Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

The Conserved Role of METTL16 m6A Methyltransferase in Gene Expression Regulation

RNA modifications emerged recently as a new layer of post-transcriptional gene expression regulation. The most common internal messenger RNA (mRNA) modification is N6-methyladenosine (m6A). It is deposited on pre-mRNA by two methyltransferases: METTL3-METTL14 heterodimer and METTL16. METTL3/14 deposits most m6A in the cell and is essential for embryonic development in plants and animals. The role of METTL16 methyltransferase is much less understood. My research aimed to understand the role of METTL16 in gene expression regulation in mice and C. elegans. In this thesis, I show that METTL16 controls S-adenosylmethionine (SAM) synthetase pre-mRNA splicing both in mice and C. elegans and is essential for SAM levels regulation. In C. elegans, SAM synthetase pre-mRNA splicing is inhibited by deposition of m6A at the 3′ splice site (3’SS), preventing an essential splicing factor U2AF35 binding. Although SAM synthetase splicing is regulated differently in mammals, the mechanism of splicing inhibition by 3′SS m6A methylation is conserved. Thus, I propose that splice-site m6A is an ancient mechanism for splicing regulation

Wpływ mikroRNA-378a na właściwości fibroblastów i keratynocytów oraz proces gojenia ran u myszy

MikroRNA (miRNA, miR) to krótkie (20 – 23 nukleotydy), endogenne, jednoniciowe, niekodujące cząsteczki RNA biorące udział w potranskrypcyjnej regulacji ekspresji genów. Dotychczasowe badania opisały rolę miR-378a w regulacji procesów migracji i proliferacji komórek nowotworowych, tworzeniu naczyń krwionośnych w guzach nowotworowych czy regulacji apoptozy. Procesy te mają także kluczowe znaczenie dla prawidłowego przebiegu gojenia ran, sugerując, że miR-378a może mieć istotne znaczenie w tym procesie.Celem pracy było zbadanie wpływu miRNA-378a na właściwości fibroblastów i keratynocytów, kluczowych komórek dla gojenia ran, oraz porównanie tempa gojenia ran między myszami z brakiem miR-378a (miR-378a-/-) a myszami typu dzikiego (miR-378a+/+). Jako model badawczy zastosowano linię mysich fibroblastów (NIH/3T3) i ludzkich keratynocytów (HaCaT) z wyciszoną lub zwiększoną ekspresją miR-378a, jak również pierwotne keratynocyty i fibroblasty izolowane z myszy miR-378-/- i miR-378+/+. Ekspresję genów regulowanych przez miR-378a badano na poziomie mRNA i białka. Weryfikowano też zdolność wiązania miR-378a do sekwencji 3’UTR takich genów. Nie wykazano jednak istotnych różnic. Nie wykazano także efektu miR-378a na migrację komórek NIH/3T3 oraz HaCaT. Jednak, pomimo że proliferacja pierwotnych fibroblastów była podobna, niezależnie od genotypu, to komórki pozbawione miR-378a wykazywały wzmożoną migrację.U myszy niedobór miR-378a opóźniał proces gojenia ran. Stwierdzono brak różnic na poziomie białek pro-angiogennych, jednakże zaobserwowano różnice w poziomie cytokin i chemokin prozapalnych między ranami zwierząt miR-378-/- a miR-378+/+, co może sugerować udział stanu zapalnego w obserwowanym fenotypie. Nie zaobserwowano zależnych od genotypu zmian w ekspresji czynników proangiogennych (FGF-2, VEGF) w ranach, jednak wykazano pewien wzrost cytokin prozapalnych takich jak IL-6 czy TNF-α, co sugeruje rolę zapalenia w obserwowanym efekcie.Podsumowując, brak miR-378a prowadzi do obniżenia tempa rany gojenia ran in vivo, jednak ze względu na brak jednoznacznej odpowiedzi na temat jego wpływu na właściwości fibroblastów i keratynocytów konieczne są dalsze badania.MicroRNA (miRNA, miR) are short (20 – 23 nucleotides), endogenous, single-stranded, non-coding RNA molecules that function as post-transcriptional regulators of gene expression. Recent studies described a role of miR-378a in the processes of migration and proliferation of cancer cells, formation of new blood vessels in tumors or regulation of apoptosis. Those processes are crucial also for the proper course of wound healing, suggesting the potential role of miR-378a in the wound repair. The aim of this study was to check the influence of miR-378a on the properties of fibroblasts and keratinocytes, key cells involved in wound healing, and comparison of wound repair between mice lacking miR-378a (miR-378-/-) and wild type mice (miR-378+/+). As a model mouse fibroblasts (NIH/3T3) and human keratinocytes (HaCaT) cell lines with the downregulation or overexpression of miR-378a as well as primary fibroblasts and keratinocytes isolated from miR-378-/- and miR-378+/+ mice were used. The expression of several target genes was studied at the level of mRNA and protein. The binding of miR-378a to 3’UTR sequences was also tested. However, no significant differences were observed. Also no effect of miR-378a was observed on migration of NIH/3T3 or HaCaT cells. However, although proliferation rate was similar in primary fibroblasts independently of genotype, the migration of miR-378a-deficient cells was increased.In mice miR-378a deficiency delayed wound closure. No genotype-dependent difference was shown at the level of pro-angiogenic factors in the wounds, however, some pro-inflammatory cytokines such as IL-6 and TNF-α was higher in in the absence of miR-378a suggesting the possible role of inflammation in the observed process. To summarize, the lack of miR-378a leads to the decreased rate of wound healing in vivo, however because there is no clear answer about its role in the properties of fibroblasts and keratinocytes further studies are required

Nxf3: a middleman with the right connections for unspliced piRNA precursor export

RNA export is tightly coupled to splicing in metazoans. In the Drosophila germline, precursors for the majority of Piwi-interacting RNAs (piRNAs) are unspliced. In this issue of Genes &amp; Development , Kneuss and colleagues (pp. 1208–1220) identify Nxf3 as a novel germline-specific export adapter for such unspliced transcripts. Their findings reveal the sequence of events leading from its role at the site of transcription to delivery of the cargo to cytoplasmic piRNA biogenesis sites. </p

The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m⁶A recognition

The functional consequence of N6-methyladenosine (m6A) RNA modification is mediated by "reader" proteins of the YTH family. YTH domain-containing 2 (YTHDC2) is essential for mammalian fertility, but its molecular function is poorly understood. Here, we identify U-rich motifs as binding sites of YTHDC2 on 3' UTRs of mouse testicular RNA targets. Although its YTH domain is an m6A-binder in vitro, the YTH point mutant mice are fertile. Significantly, the loss of its 3'→5' RNA helicase activity causes mouse infertility, with the catalytic-dead mutation being dominant negative. Biochemical studies reveal that the weak helicase activity of YTHDC2 is enhanced by its interaction with the 5'→3' exoribonuclease XRN1. Single-cell transcriptomics indicate that Ythdc2 mutant mitotic germ cells transition into meiosis but accumulate a transcriptome with mixed mitotic/meiotic identity that fail to progress further into meiosis. Finally, our demonstration that ythdc2 mutant zebrafish are infertile highlights its conserved role in animal germ cell development

Methylation of Structured RNA by the m⁶A Writer METTL16 Is Essential for Mouse Embryonic Development

International audienceInternal modification of RNAs with N-6-methyladenosine (m(6)A) is a highly conserved means of gene expression control. While the METTL3/METTL14 heterodimer adds this mark on thousands of transcripts in a single-stranded context, the substrate requirements and physiological roles of the second m(6)A writer METTL16 remain unknown. Here we describe the crystal structure of human METTL16 to reveal a methyltransferase domain furnished with an extra N-terminal module, which together form a deep-cut groove that is essential for RNA binding. When presented with a random pool of RNAs, METTL16 selects for methylation-structured RNAs where the critical adenosine is present in a bulge. Mouse 16-cell embryos lacking MeTTL16 display reduced mRNA levels of its methylation target, the SAM synthetase Mat2a. The consequence is massive transcriptome dysregulation in similar to 64-cell blastocysts that are unfit for further development. This highlights the role of an m(6)A RNA methyltransferase in facilitating early development via regulation of SAM availability