients were stratified according to the age at disease onset or the presence/absence of gastrointestinal or renal manifestations. Likewise, no ITGAM-ITGAX and DEFA haplotype differences were observed when the whole cohort of IgAV patients, along with those with nephritis and controls, as well as IgAV patients, stratified according to the abovementioned clinical characteristics, were compared. Our results suggest that mucosal immune defence polymorphisms do not represent novel genetic risk factors for IgAV pathogenesis.

Mediation Analysis of Waist Circumference in the Association of Gut Microbiota with Insulin Resistance in Children.

BACKGROUND: Persistent gut microbiota (GM) imbalance has been associated with metabolic disease development. This study evaluated the mediating role of waist circumference in the association between GM and insulin resistance (IR) in children. METHODS: This cross-sectional study included 533 children aged between 6 and 12. The anthropometry, metabolic markers, and relative abundance (RA) of five intestinal bacterial species were measured. Path coefficients were estimated using path analysis to assess direct, indirect (mediated by waist circumference), and total effects on the association between GM and IR. RESULTS: The results indicated a positive association mediated by waist circumference between the medium and high RA of S. aureus with homeostatic model assessments for insulin resistance (HOMA-IR) and for insulin resistance adiponectin-corrected (HOMA-AD). We found a negative association mediated by waist circumference between the low and medium RA of A. muciniphila and HOMA-IR and HOMA-AD. Finally, when we evaluated the joint effect of S. aureus, L. casei, and A. muciniphila, we found a waist circumference-mediated negative association with HOMA-IR and HOMA-AD. CONCLUSIONS: Waist circumference is a crucial mediator in the association between S. aureus and A. muciniphila RA and changes in HOMA-IR and HOMA-AD scores in children.

CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis.

BACKGROUND: Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA. METHODS: First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls. RESULTS: Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) but not anti-PD-1 (anti-programmed death-1) nor anti-PD-L1 (anti-programmed death-ligand 1) treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4+ (cluster of differentiation 4) T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4+ Ki-67+ regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)-mediated in vitro depletion versus controls. CONCLUSIONS: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway.

Occupational exposure to pesticides: DNA damage in horticulturist from Nativitas, Tlaxcala in Mexico.

Mexico is a country where agricultural activity is of great importance, but biomonitoring data are still scarce. With more intensive pesticides use per unit area/surface in horticultural productivity, there is a higher impact on environmental contamination and workers' health. Considering that exposure to various pesticide and pesticide mixtures represents an additional genotoxic risk, the appropriate characterization of exposure, confounding factors and the risk itself are very much needed. We compared genetic damage in 42 horticulturists and 46 unexposed controls (Nativitas, Tlaxcala) using alkaline comet (whole blood) and micronucleus (MN) test with nuclear abnormalities (NA) (buccal epithelial cells). Workers demonstrated significantly higher levels of damage (TI%=14.02 ± 2.49 vs. 5.37 ± 0.46; MN=10.14 ± 5.15 vs. 2.40 ± 0.20), with more than 90% of them not using protective clothing nor gloves during application. Combined DNA damage techniques and periodic monitoring together with educational programs for safe pesticide application is the best strategy to assess and prevent workers' health risks.