Cellular Robustness Conferred by Genetic Crosstalk Underlies Resistance against Chemotherapeutic Drug Doxorubicin in Fission Yeast

10.1371/journal.pone.0055041PLoS ONE81

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

Spin defects in hBN assisted by metallic nanotrenches for quantum sensing

The omnipresence of hexagonal boron nitride (hBN) in devices embedding two-dimensional materials has prompted it as the most sought after platform to implement quantum sensing due to its testing while operating capability. The negatively charged boron vacancy (VB-) in hBN plays a prominent role, as it can be easily generated while its spin population can be initialized and read out by optical means at room-temperature. But the lower quantum yield hinders its widespread use as an integrated quantum sensor. Here, we demonstrate an emission enhancement amounting to 400 by nanotrench arrays compatible with coplanar waveguide (CPW) electrodes employed for spin-state detection. By monitoring the reflectance spectrum of the resonators as additional layers of hBN are transferred, we have optimized the overall hBN/nanotrench optical response, maximizing thereby the luminescence enhancement. Based on these finely tuned heterostructures, we achieved an enhanced DC magnetic field sensitivity as high as 6 × 10-5 T/Hz1/2.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Submitted/Accepted versionThis research is supported by the National Research Foundsation, Singapore, and A*STAR under its Quantum Engineering Programme (No. NRF2021-QEP2-03-P09, NRF2021-QEP2-01-P02, NRF2021-QEP2-01-P01, NRF2021-QEP2-03-P01, No. NRF2021-QEP2-03-P10, NRF2022-QEP2-02-P13) and IRG programme (M21K2c0116)

Diagrammatic representation that depicts synergistic relationship between the nuclear, mitochondrial and endosomal membrane transporter genes.

<p>Lines with double arrow heads represent synthetic growth defect exhibited by the double mutants in different subcellular locations indicative of a synergistic relationship between components at these locations. Within the nucleus, chromatin modulating factors that act in similar epistatic group are joined by bold lines and these factors generally function in parallel to the DASH complex (dotted line). ‘?’ indicates undefined link between DASH and HR (Rhp55) factors. The composite crosstalk between the factors acting within and between each cellular compartment contributes to the resistance against DOXO in fission yeast.</p

Synergistic effect between the nuclear, mitochondrial and membrane transport pathways to counteract DOXO cytotoxicity.

<p>Genetic interaction between the genes encoding membrane transporters (<i>Δrav1</i> and <i>Δpmd1</i>) and (A) HR (<i>Δrhp55</i>), (B) Ino80 (<i>Δiec1</i>), and DASH subunits (<i>Δdad3</i> or <i>Δdad5</i>). Genetic interaction between mitochondrial coenzyme Q biosynthesis enzyme <i>(Δcoq2</i>) and (C) HR (<i>Δrhp55</i>), and (D) DASH subunit (<i>Δdad3</i>). All of the mutant pairs showed prominent synthetic growth defect, except <i>Δrhp55Δrav1</i> of which the synthetic growth defect was weak and masked by the strong drug-independent growth defect of the DM.</p

Cytotoxicity of wild-type and <i>Δrav1</i> cells to concentrations of DOXO ranging from 0 to 300

<p> <b>µg/ml.</b> Exponentially-growing cells were treated with the indicated level of DOXO for 4 hours. Cell viability was estimated by the number of colonies that was formed after seven day incubation from 200 cells plated on rich media without drug, and expressed as a proportion to the untreated sample. Wild-type cells did not show decrease in viability over the range tested, while <i>Δrav1</i> showed >50% loss in viability at 75 µg/ml.</p

Functional crosstalk shown by the genetic interaction between nuclear DXR factors.

<p>(A) Genetic interaction between mutants of DASH complex (<i>Δdad2</i>, <i>Δdad3</i>, and <i>Δdad5</i>) and HR genes (<i>Δrhp54</i> and <i>Δrhp55</i>). (B) Mutant of Ino80 subunit <i>Δiec1</i> showed synthetic negative effect with that of DASH mutant <i>Δdad3</i>. (C) Ino80 mutant <i>Δiec1</i> showed no synthetic growth defect with the HR mutants <i>Δrhp54</i> and <i>Δrhp55</i> suggesting that Ino80 function in the same pathway with HR genes to modulate resistance to DOXO. (D) Lack of synthetic growth defect between Ino80 mutant <i>Δiec1</i> and that of the single-stranded DNA binding protein Ssb3.</p

Functional classification and sub-cellular localization of DXR factors.

<p>(A) DXR factors were classified into 11 ontological groups. Vertical axis indicates the number of genes in each class. (B) Model of molecular mechanism for DOXO resistance in fission yeast. Cooperation of chromosome associated complexes that remodel and coordinate proper response to DNA damage were probably required for precise management of DOXO-induced DNA lesions. In addition, mitochondrial function and membrane transporters localized to various cell compartments that control intracellular accumulation of DOXO also determined the sensitivity of cells to the drug. Several factors including the COP9-Signalosome may facilitate repair of DOXO lesion via regulation of nucleotide synthesis.</p

Workflow of the screening procedure to uncover genes required for DOXO resistance (DXR).

<p>A total of 3225 strains made up of 2997 strains from Bioneer ver2.0 library and 228 unique backcrossed strains from ver1.0 were screened. Each of the auxotrophic ver2.0 strains was serially diluted and manually spotted on 75 µg/ml DOXO and 116 strains were found to be repeatedly showing hypersensitivity on DOXO. These strains were backcrossed with prototrophic wild-type cells to remove all the nutrition marker mutations in the Bioneer strains in order to link the DOXO hypersensitive phenotypes to the indicated null mutations. 91 strains that showed hypersensitivity to various level of DOXO were obtained finally.</p