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

10.1371/journal.pone.0055041PLoS ONE81

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

Periprocedural care for frail older patients with aortic stenosis undergoing transcatheter aortic valve replacement

Degenerative aortic stenosis (AS) is an aging-associated disease with alarmingly high mortality that has risen in prevalence in tandem with the global population aging. Treatment options for AS are currently limited to surgical or percutaneous valve intervention, which are associated with significant morbidity. It is increasingly recognized that the care of AS patients is frequently constrained by concomitant frailty, an under-recognized syndrome among older individuals. Many AS patients have concurrent aging-associated diseases, including atherosclerotic diseases, organ impairment, physical frailty, and nutritional deficiencies which limit functional improvement after valve intervention. It has become increasingly crucial for clinicians to address these concurrent issues in frail, older individuals with AS to achieve the best possible outcomes. We aim to review the well-studied relationship between frailty and AS, as well as possible strategies for periprocedural optimization and risk management

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)

Prototrophic DXR haploid deletion strains showed differential sensitivity to DOXO.

<p>Hypersensitivity demonstrated by DXR strains at (A) 75 µg/ml, (B) 165 µg/ml and (C) 310 µg/ml DOXO. Exponentially growing prototrophic strains were ten-fold serially diluted and individually spotted on DOXO-containing plates.</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

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

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