Critical knowledge gaps and research needs related to the environmental dimensions of antibiotic resistance

There is growing understanding that the environment plays an important role both in the transmission of antibiotic resistant pathogens and in their evolution. Accordingly, researchers and stakeholders world-wide seek to further explore the mechanisms and drivers involved, quantify risks and identify suitable interventions. There is a clear value in establishing research needs and coordinating efforts within and across nations in order to best tackle this global challenge. At an international workshop in late September 2017, scientists from 14 countries with expertise on the environmental dimensions of antibiotic resistance gathered to define critical knowledge gaps. Four key areas were identified where research is urgently needed: 1) the relative contributions of different sources of antibiotics and antibiotic resistant bacteria into the environment; 2) the role of the environment, and particularly anthropogenic inputs, in the evolution of resistance; 3) the overall human and animal health impacts caused by exposure to environmental resistant bacteria; and 4) the efficacy and feasibility of different technological, social, economic and behavioral interventions to mitigate environmental antibiotic resistance.(1)Peer reviewe

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Prevalencia de portadores nasales de Staphylococcus aureus y Streptococcus pneumoniae en atención primaria y factores asociados a la colonización [Prevalence of nasal carriage of Staphylococcus aureus and Streptococcus pneumoniae in Primary Care and factors associated with colonization.]

OBJECTIVE: To determine (i) the prevalence of Staphylococcus aureus (S.aureus) and Streptococcus pneumoniae (S.pneumoniae) nasal carriage in Primary Health Care patients in area of Barcelona, and (ii) the factors associated with S.aureus and S.pneumoniae colonization. METHODS: Multi-center cross-sectional study conducted in 2010-2011 with the participation of 27 Primary Health Care professionals. Nasopharyngeal swabs were obtained from 3,969 patients over 4 years of age who did not present with any sign of infection. Dependent variables: S.aureus and/or S.pneumoniae carrier state. Independent variables: socio-demographic characteristics, health status, vaccination status, occupation, and living with children. A descriptive analysis was performed. The prevalence of carriers of S.aureus and/or S.pneumoniae was calculated and logistic regression models were adjusted by age. RESULTS: In children from 4 to 14 years old, the prevalence of S.aureus carriers was 35.7%, of S.pneumoniae 27.1%, and 5.8% were co-colonized. In adults older than 14 years old, the prevalence was 17.8%, 3.5%, and 0.5%, respectively. In children, S.aureus carrier state was inversely associated with S.pneumoniae carrier state; S.pneumoniae was associated with younger age, and inversely associated with S.aureus carrier state. In adults, being a carrier of S.aureus was associated with male gender, younger age, and a health-related occupation, whereas S.pneumoniae carrier state was associated with living with children under 6 years of age. The proportion of co-colonized carriers was low (1.0%). CONCLUSIONS: The proportion of S.aureus and S.pneumoniae carriers was higher in children than in adults. Age was the only factor associated with healthy carrier status for S.aureus and for S.pneumoniae

Birth outcomes and infant mortality among First Nations Inuit, and non-Indigenous women by northern versus southern residence, Quebec

Background: In circumpolar countries such as Canada, northern regions represent a unique geographical entity climatically, socioeconomically and environmentally. There is a lack of comparative data on birth outcomes among Indigenous and non-Indigenous subpopulations within northern regions and compared with southern regions. Methods: A cohort study of all births by maternal mother tongue to residents of northern (2616 First Nations (North American Indians), 2388 Inuit and 5006 non-Indigenous) and southern (2563 First Nations, 810 643 non-Indigenous) Quebec, 1991-2000. Results: Compared with births to southern non-Indigenous mother tongue women, births to northern women of all three mother tongue groups were at substantially elevated risks of infant death (adjusted OR (aOR) 1.7-2.9), especially postneonatal death (aOR 2.2-4.4) after controlling for maternal education, age, marital status and parity. The risk elevation in perinatal death was greater for southern First Nations (aOR 1.6) than for northern First Nations (aOR 1.2). Infant macrosomia was highly prevalent among First Nations in Quebec, especially in the north (31% vs 24% in the south). Within northern regions, Inuit births were at highest risk of preterm delivery (aOR 1.4) and infant death (aOR 1.6). Conclusion: All northern infants (First Nations, Inuit or non-Indigenous) were at substantially elevated risk of infant death in Quebec, despite a universal health