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.

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.

Nanotechnology in agriculture: a review of genotoxic studies of nanopesticides in animal cells.

Agriculture has been and still is one of the most influential primary operations in economic history worldwide. Its social, cultural, and political impact allows the progression and survival of humanity. Sustaining the supply of primary resources is crucial for the future. Therefore, the development of new technologies applied to agrochemicals is growing to obtain better food quality faster. Recently, nanotechnology has gained strength in this field in the last decade, mainly because of the presumed benefits that will carry with it compared with the current commercial presentations, like the decrease of risk in non-target organisms. The harm of pesticides is commonly associated with unwanted effects on human health, some with long-term genotoxic effects. Therefore, it would be relevant to set the existence of a risk or a benefit of the nanopesticides from a genotoxic point of view, comparing against those without this technology. Although some studies are concerned with its genotoxicity in live aquatic organisms, few focus on human in vitro models. Several studies conclude that some of them can induce oxidative stress, leading to DNA damage or cell death. However, there is still much to investigate to establish an accurate and complete assessment. In this review, we aim to give an overview of the genotoxic effect caused by nanopesticides in animal cells and a guide to the evolution of this topic, offering a base and critical review to facilitate future research.

Nursing training and its association with burnout syndrome among Mexican undergraduate students / Formación académica en enfermería y su asociación con el síndrome de burnout en estudiantes Mexicanos de pregrado

Abstract Introduction Previous data suggest that healthcare students, such as nursing students, might have a differential risk of presenting burnout syndrome caused by the stress they are subjected to. However, the evidence is still scarce and inconclusive. Objective To evaluate the association between nursing training and burnout syndrome among undergraduate students in Hidalgo, Mexico. Method A cross-sectional analytical study was conducted on 566 undergraduate students (56% were nursing students and the rest were non-healthcare students). Burnout syndrome was identified using the Spanish version of the Maslach Burnout Inventory-Student Survey, consisting of subscales: emotional exhaustion, depersonalization, and diminished academic efficacy. The association between the variables of interest was evaluated using logistic regression models adjusted for confounders. Results In the depersonalization subscale, nursing students, compared with non-healthcare students, had an adjusted Odds Ratio (aOR) of moderate/high burnout syndrome of 2.08 (95% confidence interval [CI] = [1.34, 3.22]). In addition, the association was stronger among students in the third and fourth school years (aOR = 3.58; 95% CI = [1.62, 7.89]) compared with those in the first and second school years (aOR = 1.20; 95% CI = [.71, 2.03]). Discussion and conclusion It is necessary that universities provide nursing students with tools that allow them to cope with stressful situations during their academic training and their future life as health professionals.

Resumen Introducción Datos previos sugieren que los estudiantes del cuidado a la salud, como es el caso de enfermería, podrían tener un riesgo diferencial de presentar síndrome de burnout debido al estrés al que están sometidos, no obstante, la evidencia aun es escaza y no concluyente. Objetivo Evaluar la asociación entre la formación académica en enfermería con el síndrome de burnout en estudiantes universitarios de Hidalgo, México. Método Estudio trasversal analítico realizado en una muestra de 566 estudiantes universitarios (56% eran estudiantes de enfermería y el resto de las áreas diferentes a la salud). Para determinar la presencia de síndrome de burnout se utilizó la versión en español de la escala Maslach Burnout Inventory-Student Survey, conformada por las subescalas: agotamiento, eficacia académica y despersonalización. La asociación entre las variables de interés se evalúo mediante modelos de regresión logística ajustados por confusores. Resultados En la subescala de despersonalización los estudiantes de enfermería tuvieron mayores posibilidades de presentar síndrome de burnout medio/alto en comparación con los de las otras formaciones académicas (razón de momios ajustada [RMa] = 2.08; intervalo de confianza [IC] al 95% = [1.34, 3.22]). Además, la asociación fue más fuerte entre aquellos que cursaban el tercer y cuarto año escolar (RMa = 3.58; IC 95% = [1.62, 7.89]) a diferencia de los que cursaban los primeros dos años escolares (RMa = 1.20; IC 95% = [.71, 2.03]). Discusión y conclusión Es importante que las universidades brinden a los estudiantes de enfermería herramientas que les permitan sobrellevar las situaciones estresantes durante su formación académica y su futura vida profesional.

Phototrophy by antenna-containing rhodopsin pumps in aquatic environments.

Energy transfer from light-harvesting ketocarotenoids to the light-driven proton pump xanthorhodopsins has been previously demonstrated in two unique cases: an extreme halophilic bacterium1 and a terrestrial cyanobacterium2. Attempts to find carotenoids that bind and transfer energy to abundant rhodopsin proton pumps3 from marine photoheterotrophs have thus far failed4-6. Here we detected light energy transfer from the widespread hydroxylated carotenoids zeaxanthin and lutein to the retinal moiety of xanthorhodopsins and proteorhodopsins using functional metagenomics combined with chromophore extraction from the environment. The light-harvesting carotenoids transfer up to 42% of the harvested energy in the violet- or blue-light range to the green-light absorbing retinal chromophore. Our data suggest that these antennas may have a substantial effect on rhodopsin phototrophy in the world's lakes, seas and oceans. However, the functional implications of our findings are yet to be discovered.

Determining the Optimal SARS-CoV-2 mRNA Vaccine Dosing Interval for Maximum Immunogenicity.

OBJECTIVE: Emerging evidence indicates that longer SARS-CoV-2 vaccine dosing intervals results in an enhanced immune response. However, the optimal vaccine dosing interval for achieving maximum immunogenicity is unclear. METHODS: This study included samples from adult paramedics in Canada who received two doses of either BNT162b2 or mRNA-1273 vaccines and provided blood samples six months (170 to 190 days) after the first vaccine dose. The main exposure variable was vaccine dosing interval (days), categorized as "short" (first quartile), "moderate" (second quartile), "long" (third quartile), and "longest" interval (fourth quartile). The primary outcome was total spike antibody concentrations, measured using the Elecsys SARS-CoV-2 total antibody assay. Secondary outcomes included spike and receptor-binding domain (RBD) immunoglobulin G (IgG) antibody concentrations, and inhibition of angiotensin-converting enzyme 2 (ACE-2) binding to wild-type spike protein and several different Delta variant spike proteins. We fit a multiple log-linear regression model to investigate the association between vaccine dosing intervals and the antibody concentrations. RESULTS: A total of 564 adult paramedics (mean age 40 years, SD=10) were included. Compared to "short interval" (≤30 days), vaccine dosing intervals of the long (39-73 days) group (ß= 0.31, 95% Confidence interval (CI): 0.10-0.52) and the longest (≥74 days) group (ß = 0.82. 95% CI: 0.36-1.28) were associated with increased spike total antibody concentration. Compared to the short interval, the longest interval quartile was associated with higher spike IgG antibodies, while the long and longest intervals were associated with higher RBD IgG antibody concentrations. Similarly, the longest dosing intervals increased inhibition of ACE-2 binding to viral spike protein. CONCLUSION: Increased mRNA vaccine dosing intervals longer than 38 days result in higher levels of anti-spike antibodies and ACE-2 inhibition when assessed six months after the first COVID-19 vaccine.

A low-protein maternal diet during gestation affects the expression of key pancreatic ß-cell genes and the methylation status of the regulatory region of the MafA gene in the offspring of Wistar rats.

Maternal nutrition during gestation has important effects on gene expression-mediated metabolic programming in offspring. To evaluate the effect of a protein-restricted maternal diet during gestation, pancreatic islets from male progeny of Wistar rats were studied at postnatal days (PND) 36 (juveniles) and 90 (young adults). The expression of key genes involved in ß-cell function and the DNA methylation pattern of the regulatory regions of two such genes, Pdx1 (pancreatic and duodenal homeobox 1) and MafA (musculoaponeurotic fibrosarcoma oncogene family, protein A), were investigated. Gene expression analysis in the pancreatic islets of restricted offspring showed significant differences compared with the control group at PND 36 (P < 0.05). The insulin 1 and 2 (Ins1 and Ins2), Glut2 (glucose transporter 2), Pdx1, MafA, and Atf2 (activating transcription factor 2), genes were upregulated, while glucokinase (Gck) and NeuroD1 (neuronal differentiation 1) were downregulated. Additionally, we studied whether the gene expression differences in Pdx1 and MafA between control and restricted offspring were associated with differential DNA methylation status in their regulatory regions. A decrease in the DNA methylation levels was found in the 5' flanking region between nucleotides -8118 to -7750 of the MafA regulatory region in restricted offspring compared with control pancreatic islets. In conclusion, low protein availability during gestation causes the upregulation of MafA gene expression in pancreatic ß-cells in the male juvenile offspring at least in part through DNA hypomethylation. This process may contribute to developmental dysregulation of ß-cell function and influence the long-term health of the offspring.

Management of Suprachoroidal Hemorrhage during Phacoemulsification: A Comprehensive Review.

Suprachoroidal hemorrhage (SCH) is a rare and sight-threatening complication of various intraocular surgeries, including cataract surgery. Although the rate of SCH complicating cataract surgery has decreased in the era of phacoemulsification, most likely due to smaller self-sealing incisions and modern equipment, it remains a challenging complication to manage. The aim of this review is to summarize the current evidence of the pathophysiology and management of SCH complicating phaco surgery. A literature review was performed using the PubMed database searching for diagnosis, therapy, and management of SCH during phacoemulsification. The evidence available on the optimal management of this condition is low, and there is no consensus so far. An early diagnosis is thought to be essential to avoid progression to the devastating stage of expulsion of intraocular contents (expulsive hemorrhage). Sudden intraoperative anterior chamber shallowing, red reflex loss, and a significant increase in intraocular pressure are highly suspicious for this severe complication. A fundus examination and ocular ultrasound are crucial to confirm the diagnosis and, if it is confirmed, stabilize the globe immediately. The initial therapeutic approach includes aggressive topical and systemic medication focused on controlling ocular inflammation and intraocular pressure, whereas the timing and the indications of surgical intervention remain controversial.

Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing.

OBJECTIVES: The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due in part to small cohort sizes, a consequence of the low prevalence of vasculitides. This study aimed to identify new genetic risk loci for the main systemic vasculitides through a comprehensive analysis of their genetic overlap. METHODS: Genome-wide data from 8467 patients with any of the main forms of vasculitis and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants were functionally annotated and linked to their target genes. Prioritised genes were queried in DrugBank to identify potentially repositionable drugs for the treatment of vasculitis. RESULTS: Sixteen variants were independently associated with two or more vasculitides, 15 of them representing new shared risk loci. Two of these pleiotropic signals, located close to CTLA4 and CPLX1, emerged as novel genetic risk loci in vasculitis. Most of these polymorphisms appeared to affect vasculitis by regulating gene expression. In this regard, for some of these common signals, potential causal genes were prioritised based on functional annotation, including CTLA4, RNF145, IL12B, IL5, IRF1, IFNGR1, PTK2B, TRIM35, EGR2 and ETS2, each of which has key roles in inflammation. In addition, drug repositioning analysis showed that several drugs, including abatacept and ustekinumab, could be potentially repurposed in the management of the analysed vasculitides. CONCLUSIONS: We identified new shared risk loci with functional impact in vasculitis and pinpointed potential causal genes, some of which could represent promising targets for the treatment of vasculitis.