PrkA controls peptidoglycan biosynthesisthrough the essential phosphorylation ofReoM

Peptidoglycan (PG) is the main component of bacterial cell walls and the target formany antibiotics. PG biosynthesis is tightly coordinated with cell wall growth and turnover, andmany of these control activities depend upon PASTA-domain containing eukaryotic-like serine/threonine protein kinases (PASTA-eSTK) that sense PG fragments. However, only a few PGbiosynthetic enzymes are direct kinase substrates. Here, we identify the conserved ReoM proteinas a novel PASTA-eSTK substrate in the Gram-positive pathogenListeria monocytogenes. Our datashow that the phosphorylation of ReoM is essential as it controls ClpCP-dependent proteolyticdegradation of the essential enzyme MurA, which catalyses the first committed step in PGbiosynthesis. We also identify ReoY as a second novel factor required for degradation of ClpCPsubstrates. Collectively, our data imply that the first committed step of PG biosynthesis is activatedthrough control of ClpCP protease activity in response to signals of PG homeostasis imbalance.Peer Reviewe

Metallothionein-I/II expression associates with the astrocyte DNA damage response and not Alzheimer-type pathology in the ageing brain

Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer’s disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro- and anti-oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti-oxidants including metallothionein-I and –II (MT-I/II). In the present study we characterized the immunoreactive profile of MT-I/II in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) aging population-representative neuropathology cohort, and examined H2O2-modulation of MT transcription by human astrocytes. MT-I/II is primarily expressed by astrocytes in the aging brain, but is also associated with pyramidal neurons in a small proportion of cases. Astrocyte expression of MT-I/II does not correlate with Alzheimer-type pathology (Aβ plaques and neurofibrillary tangles) but does relate to astrocyte oxidative DNA damage (rs= 0.312, p= 0.006) and the astrocyte response to oxidative DNA damage in vivo (rs= 0.238, p= 0.04), and MT gene expression is significantly induced in human astrocytes response to oxidative stress in vitro (p=0.01). In contrast, neuronal MT-I/II does not relate to oxidative DNA damage or the neuronal DNA damage response, but is significantly higher in cases with high levels of local tangle pathology (p=0.007). As MT-I/II is neuroprotective against oxidative stress, modulation of MT-I/II expression is a potential therapeutic target to treat the onset and progression of cognitive impairment

The structure of protostellar envelopes derived from submillimeter continuum images

High dynamic range imaging of submillimeter dust emission from the envelopes of eight young protostars in the Taurus and Perseus star-forming regions has been carried out using the SCUBA submillimeter camera on the James Clerk Maxwell Telescope. Good correspondence between the spectral classifications of the protostars and the spatial distributions of their dust emission is observed, in the sense that those with cooler spectral energy distributions also have a larger fraction of the submillimeter flux originating in an extended envelope compared with a disk. This results from the cool sources having more massive envelopes rather than warm sources having larger disks. Azimuthally-averaged radial profiles of the dust emission are used to derive the power-law index of the envelope density distributions, p (defined by rho proportional to r^-p), and most of the sources are found to have values of p consistent with those predicted by models of cloud collapse. However, the youngest protostars in our sample, L1527 and HH211-mm, deviate significantly from the theoretical predictions, exhibiting values of p somewhat lower than can be accounted for by existing models. For L1527 heating of the envelope by shocks where the outflow impinges on the surrounding medium may explain our result. For HH211-mm another explanation is needed, and one possibility is that a shallow density profile is being maintained in the outer envelope by magnetic fields and/or turbulence. If this is the case star formation must be determined by the rate at which the support is lost from the cloud, rather than the hydrodynamical properties of the envelope, such as the sound speed.Comment: Accepted for publication in the Astrophysical Journa

Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach

Structure-guided expansion of a fragment hit for the ATAD2 bromodomain enabled improvement in ATAD2 inhibition and selectivity over BRD4.</p

Perceptions of nurse practitioners by emergency department doctors in Australia

BACKGROUND: The Australian Medical Association is strongly opposed to the nurse practitioner (NP) role with concerns that NPs may become doctor substitutes without the requisite training and education that the medical role demands. Despite this, NPs have been heralded by some as a potential solution to the access block, workforce shortage and increased demand affecting emergency departments (EDs). AIMS: The purpose of this study was to determine the perception of NPs by medical staff working in Australian EDs. METHODS: Semi-structured telephone interviews were conducted with closed and open-ended questions. Participants were drawn from a representative stratified sample of two city, two metropolitan and two provincial hospitals of each State/Territory. RESULTS: A total of 95 doctors from 35 EDs participated in this study including 36 Departmental Directors; 36% of participating Directors indicated having an NP on staff. Doctors were strongly opposed to the statement that NPs could replace either nurses or other prevocational doctors; 71 interviewees commented on the role of NPs in the ED. Thematic analyses revealed polarised views held by doctors. Eight major themes were identified, the most common being that there is a lack of clarity of the NP role definition, their scope of practice and differentiation from the medical role. CONCLUSION: Although ED NPs represent a highly skilled professional group their role is poorly understood by ED doctors. Opposition to the NP role is a significant barrier to the introduction of great numbers of ED NPs as a strategy to overcome the medical workforce shortage. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12245-010-0214-8) contains supplementary material, which is available to authorized users

Effectiveness and cost-effectiveness of psychiatric mother and baby units: quasi-experimental study

BACKGROUND: Psychiatric mother and baby units (MBUs) are recommended for severe perinatal mental illness, but effectiveness compared with other forms of acute care remains unknown. AIMS: We hypothesised that women admitted to MBUs would be less likely to be readmitted to acute care in the 12 months following discharge, compared with women admitted to non-MBU acute care (generic psychiatric wards or crisis resolution teams (CRTs)). METHOD: Quasi-experimental cohort study of women accessing acute psychiatric care up to 1 year postpartum in 42 healthcare organisations across England and Wales. Primary outcome was readmission within 12 months post-discharge. Propensity scores were used to account for systematic differences between MBU and non-MBU participants. Secondary outcomes included assessment of cost-effectiveness, experience of services, unmet needs, perceived bonding, observed mother-infant interaction quality and safeguarding outcome. RESULTS: Of 279 women, 108 (39%) received MBU care, 62 (22%) generic ward care and 109 (39%) CRT care only. The MBU group (n = 105) had similar readmission rates to the non-MBU group (n = 158) (aOR = 0.95, 95% CI 0.86-1.04, P = 0.29; an absolute difference of -5%, 95% CI -14 to 4%). Service satisfaction was significantly higher among women accessing MBUs compared with non-MBUs; no significant differences were observed for any other secondary outcomes. CONCLUSIONS: We found no significant differences in rates of readmission, but MBU advantage might have been masked by residual confounders; readmission will also depend on quality of care after discharge and type of illness. Future studies should attempt to identify the effective ingredients of specialist perinatal in-patient and community care to improve outcomes

Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings. Keywords: children; cystic fibrosis; elexacaftor; ivacaftor; tezacaftor

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Examining the validity and utility of two secondary sources of food environment data against street audits in England

Background: Secondary data containing the locations of food outlets is increasingly used in nutrition and obesity research and policy. However, evidence evaluating these data is limited. This study validates two sources of secondary food environment data: Ordnance Survey Points of Interest data (POI) and food hygiene data from the Food Standards Agency (FSA), against street audits in England and appraises the utility of these data. Methods: Audits were conducted across 52 Lower Super Output Areas in England. All streets within each Lower Super Output Area were covered to identify the name and street address of all food outlets therein. Audit-identified outlets were matched to outlets in the POI and FSA data to identify true positives (TP: outlets in both the audits and the POI/FSA data), false positives (FP: outlets in the POI/FSA data only) and false negatives (FN: outlets in the audits only). Agreement was assessed using positive predictive values (PPV: TP/(TP+FP)) and sensitivities (TP/(TP+FN)). Variations in sensitivities and PPVs across environment and outlet types were assessed using multi-level logistic regression. Proprietary classifications within the POI data were additionally used to classify outlets, and agreement between audit-derived and POI-derived classifications was assessed. Results: Street audits identified 1172 outlets, compared to 1100 and 1082 for POI and FSA respectively. PPVs were statistically significantly higher for FSA (0.91, CI: 0.89-0.93) than for POI (0.86, CI: 0.84-0.88). However, sensitivity values were not different between the two datasets. Sensitivity and PPVs varied across outlet types for both datasets. Without accounting for this, POI had statistically significantly better PPVs in rural and affluent areas. After accounting for variability across outlet types, FSA had statistically significantly better sensitivity in rural areas and worse sensitivity in rural middle affluence areas (relative to deprived). Audit-derived and POI-derived classifications exhibited substantial agreement (p < 0.001; Kappa = 0.66, CI: 0.63 - 0.70). Conclusions: POI and FSA data have good agreement with street audits; although both datasets had geographic biases which may need to be accounted for in analyses. Use of POI proprietary classifications is an accurate method for classifying outlets, providing time savings compared to manual classification of outlets

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