Nutritional Control of DNA Replication Initiation through the Proteolysis and Regulated Translation of DnaA

Bacteria can arrest their own growth and proliferation upon nutrient depletion and under various stressful conditions to ensure their survival. However, the molecular mechanisms responsible for suppressing growth and arresting the cell cycle under such conditions remain incompletely understood. Here, we identify post-transcriptional mechanisms that help enforce a cell-cycle arrest in Caulobacter crescentus following nutrient limitation and during entry into stationary phase by limiting the accumulation of DnaA, the conserved replication initiator protein. DnaA is rapidly degraded by the Lon protease following nutrient limitation. However, the rate of DnaA degradation is not significantly altered by changes in nutrient availability. Instead, we demonstrate that decreased nutrient availability downregulates dnaA translation by a mechanism involving the 5' untranslated leader region of the dnaA transcript; Lon-dependent proteolysis of DnaA then outpaces synthesis, leading to the elimination of DnaA and the arrest of DNA replication. Our results demonstrate how regulated translation and constitutive degradation provide cells a means of precisely and rapidly modulating the concentration of key regulatory proteins in response to environmental inputs.National Institutes of Health (U.S.) (Grant 5R01GM082899

Undergraduate teaching of surgical skills in the UK: systematic review

Background: Students must be proficient in surgical skills according to General Medical Council and Royal College of Surgeons of England guidelines. If these skills are not appropriately taught, there is a risk of an incoming junior workforce with inadequate surgical skills. This paper aimed to review the literature relating to undergraduate teaching of surgical skills in the UK and summarize future suggested training methods. Methods: The databases MEDLINE, Embase and SCOPUS were searched, and the existing literature relating to methodology of undergraduate teaching of surgical skills in the UK over the past 10 years was summarized. The Medical Education Research Quality Instrument was used to assess research quality. Results: A total of 19 papers were included. Cross-sectional evaluations and survey-based studies highlight a clear deficit in surgical skills teaching in the UK. Medical students are currently unable to fulfil their own learning needs and meet requirements set out by the General Medical Council. This lack of surgical teaching appears to negatively affect student desire to pursue a surgical career. The three main themes for improvement are extracurricular surgical skills days, near-peer teaching and simulation. Each method appeared to improve learning, although no studies utilized medium- to long-term follow-up to demonstrate efficacy and there lacks a clear consensus as to the ‘standard’ of undergraduate surgical skill education. There was also potential for selection bias and response shift bias in many of the studies assessing pre- and postintervention confidence and opinions. Conclusion: There is a concerning lack of surgical skills teaching that has resulted in medical students and junior doctors not having the necessary surgical skills as per General Medical Council guidance and students feel that their own learning needs are not met. This failure to address the learning deficit may be responsible for the fall in surgical competition ratios. While surgical skills teaching must be improved urgently, more robust evidence is required to evaluate the optimal ways of approaching this issue

Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489]

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and tolerability of etoricoxib, a COX-2 selective inhibitor, in osteoarthritis (OA) patients. METHODS: A double-blind, randomized, multicenter study was conducted in 617 patients with OA of the knee. The base study was 14 weeks in duration and consisted of 2 parts; in Part I (6 weeks), patients were allocated to once daily oral etoricoxib 5, 10, 30, 60, 90 mg or placebo. In Part II (8 weeks); the placebo, etoricoxib 5 and 10 mg groups were reallocated to etoricoxib 30, 60, or 90 mg qd or diclofenac 50 mg t.i.d. Treatment was continued for consecutive 12 and 26 week extensions. Primary efficacy endpoints were the WOMAC VA 3.0 pain subscale and investigator global assessment of disease status. Safety and tolerability were assessed by collecting adverse events throughout the study. RESULTS: Compared with placebo, the etoricoxib groups displayed significant (p < 0.05), dose-dependent efficacy for all primary endpoints in Part I; efficacy was maintained throughout the 52 weeks of the study. During the 46-week active-comparator controlled period, the etoricoxib groups demonstrated clinical efficacy that was similar to that of diclofenac 150 mg and was generally well tolerated, with a lower incidence of gastrointestinal (GI) nuisance symptoms compared with diclofenac (13.1, 14.7, and 13.5% for etoricoxib 30, 60, and 90 mg, respectively compared with 22.5% for diclofenac). CONCLUSION: In this extension study, etoricoxib, at doses ranging from 30 to 90 mg, demonstrated a maintenance of significant clinical efficacy in patients with OA through 52 weeks of treatment. Etoricoxib displayed clinical efficacy similar to diclofenac 150 mg and was generally well tolerated

The Ginninderra CH4 and CO2 release experiment: An evaluation of gas detection and quantification techniques

A methane (CH4) and carbon dioxide (CO2) release experiment was held from April to June 2015 at the Ginninderra Controlled Release Facility in Canberra, Australia. The experiment provided an opportunity to compare different emission quantification techniques against a simulated CH4 and CO2 point source release, where the actual release rates were unknown to the participants. Eight quantification techniques were assessed: three tracer ratio techniques (two mobile); backwards Lagrangian stochastic modelling; forwards Lagrangian stochastic modelling; Lagrangian stochastic (LS) footprint modelling; atmospheric tomography using point and using integrated line sensors. The majority of CH4 estimates were within 20% of the actual CH4 release rate (5.8 g/min), with the tracer ratio technique providing the closest estimate to both the CH4 and CO2 release rates (100 g/min). Once the release rate was known, the majority of revised estimates were within 10% of the actual release rate. The study illustrates the power of measuring the emission rate using multiple simultaneous methods and obtaining an ensemble median or mean. An ensemble approach to estimating the CH4 emission rate proved successful with the ensemble median estimate within 16% for the actual release rate for the blind release experiment and within 2% once the release rate was known. The release also provided an opportunity to assess the effectiveness of stationary and mobile ground and aerial CH4 detection technologies. Sensor detection limits and sampling rates were found to be significant limitations for CH4 and CO2 detection. A hyperspectral imager\u27s capacity to image the CH4 release from 100 m, and a Boreal CH4 laser sensor\u27s ability to track moving targets suggest the future possibility to map gas plumes using a single laser and mobile aerial reflector

A Comprehensive X-ray Report on AT2019wey

The Galactic low-mass X-ray binary AT2019wey (ATLAS19bcxp, SRGA J043520.9+552226, SRGE J043523.3+552234, ZTF19acwrvzk) was discovered as a new optical transient in Dec 2019, and independently as an X-ray transient in Mar 2020. In this paper, we present comprehensive NICER, NuSTAR, Chandra, Swift, and MAXI observations of AT2019wey from ~1 year prior to the discovery to the end of September 2020. AT2019wey appeared as a ~1 mCrab source and stayed at this flux density for several months, displaying a hard X-ray spectrum that can be modeled as a power-law with photon index Gamma~1.8. In June 2020 it started to brighten, and reached ~20 mCrab in ~2 months. The inclination of this system can be constrained to i≾30 deg by modeling the reflection spectrum. Starting from late-August (~59082 MJD), AT2019wey entered into the hard-intermediate state (HIMS), and underwent a few week-long timescale outbursts, where the brightening in soft X-rays is correlated with the enhancement of a thermal component. Low-frequency quasi-periodic oscillation (QPO) was observed in the HIMS. We detect no pulsation and in timing analysis of the NICER and NuSTAR data. The X-ray states and power spectra of AT2019wey are discussed against the landscape of low-mass X-ray binaries

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

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

Chasing the Identification of ASCA Galactic Objects (ChIcAGO) - An X-ray Survey of Unidentified Sources in the Galactic Plane I: Source Sample and Initial Results

We present the Chasing the Identification of ASCA Galactic Objects (ChIcAGO) survey, which is designed to identify the unknown X-ray sources discovered during the ASCA Galactic Plane Survey (AGPS). Little is known about most of the AGPS sources, especially those that emit primarily in hard X-rays (2-10 keV) within the Fx ~ 10–13 to 10–11 erg cm–2 s–1 X-ray flux range. In ChIcAGO, the subarcsecond localization capabilities of Chandra have been combined with a detailed multiwavelength follow-up program, with the ultimate goal of classifying the >100 unidentified sources in the AGPS. Overall to date, 93 unidentified AGPS sources have been observed with Chandra as part of the ChIcAGO survey. A total of 253 X-ray point sources have been detected in these Chandra observations within 3' of the original ASCA positions. We have identified infrared and optical counterparts to the majority of these sources, using both new observations and catalogs from existing Galactic plane surveys. X-ray and infrared population statistics for the X-ray point sources detected in the Chandra observations reveal that the primary populations of Galactic plane X-ray sources that emit in the Fx ~ 10–13 to 10–11 erg cm–2 s–1 flux range are active stellar coronae, massive stars with strong stellar winds that are possibly in colliding wind binaries, X-ray binaries, and magnetars. There is also another primary population that is still unidentified but, on the basis of its X-ray and infrared properties, likely comprises partly Galactic sources and partly active galactic nuclei.Astronom