The Shared Pathoetiological Effects of Particulate Air Pollution and the Social Environment on Fetal-Placental Development

Exposure to particulate air pollution and socioeconomic risk factors are shown to be independently associated with adverse pregnancy outcomes; however, their confounding relationship is an epidemiological challenge that requires understanding of their shared etiologic pathways affecting fetal-placental development. The purpose of this paper is to explore the etiological mechanisms associated with exposure to particulate air pollution in contributing to adverse pregnancy outcomes and how these mechanisms intersect with those related to socioeconomic status. Here we review the role of oxidative stress, inflammation and endocrine modification in the pathoetiology of deficient deep placentation and detail how the physical and social environments can act alone and collectively to mediate the established pathology linked to a spectrum of adverse pregnancy outcomes. We review the experimental and epidemiological literature showing that diet/nutrition, smoking, and psychosocial stress share similar pathways with that of particulate air pollution exposure to potentially exasperate the negative effects of either insult alone. Therefore, socially patterned risk factors often treated as nuisance parameters should be explored as potential effect modifiers that may operate at multiple levels of social geography. The degree to which deleterious exposures can be ameliorated or exacerbated via community-level social and environmental characteristics needs further exploration

Red blood cell folate levels in Canadian Inuit women of childbearing years: influence of food security, body mass index, smoking, education, and vitamin use

Background: The benefits of folic acid for prevention of congenital anomalies are well known. For the Inuit of Canada, where vitamin use is low and access to folate-rich foods limited, fortification is likely a major source of intake. We sought to determine whether red blood cell folate (RBCF) levels of Inuit women reached accepted target levels. Methods: The Inuit Health Survey, 2007–2008, included evaluation of RBCF levels among 249 randomly selected non-pregnant women of reproductive age. Using descriptive statistics and linear regression analyses, RBCF levels were assessed and compared across several socio-demographic variables to evaluate the characteristics associated with RBCF status. Results: Mean (SD) RBCF levels of 935.5 nmol/L (± 192) reached proposed target levels (> 906 nmol/L); however, 47% of women had lower than target levels. In bivariate analysis, non-smoking, higher education, higher income, food security, increased body mass index, and vitamin use were each significantly associated with higher RBCF. Increased levels of smoking had a negative association with RBCF levels (− 5.8 nmol/L per cigarette smoked per day (p = 0.001)). A total of 6.8% of women reported taking vitamin supplements, resulting in a 226 nmol/L higher RBCF level on average compared to non-users (p < 0.001). Conclusion: While mean levels of folate reached target levels, this was largely driven by the small number of women taking vitamin supplements. Our results suggest that folate status is often too low in Inuit women of childbearing years. Initiatives to improve food security, culturally relevant education on folate-rich traditional foods, vitamin supplements, and smoking cessation/reduction programs may benefit Inuit women and improve birth outcomes.publishedVersio

A mild phenotype associated with KCNQ1 p.V205M mediated long QT syndrome in First Nations children of Northern British Columbia: effect of additional variants and considerations for management

IntroductionCongenital Long QT Syndrome (LQTS) is common in a First Nations community in Northern British Columbia due to the founder variant KCNQ1 p.V205M. Although well characterized molecularly and clinically in adults, no data have been previously reported on the pediatric population. The phenotype in adults has been shown to be modified by a splice site variant in KCNQ1 (p.L353L). The CPT1A p.P479L metabolic variant, also common in Northern Indigenous populations, is associated with hypoglycemia and infant death. Since hypoglycemia can affect the corrected QT interval (QTc) and may confer risk for seizures (also associated with LQTS), we sought to determine the effect of all three variants on the LQTS phenotype in children within our First Nations cohort.MethodsAs part of a larger study assessing those with LQTS and their relatives in a Northern BC First Nation, we assessed those entering the study from birth to age 18 years. We compared the corrected peak QTc and potential cardiac events (syncope/seizures) of 186 children from birth to 18 years, with and without the KCNQ1 (p.V205M and p.L353L) and CPT1A variants, alone and in combination. Linear and logistic regression and student t-tests were applied as appropriate.ResultsOnly the KCNQ1 p.V205M variant conferred a significant increase in peak QTc 23.8 ms (p &lt; 0.001) above baseline, with females increased by 30.1 ms (p &lt; 0.001) and males by 18.9 ms (p &lt; 0.01). There was no evidence of interaction effects with the other two variants studied. Although the p.V205M variant was not significantly associated with syncope/seizures, the odds of having a seizure/syncope were significantly increased for those homozygous for CPT1A p.P479L compared to homozygous wild type (Odds Ratio [OR]3.0 [95% confidence interval (CI) 1.2–7.7]; p = 0.019).ConclusionWhile the KCNQ1 p.V205M variant prolongs the peak QTc, especially in females, the CPT1A p.P479L variant is more strongly associated with loss of consciousness events. These findings suggest that effect of the KCNQ1 p.V205M variant is mild in this cohort, which may have implications for standard management. Our findings also suggest the CPT1A p.P479L variant is a risk factor for seizures and possibly syncope, which may mimic a long QT phenotype

Portrait des ressources en eau souterraine des îles de la Madeleine : atlas hydrogéologique

L’eau souterraine constitue l’unique source d’approvisionnement en eau potable des îles de la Madeleine. Elle est vulnérable à l’intrusion d’eau salée qui provient de la mer et aux nombreuses activités humaines qui peuvent avoir un impact sur la quantité ou la qualité de la ressource. Les changements climatiques pourraient aussi influer sur la disponibilité future de cette ressource. Une connaissance accrue sur l’eau souterraine et les aquifères qui la contiennent est nécessaire pour la mise en place de mesures de protection et de gestion durable de la ressource. La présente étude établit le Portrait des ressources en eau souterraine des îles de la Madeleine en recensant d’abord l’ensemble des connaissances existantes sur les eaux souterraines du territoire d’étude. Des données complémentaires de terrain ont ensuite été acquises. L’ensemble des informations récoltées ont enfin été intégrées et interprétées en format cartographique, principalement à l’aide d’une approche méthodologique basée sur la modélisation numérique des écoulements. Les aquifères au potentiel d’exploitation moyen à très élevé, composés principalement de grès, ont été identifiés. Ceux-ci contiennent la presque totalité de l’eau souterraine qui est actuellement exploitée et constituent la réserve principale en eau douce disponible pour les besoins futurs. Cette eau est de très bonne qualité et peut souvent être distribuée sans traitement particulier. Les aires d’alimentation de ces aquifères correspondent aux territoires qui devraient être ciblés par les mesures de protection et de gestion de la ressource. La consommation annuelle en eau douce est faible comparativement à la réalimentation annuelle des aquifères. Ainsi, la quantité d’eau contenue dans les aquifères suffit aux besoins en eau potable actuels. Les ressources en eau souterraine et les réseaux d'exploitation actuels semblent suffisants pour les besoins futurs de la municipalité selon les projections en 2050 de la hausse de la consommation et de la diminution du volume d’eau disponible causée par les changements climatiques

Portrait des ressources en eau souterraine des îles de la Madeleine : rapport scientifique

L’eau souterraine constitue l’unique source d’approvisionnement en eau potable des îles de la Madeleine. Elle est vulnérable à l’intrusion d’eau salée qui provient de la mer et aux nombreuses activités humaines qui peuvent avoir un impact sur la quantité ou la qualité de la ressource. Les changements climatiques pourraient aussi influer sur la disponibilité future de cette ressource. Une connaissance accrue sur l’eau souterraine et les aquifères qui la contiennent est nécessaire pour la mise en place de mesures de protection et de gestion durable de la ressource. La présente étude établit le Portrait des ressources en eau souterraine des îles de la Madeleine en recensant d’abord l’ensemble des connaissances existantes sur les eaux souterraines du territoire d’étude. Des données complémentaires de terrain ont ensuite été acquises. L’ensemble des informations récoltées ont enfin été intégrées et interprétées en format cartographique, principalement à l’aide d’une approche méthodologique basée sur la modélisation numérique des écoulements. Les aquifères au potentiel d’exploitation moyen à très élevé, composés principalement de grès, ont été identifiés. Ceux-ci contiennent la presque totalité de l’eau souterraine qui est actuellement exploitée et constituent la réserve principale en eau douce disponible pour les besoins futurs. Cette eau est de très bonne qualité et peut souvent être distribuée sans traitement particulier. Les aires d’alimentation de ces aquifères correspondent aux territoires qui devraient être ciblés par les mesures de protection et de gestion de la ressource. La consommation annuelle en eau douce est faible comparativement à la réalimentation annuelle des aquifères. Ainsi, la quantité d’eau contenue dans les aquifères suffit aux besoins en eau potable actuels. Les ressources en eau souterraine et les réseaux d'exploitation actuels semblent suffisants pour les besoins futurs de la municipalité selon les projections en 2050 de la hausse de la consommation et de la diminution du volume d’eau disponible causée par les changements climatiques

Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer

Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. We identified patients who were PD-(L)1-naïve with advanced non-small-cell lung cancer from two institutions-Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center-who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti-PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non-small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended

Nasopharyngeal Bacterial Colonization and Gene Polymorphisms of Mannose-Binding Lectin and Toll-Like Receptors 2 and 4 in Infants

BACKGROUND: Human nasopharynx is often colonized by potentially pathogenic bacteria. Gene polymorphisms in mannose-binding lectin (MBL), toll-like receptor (TLR) 2 and TLR4 have been reported. The present study aimed to investigate possible association between nasopharyngeal bacterial colonization and gene polymorphisms of MBL, TLR2 and TLR4 in healthy infants. METHODOLOGY/PRINCIPAL FINDINGS: From August 2008 to June 2010, 489 nasopharyngeal swabs and 412 blood samples were taken from 3-month-old healthy Finnish infants. Semi-quantitative culture was performed and pyrosequencing was used for detection of polymorphisms in MBL structural gene at codons 52, 54, and 57, TLR2 Arg753Gln and TLR4 Asp299Gly. Fifty-nine percent of subjects were culture positive for at least one of the four species: 11% for Streptococcus pneumoniae, 23% for Moraxella catarrhalis, 1% for Haemophilus influenzae and 25% for Staphylococcus aureus. Thirty-two percent of subjects had variant types in MBL, 5% had polymorphism of TLR2, and 18% had polymorphism of TLR4. Colonization rates of S. pneumoniae and S. aureus were significantly higher in infants with variant types of MBL than those with wild type (p = .011 and p = .024). Colonization rates of S. aureus and M. catarrhalis were significantly higher in infants with polymorphisms of TLR2 and of TLR4 than those without (p = .027 and p = .002). CONCLUSIONS: Our study suggests that there is an association between nasopharyngeal bacterial colonization and genetic variation of MBL, TLR2 and TLR4 in young infants. This finding supports a role for these genetic variations in susceptibility of children to respiratory infections

Acquired Resistance to KRAS (G12C) Inhibition in Cancer

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C) -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)

TRAIL/TRAIL Receptor System and Susceptibility to Multiple Sclerosis

The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values<0.05 were successfully replicated: rs4894559 in TRAIL gene, p = 9.8×10−4, OR = 1.34; rs4872077, in TRAILR-1 gene, p = 0.005, OR = 1.72; and rs1001793 in TRAILR-2 gene, p = 0.012, OR = 0.84. The combination of the alleles G/T/A in these SNPs appears to be associated with a reduced risk of developing MS (p = 2.12×10−5, OR = 0.59). These results suggest that genes of the TRAIL/TRAIL receptor system exerts a genetic influence on MS