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 Role For Dna Replication And Repair Genes In Germ-Line Maintenance And Tumor Suppression

: Faithful DNA replication and repair of DNA damage is important for prevention of disease and birth defects. My thesis work utilized reverse and forward genetic approaches to identify novel genes involved in these processes. In one set of studies, I investigated the function of MCM9, a protein specific to multicellular eukaryotes that is related to subunits of the DNA replicative helicase. Utilizing multiple mouse disruption alleles, I have shown MCM9 is dispensable for DNA replication, however it has a role in germ-line stem cell maintenance and/or proliferation. Additionally, in the soma, Mcm9 mutation leads to increased cancer susceptibility, particularly hepatocellular carcinoma in males. The phenotypes of MCM9 mutant mice and cells suggest that MCM9 evolved a specialized but nonessential role in DNA replication or replication-linked quality-control mechanisms. In a second set of studies, I identified a hypomorphic allele of Fancm in a forward genetic screen for GIN mutations in mice. Fancm is a member of the Fanconi Anemia complementation group and facilitates repair of lesions at the DNA replication fork. Similar to Mcm9, Fancm is required for producing a normal germ-line stem cell pool and for tumor suppression in the soma. Together, these genetic studies underscore the importance of accurate DNA replication and repair of replication-associated damage in mammalian reproduction and cancer

Random mutagenesis of proximal mouse chromosome 5 uncovers predominantly embryonic lethal mutations

A region-specific ENU mutagenesis screen was conducted to elucidate the functional content of proximal mouse Chr 5. We used the visibly marked, recessive, lethal inversion Rump White (Rw) as a balancer in a three-generation breeding scheme to identify recessive mutations within the ∼50 megabases spanned by Rw. A total of 1003 pedigrees were produced, representing the largest inversion screen performed in mice. Test-class animals, homozygous for the ENU-mutagenized proximal Chr 5 and visibly distinguishable from nonhomozygous littermates, were screened for fertility, hearing, vestibular function, DNA repair, behavior, and dysmorphology. Lethals were identifiable by failure to derive test-class animals within a pedigree. Embryonic lethal mutations (total of 34) were overwhelmingly the largest class of mutants recovered. We characterized them with respect to the time of embryonic death, revealing that most act at midgestation (8.5–10.5) or sooner. To position the mutations within the Rw region and to guide allelism tests, we performed complementation analyses with a set of new and existing chromosomal deletions, as well as standard recombinational mapping on a subset of the mutations. By pooling the data from this and other region-specific mutagenesis projects, we calculate that the mouse genome contains ∼3479–4825 embryonic lethal genes, or about 13.7%–19% of all genes

Hypersensitivity of Primordial Germ Cells to Compromised Replication-Associated DNA Repair Involves ATM-p53-p21 Signaling

<div><p>Genome maintenance in germ cells is critical for fertility and the stable propagation of species. While mechanisms of meiotic DNA repair and chromosome behavior are well-characterized, the same is not true for primordial germ cells (PGCs), which arise and propagate during very early stages of mammalian development. Fanconi anemia (FA), a genomic instability syndrome that includes hypogonadism and testicular failure phenotypes, is caused by mutations in genes encoding a complex of proteins involved in repair of DNA lesions associated with DNA replication. The signaling mechanisms underlying hypogonadism and testicular failure in FA patients or mouse models are unknown. We conducted genetic studies to show that hypogonadism of <i>Fancm</i> mutant mice is a result of reduced proliferation, but not apoptosis, of PGCs, resulting in reduced germ cells in neonates of both sexes. Progressive loss of germ cells in adult males also occurs, overlaid with an elevated level of meiotic DNA damage. Genetic studies indicated that ATM-p53-p21 signaling is partially responsible for the germ cell deficiency.</p></div

The <i>Chaos4</i> allele is a point mutation in <i>Fancm</i>.

<p>(A) Flow cytometric analysis of erythrocytes to quantify red blood cells (RBC) with micronuclei. (B) Genetic mapping of <i>Chaos4</i> to a 9-Mb region of chromosome 12 containing <i>Fancm</i> between <i>rs13481482</i> and <i>D12Mit71</i>. (C). Sequence traces showing the T524C transversion (arrows) identified in the <i>Chaos4</i> allele of <i>Fancm</i>. (D) The <i>Chaos4</i> point mutation is in the first exon, and the <i>XH297</i> gene-trap is in the 14th exon. DEXDc, DEAD-like helicase domain; HELICc, Helicase superfamily c-terminal domain; ERCC4, ERCC4 endonuclease domain; HhH, Helix-hairpin-helix domain which interacts with FAAP24. Sequence alignment surrounding C142 is highly conserved from human to budding yeast. (E) SCE rates are significantly increased in <i>Fancm^C4/C4</i> MEFs (p<0.05).</p

<i>Fancm^C4/C4</i> MEFs undergo premature senescence, but are not sensitive to interstrand crosslinks.

<p>(A) MEF growth assays. (B) Immortalization timeline of primary MEFs using a 3T3 growth protocol. Cultures were passaged every 3 days.</p

Germ cell depletion in <i>Fancm^C4/C4</i> occurs before birth.

<p>Immunofluorescence of 1(A and B) and ovaries (C and D) of the indicated genotypes. <i>MVH</i> (green) stains germ cells and DAPI stains nuclei (blue). (E and F) Germ-cell counts at 1 dpp. Germ cell number is averaged on a per seminiferous tubule cross-section basis for males. Female counts correspond to the total from three medial sections. **, p<0.01; ***, p<0.001; Error bars indicate SD.</p

Hypogonadism and spermatogenesis defects in <i>Fancm</i> mutant males.

<p>(A,B) <i>Fancm^C4/C4</i> mice (12 weeks old) have smaller testes and lower epididymal sperm counts. (C–F) H&E-staining of testis sections of the indicated genotypes. Samples in panels C–D are from 16 week old males. Arrowhead points to a giant multinucleated cell. (*) indicates an example of a seminiferous tubule with abnormal spermatogenesis. Panels E and F are from 80-wk-old males. Most tubules in 80 week <i>Fancm^C4/C4</i> testes have only Sertoli cells. (G) Primordial follicles quantification in mutants. * p<0.05, ** p<0.01 n>10 for each genotype.</p