Identification of new DNA i-motif binding ligands through a fluorescent intercalator displacement assay

i-Motifs are quadruplex DNA structures formed from sequences rich in cytosine and held together by intercalated, hemi-protonated cytosine–cytosine base pairs. These sequences are prevalent in gene promoter regions and may play a role in gene transcription. Targeting these structures with ligands could provide a novel way to target genetic disease but there are very few ligands which have been shown to interact with i-motif DNA. Fluorescent intercalator displacement (FID) assays are a simple way to screen ligands against DNA secondary structures. Here we characterise how thiazole orange interacts with i-motif DNA and assess its ability for use in a FID assay. Additionally, we report FID-based ligand screening using thiazole orange against the i-motif forming sequence from the human telomere to reveal new i-motif binding compounds which have the potential for further development

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

Global Spatial Risk Assessment of Sharks Under the Footprint of Fisheries

Effective ocean management and conservation of highly migratory species depends on resolving overlap between animal movements and distributions and fishing effort. Yet, this information is lacking at a global scale. Here we show, using a big-data approach combining satellite-tracked movements of pelagic sharks and global fishing fleets, that 24% of the mean monthly space used by sharks falls under the footprint of pelagic longline fisheries. Space use hotspots of commercially valuable sharks and of internationally protected species had the highest overlap with longlines (up to 76% and 64%, respectively) and were also associated with significant increases in fishing effort. We conclude that pelagic sharks have limited spatial refuge from current levels of high-seas fishing effort. Results demonstrate an urgent need for conservation and management measures at high-seas shark hotspots and highlight the potential of simultaneous satellite surveillance of megafauna and fishers as a tool for near-real time, dynamic management

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

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale

Simultaneous permeation of tamoxifen and gamma linolenic acid across excised human skin. Further evidence of the permeation of solvated complexes

Tamoxifen is the hormonal treatment of choice in women who have hormone-dependent breast cancer and its efficacy in those women considered to have a high risk of developing breast cancer, has also been established. Gamma linolenic acid (GLA) has been shown to decrease the invasion of breast cancer and recent studies have demonstrated that GLA can enhance the oestrogen receptor down-regulation induced by tamoxifen. However, tamoxifen is associated with serious side-effects due mainly to systemic delivery, and targeted delivery of both tamoxifen and GLA would be highly beneficial. This work was a preliminary study for the development of a transcutaneous system to simultaneously deliver both tamoxifen and GLA directly to the breast. Full thickness human skin was dosed with 500 microl saturated solution of tamoxifen in borage oil (25% GLA) and the simultaneous permeation of the two actives determined. There was rapid flux with minimal lag time, the cumulative permeation at 24 h was 764.3 +/- 94.2 microg cm(-2) for GLA and 5.44 +/- 0.67 microg cm(-2) for tamoxifen: the latter being comparable to the amount of tamoxifen associated with cancerous breast tissue from a 20 mg oral dose. The ratio of GLA/tamoxifen permeated at different timepoints was quite consistent, both in terms of mass (mean 138, S.D. 15.1) and mols (mean 184, S.D. 20.3). It was determined that 2.5 molecules of GLA were associated with each molecule of tamoxifen in the permeation process, equating to a solvation cage of three molecules of triacylglycerol. This study has demonstrated the feasibility of administering simultaneously tamoxifen and GLA using borage oil as vehicle, which warrants further investigation as a novel topical two-component system in relation to or prophylaxis of those perceived at high risk of developing breast cancer. The study also provides further evidence of the permeation of solvated complexes across skin, rather than discrete penetrant molecules

Using antimicrobial surgihoney to prevent caesarean wound infection

Caesarean section (CS) wound infection rates are unacceptably high; around 10% according to figures from the Health Protection Agency (2012). This service evaluation assessed the effects of Surgihoney on surgical site infection rates in women undergoing caesarean section. All women presenting for CS were offered Surgihoney as a single application wound dressing at the end of the procedure. All women were followed up and examined for surgical site infection for 30 days after CS. A single application of Surgihoney dressing reduced surgical site infection (SSI) by 60.33% from a rate of 5.42% (n=590) to 2.15% (n=186) (p-value=0.042). The potential saving to the NHS of using Surgihoney as a single application achieving this level of wound infection reduction is considerable. Surgihoney offers a simple, costeffective intervention to reduce SSI in women undergoing CS. It is applicable to practice in all health economies and could potentially save considerable surgical infective morbidity in patients undergoing surgical delivery.</p

Person-centred rhetoric in chronic care: A review of health policies

Baldwin, AE ORCiD: 0000-0002-6325-4142; Byrne, AJ ORCiD: 0000-0002-8679-8310; Harvey, CL ORCiD: 0000-0001-9016-8840; Willis, EM ORCiD: 0000-0001-7576-971XPurpose: The purpose of the paper is to explore how the national, state and organisational health policies in Australia support the implementation of person-centred care in managing chronic care conditions. Design/methodology/approach: A qualitative content analysis was performed regarding the national, state and organisational Queensland Health policies using Elo and Kyngas' (2008) framework. Findings: Although the person-centred care as an approach is well articulated in health policies, there is still no definitive measure or approach to embedding it into operational services. Complex funding structures and competing priorities of the governments and the health organisations carry the risk that person-centred care as an approach gets lost in translation. Three themes emerged: the patient versus the government; health care delivery versus the political agenda; and health care organisational processes versus the patient. Research limitations/implications: Given that person-centred care is the recommended approach for responding to chronic health conditions, further empirical research is required to evaluate how programs designed to deliver person-centred care achieve that objective in practice. Practical implications: This research highlights the complex environment in which the person-centred approach is implemented. Short-term programmes created specifically to focus on person-centred care require the right organisational infrastructure, support and direction. This review demonstrates the need for alignment of policies related to chronic disease management at the broader organisational level. Originality/value: Given the introduction of the nurse navigator program to take up a person-centred care approach, the review of the recent policies was undertaken to understand how they support this initiative. © 2020, Emerald Publishing Limited

Person-centred rhetoric in chronic care: A review of health policies

Purpose: The purpose of the paper is to explore how the national, state and organisational health policies in Australia support the implementation of person-centred care in managing chronic care conditions. Design/methodology/approach: A qualitative content analysis was performed regarding the national, state and organisational Queensland Health policies using Elo and Kyngas' (2008) framework. Findings: Although the person-centred care as an approach is well articulated in health policies, there is still no definitive measure or approach to embedding it into operational services. Complex funding structures and competing priorities of the governments and the health organisations carry the risk that person-centred care as an approach gets lost in translation. Three themes emerged: the patient versus the government; health care delivery versus the political agenda; and health care organisational processes versus the patient. Research limitations/implications: Given that person-centred care is the recommended approach for responding to chronic health conditions, further empirical research is required to evaluate how programs designed to deliver person-centred care achieve that objective in practice. Practical implications: This research highlights the complex environment in which the person-centred approach is implemented. Short-term programmes created specifically to focus on person-centred care require the right organisational infrastructure, support and direction. This review demonstrates the need for alignment of policies related to chronic disease management at the broader organisational level. Originality/value: Given the introduction of the nurse navigator program to take up a person-centred care approach, the review of the recent policies was undertaken to understand how they support this initiative. © 2020, Emerald Publishing Limited