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Educating students to become evidence-based practitioners remains a significant challenge in health professional education. Clinical placements form a significant element of curriculum, and the impact of students' work integrated learning experiences on their ability and desire to practice in an evidence-based manner remains largely unexplored. This study used focus groups to explore students' experiences of evidence-based practice (EBP) during clinical placements, the impact of these experiences on their education, and their future EBP tendencies within the profession. Reflexive thematic analysis was utilized to analyze data and three main overarching themes were identified. These themes are education, culture and responsibility and hopes, fears and barriers and they were explored in detail. Improving the teaching of EBP skills within health professional education, which includes the strengthening of the integration of these skills across work-integrated learning curricula, has the potential to enhance the translation of knowledge into practice as these graduates become qualified clinicians within the profession.

Abstract Introduction Liver cancer presents a growing global health concern, necessitating advanced approaches for intervention. This review investigates the use and effectiveness of software navigation in interventional radiology for liver tumour procedures. Methods In accordance with Preferred Reporting Items for Systematic reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐ScR) guidelines, a scoping review was conducted of the literature published between 2013 and 2023 sourcing articles through MEDLINE, Scopus, CINAHL and Embase. Eligible studies focused on liver cancer, utilised cone‐beam computed tomography (CBCT), and employed software for intervention. Twenty‐one articles were deemed eligible for data extraction and analysis. Results Categorised by type, software applications yielded diverse benefits. Feeder detection software significantly enhanced vessel identification, reducing non‐target embolisation by up to 43%. Motion correction software demonstrated a 20% enhancement in image quality, effectively mitigating breathing‐induced motion artefacts. Liver perfusion software facilitated efficient tumour targeting while simultaneously reducing the occurrence of side effects. Needle guide software enabled precise radiofrequency ablation needle placement. Additionally, these software applications provided detailed anatomical simulations. Overall, software integration resulted in shorter procedures, reduced radiation exposure and decreased contrast media usage. Conclusion This scoping review highlights the innovative yet relatively underexplored role of software navigation for liver tumour procedures. The integration of software applications not only enhances procedural efficiency but also bolsters operator confidence, and contributes to improved patient outcomes. Despite the current lack of uniformity and standardisation, these software‐driven advancements hold significant promise for transforming liver tumour interventions. To realise these benefits, further research is needed to explore the clinical impact and optimal utilisation of software navigation tools in interventional radiology.

Abstract Radiomics is an emerging field that aims to extract and analyse a comprehensive set of quantitative features from medical images. This scoping review is focused on MRI‐based radiomic features for the molecular profiling of breast tumours and the implications of this work for predicting patient outcomes. A thorough systematic literature search and outcome extraction were performed to identify relevant studies published in MEDLINE/PubMed (National Centre for Biotechnology Information), EMBASE and Scopus from 2015 onwards. The following information was retrieved from each article: study purpose, study design, extracted radiomic features, machine learning technique(s), sample size/characteristics, statistical result(s) and implications on patient outcomes. Based on the study purpose, four key themes were identified in the included 63 studies: tumour subtype classification (n = 35), pathologically complete response (pCR) prediction (n = 15), lymph node metastasis (LNM) detection (n = 7) and recurrence rate prediction (n = 6). In all four themes, reported accuracies widely varied among the studies, for example, area under receiver characteristics curve (AUC) for detecting LNM ranged from 0.72 to 0.91 and the AUC for predicting pCR ranged from 0.71 to 0.99. In all four themes, combining radiomic features with clinical data improved the predictive models. Preliminary results of this study showed radiomics potential to characterise the whole tumour heterogeneity, with clear implications for individual‐targeted treatment. However, radiomics is still in the pre‐clinical phase, currently with an insufficient number of large multicentre studies and those existing studies are often limited by insufficient methodological transparency and standardised workflow. Consequently, the clinical translation of existing studies is currently limited.

Aims: To compare four media--UTI medium, BBL CHROMagar, CPS ID2, and Harlequin CLED--using a collection of fully characterised organisms and subsequent 'field trial'. Methods: Seven hundred and eighty seven fully [...]

Previous studies showed that radiologists can detect the gist of an abnormality in a mammogram based on a half-second image presentation through global processing of screening mammograms. This study investigated the intra- and inter-observer reliability of the radiologists' initial impressions about the abnormality (or "gist signal"). It also examined if a subset of radiologists produced more reliable and accurate gist signals. Thirty-nine radiologists provided their initial impressions on two separate occasions, viewing each mammogram for half a second each time. The intra-class correlation (ICC) values showed poor to moderate intra-reader reliability. Only 13 radiologists had an ICC of 0.6 or above, which is considered the minimum standard for reliability, and only three radiologists had an ICC exceeding 0.7. The median value for the weighted Cohen's Kappa was 0.478 (interquartile range = 0.419-0.555). The Mann-Whitney U-test showed that the "Gist Experts", defined as those who outperformed others, had significantly higher ICC values (p = 0.002) and weighted Cohen's Kappa scores (p = 0.026). However, even for these experts, the intra-radiologist agreements were not strong, as an ICC of at least 0.75 indicates good reliability and the signal from none of the readers reached this level of reliability as determined by ICC values. The inter-reader reliability of the gist signal was poor, with an ICC score of 0.31 (CI = 0.26-0.37). The Fleiss Kappa score of 0.106 (CI = 0.105-0.106), indicating only slight inter-reader agreement, confirms the findings from the ICC analysis. The intra- and inter-reader reliability analysis showed that the radiologists' initial impressions are not reliable signals. In particular, the absence of an abnormal gist does not reliably signal a normal case, so radiologists should keep searching. This highlights the importance of "discovery scanning," or coarse screening to detect potential targets before ending the visual search.

Abstract Diverticular disease is one of the most common causes of outpatient visits and hospitalisations across Australia, North America and Europe. According to the Gastroenterological Society of Australia (GESA, 2010), approximately 33% of Australians over 45 years of age and 66% over 85 years of age have some form of colonic diverticulosis. Patients with colonic diverticulosis are known to develop subsequent complications such as acute colonic diverticulitis (ACD), and when more than one attack of diverticulitis occurs, there is a 70‐90% chance that the individual will experience ongoing problems and recurring infections throughout their lifetime. Medical imaging is fundamental in the diagnosis, treatment and ongoing management of ACD and its complications, with Computed Tomography (CT) identified as the prevailing gold standard in the last few decades. Cross‐database searching highlighted a large gap in the literature regarding the effectiveness of Magnetic Resonance Imaging (MRI) as a non‐ionising radiation alternative imaging tool for ACD imaging after the mid‐2000s, despite ongoing technological advancements in this modality. This narrative review identified 13 key publications (11 primary prospective cohort studies, 1 systematic review and 1 meta‐analysis) that evaluate MRI for ACD imaging, of which five were published within the last decade. Several existing MRI protocols are deemed suitable for ACD imaging, and it is recommended they be re‐evaluated in larger cohorts. Future studies should consider the rapidly growing technological improvements of MRI, its cost efficiency and its applicability in modern day healthcare settings when addressing ACD management. This is especially important considering the gradual rise in radiation dose among the Australian population attributable to increased CT referrals, alongside increased reporting of ACD cases in younger individuals.

Studies show the cancer transcriptome correlates poorly with the cancer proteome, questioning the role of chromatin regulation. Here the authors demonstrate proximal-gene-body chromatin elements and transcription predict abundances of differentially expressed proteins in thyroid and breast cancers.

Abstract Introduction Uterine artery embolisation (UAE) is regarded as a safe and effective treatment for symptomatic uterine fibroids and/or adenomyosis. Dose reduction during UAE is critical for this reproductive‐age patient population to minimise the risks of radiation‐induced effects. The aim of this study was to identify the predictors of radiation dose which can be controlled and optimised for patients during UAE. Methods A total of 150 patients between June 2018 and August 2019 were included in this study. Demographic and clinical information such as age, body mass index (BMI), total number of fibroids, total fibroid volume, total uterus volume and dosimetric measurements on Dose Area Product (DAP), Air Kerma (AK) and fluoroscopy time were recorded. Total digital subtraction angiography (DSA), total conventional roadmap (CRM), total last‐image hold (LIH) and total fluoroscopy were calculated from the dose report. Multiple linear regression analysis was used to identify the independent predictor variables of total dose (DAP) using a regression model. Results Total DSA, total CRM and total LIH were identified as the determinants of dose for UAE (P

Abstract Introduction 3D‐printed imaging phantoms are now increasingly available and used for computed tomography (CT) dose optimisation study and image quality analysis. The aim of this study was to evaluate the integrated 3D‐printed cardiac insert phantom when evaluating iterative reconstruction (IR) algorithm in coronary CT angiography (CCTA) protocols. Methods The 3D‐printed cardiac insert phantom was positioned into a chest phantom and scanned with a 16‐slice CT scanner. Acquisitions were performed with CCTA protocols using 120 kVp at four different tube currents, 300, 200, 100 and 50 mA (protocols A, B, C and D, respectively). The image data sets were reconstructed with a filtered back projection (FBP) and three different IR algorithm strengths. The image quality metrics of image noise, signal–noise ratio (SNR) and contrast–noise ratio (CNR) were calculated for each protocol. Results Decrease in dose levels has significantly increased the image noise, compared to FBP of protocol A (P

Abstract Studies have shown that the use of artificial intelligence can reduce errors in medical image assessment. The diagnosis of breast cancer is an essential task; however, diagnosis can include ‘detection’ and ‘interpretation’ errors. Studies to reduce these errors have shown the feasibility of using convolution neural networks (CNNs). This narrative review presents recent studies in diagnosing mammographic malignancy investigating the accuracy and reliability of these CNNs. Databases including ScienceDirect, PubMed, MEDLINE, British Medical Journal and Medscape were searched using the terms ‘convolutional neural network or artificial intelligence’, ‘breast neoplasms [MeSH] or breast cancer or breast carcinoma’ and ‘mammography [MeSH Terms]’. Articles collected were screened under the inclusion and exclusion criteria, accounting for the publication date and exclusive use of mammography images, and included only literature in English. After extracting data, results were compared and discussed. This review included 33 studies and identified four recurring categories of studies: the differentiation of benign and malignant masses, the localisation of masses, cancer‐containing and cancer‐free breast tissue differentiation and breast classification based on breast density. CNN's application in detecting malignancy in mammography appears promising but requires further standardised investigations before potentially becoming an integral part of the diagnostic routine in mammography.

Cadmium (Cd) is a highly toxic heavy metal considered carcinogenic to humans. The adsorption behavior of cadmium adsorption using untreated and chemically modified rice husk was investigated. Experimental tests were carried out to evaluate the influence of the variables pH, initial concentration of cadmium, and dosage of adsorbent in the adsorption process. In optimal experimental conditions, the maximum adsorption efficiency was 92.65%. Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM) were used allowing the identification of the main functional groups and morphology of rice husk and treated rice husk, and the results showed an improvement of adsorption characteristics after rice husk treatment with NaOH. The optimum adsorption pH for both types of rice husk was 7. The maximum adsorption capacities of RH and treated RH fitted by the Langmuir model were 5.13 mg/g and 11.06 mg/g, respectively. The pseudosecond order kinetics has the best coefficients of determination for untreated (R2=0.992) and treated (R2=0.999) rice husk. The adsorption process was found to be endothermic in nature with enthalpy of 14.08 kJ/mol and entropy of 170.98 J/mol.K. The calculated activation energy was 24 kJ/mol. The results showed the potential of rice husk as a low-cost, easily managed, and efficient biosorbent for Cd removal from waters.

Abstract Uterine artery embolisation (UAE) is an interventional angiography procedure for the treatment of symptomatic fibroids and/or adenomyosis in women. UAE is a less invasive and non‐surgical alternative to hysterectomy or myomectomy. However, ionising radiation is used for both fluoroscopic and angiographic image guidance to visualise and access the uterine arteries for embolisation and treatment of these benign conditions. Identifying the contributors and implementing dose reduction techniques are particularly important as UAE patients are usually of child‐bearing age. The purpose of this review was to examine the progression of literature on radiation exposure measurements and identifying the factors contributing to the total radiation exposure of female patients undergoing UAE. A Medline, ProQuest Central, ScienceDirect and Scopus database search from 2000 to 2018 was performed and forty articles were deemed acceptable for review following the inclusion and exclusion criteria set. UAE is a viable alternative to hysterectomy and myomectomy, as the reviewed literature demonstrated that the reported radiation exposure doses appear to be below the threshold for any deterministic radiation risks. The total radiation exposure of UAE patients is affected independently by multiple patient, operator expertise and technique, angiographic imaging and x‐ray unit variables. Uterus preservation can be attained post‐UAE with dose reduction and optimisation, however, a longitudinal study on UAE patients and their risk of radiation‐induced deterministic and/or stochastic effects is recommended.

Abstract Trauma to the facial area accounts for a significant number of admissions to the emergency department. Diagnostic imaging is almost always required, and is critical in determining patient management. Multi‐detector computed tomography (MDCT) appears consistently in the literature as the gold‐standard imaging modality for facial bones, but results in a high radiation dose to the patient. This makes the application and advancement of dose reduction and dose optimisation methods vital. This narrative review presents a critical analysis of the literature concerning diagnostic imaging of facial bone trauma, with an emphasis on dose reduction methods for MDCT. Databases including Pubmed, Medline, Web of Science and Scopus were used to investigate this topic, with the key words: facial bone trauma, computed tomography (CT) imaging and dose reduction. Exclusion criteria included studies on nasal bone fracturing, dental imaging, elective surgeries and paediatric imaging. The literature shows overwhelming support for MDCT, given its accuracy, efficiency and ease of operation. Noise reducing reconstruction algorithms show promise as a successful method of dose reduction in facial bone imaging. Investigations of more innovative techniques also appear within the literature, including diagnostic cone‐beam CT (CBCT), intraoperative CBCT and dual‐source CT (DSCT), but further research is required to confirm their clinical value.

Objectives. To characterize the total content of heavy metals (Cd, Cr, Cu, Hg, Mo, Ni, Pb, and Zn) and trace elements (As and Se) of interest, their bioavailability and solubility during the composting of cow manure and tree litter in piles inoculated with beneficial microorganism (IBM), or not inoculated (NBM), on the university campus of the Universidad Nacional Agraria La Molina (UNALM). Methods. The investigation evaluated composting in six piles, three IBM piles and three NBM piles, for 120 days. Every 30 days, a composite sample was taken from each pile. The raw materials used were cattle manure and tree litter. The variables analyzed were the total concentrations (content) of metals and trace elements of interest, extracted with diethylenetriaminepentaacetic acid/pentatetic acid (DTPA) (for the bioavailability study) and extracted with deionized water (for the solubility study). Results. The average values (n = 3) of the total content (mg·kg−1) on day 120 in IBM were in the following order: Zn (404.33) > Cu (86.33) > Pb (71.2) > Cr (34.33) > As (28.0) > Ni (13.83) > Mo (2.86) > Se (1.38) > Cd (1.32) > Hg (0.39) and in NBM: Zn (466.0) > Cu (112.23) > Pb (73.23) > Cr (35.33) > As (29.67) > Ni (14.37) > Mo (3.23) > Se (1.55) > Cd (1.38) > Hg (0.38). The values complied with the Austrian Compost Standard for Landscaping and Land Rehabilitation and the Peruvian Standard for Nonorganic Agriculture. Significant differences were observed in some elements (p

Abstract Background Automatic identification of term variants or acceptable alternative free-text terms for gene and protein names from the millions of biomedical publications is a challenging task. Ontologies, such as the Cardiovascular Disease Ontology (CVDO), capture domain knowledge in a computational form and can provide context for gene/protein names as written in the literature. This study investigates: 1) if word embeddings from Deep Learning algorithms can provide a list of term variants for a given gene/protein of interest; and 2) if biological knowledge from the CVDO can improve such a list without modifying the word embeddings created. Methods We have manually annotated 105 gene/protein names from 25 PubMed titles/abstracts and mapped them to 79 unique UniProtKB entries corresponding to gene and protein classes from the CVDO. Using more than 14 M PubMed articles (titles and available abstracts), word embeddings were generated with CBOW and Skip-gram. We setup two experiments for a synonym detection task, each with four raters, and 3672 pairs of terms (target term and candidate term) from the word embeddings created. For Experiment I, the target terms for 64 UniProtKB entries were those that appear in the titles/abstracts; Experiment II involves 63 UniProtKB entries and the target terms are a combination of terms from PubMed titles/abstracts with terms (i.e. increased context) from the CVDO protein class expressions and labels. Results In Experiment I, Skip-gram finds term variants (full and/or partial) for 89% of the 64 UniProtKB entries, while CBOW finds term variants for 67%. In Experiment II (with the aid of the CVDO), Skip-gram finds term variants for 95% of the 63 UniProtKB entries, while CBOW finds term variants for 78%. Combining the results of both experiments, Skip-gram finds term variants for 97% of the 79 UniProtKB entries, while CBOW finds term variants for 81%. Conclusions This study shows performance improvements for both CBOW and Skip-gram on a gene/protein synonym detection task by adding knowledge formalised in the CVDO and without modifying the word embeddings created. Hence, the CVDO supplies context that is effective in inducing term variability for both CBOW and Skip-gram while reducing ambiguity. Skip-gram outperforms CBOW and finds more pertinent term variants for gene/protein names annotated from the scientific literature.

These evidence-based guidelines are an updated version of those published in 2006. They have been produced after a literature review of the treatment and prophylaxis of methicillin-resistant Staphylococcus aureus (MRSA). The guidelines aim to complement those recently published for the antibiotic treatment of common and emerging community-onset MRSA infections in the UK. The guidelines have reviewed and updated, where appropriate, previous recommendations, taking into account any changes in the UK epidemiology of MRSA, ongoing national surveillance data and the value of new antistaphylococcal agents licensed for use in UK practice. Emerging therapies that have not been licensed for UK use are not reviewed, but their future potential role has been mentioned where deemed appropriate. Recommendations are given for the treatment of common infections caused by MRSA, elimination of MRSA from carriage sites and prophylaxis of surgical site infection. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Some aspects of memory performance are impaired during acute hypoglycaemia. The hippocampus is critical to formation of long-term memory, and may be particularly sensitive to hypoglycaemia. This study examined whether moderate hypoglycaemia occurring after learning would disrupt the consolidation process, and used functional magnetic resonance imaging (fMRI) to identify accompanying changes in brain activation. METHODS: Sixteen non-diabetic subjects each underwent two glucose clamp studies. During euglycaemia (4.5 mmol/L), subjects tried to memorize a series of words and a series of pictures of faces. Then, either hypoglycaemia (2.5 mmol/L) was induced for one hour, or euglycaemia was maintained. During subsequent uncontrolled euglycaemia, subjects' recognition of the word and face stimuli was tested, with simultaneous fMRI to measure brain activation during recognition. RESULTS: Face identification scores were 67.2% after euglycaemia and 66.9% after hypoglycaemia (p = 0.895). Word identification scores were 78.0 and 77.1% respectively (p = 0.701). Analysis of the fMRI identified two foci where activation was altered after hypoglycaemia compared with euglycaemia, but these were not in regions associated with memory, and were probably statistical artefacts. CONCLUSIONS: One hour of hypoglycaemia at 2.5 mmol/L induced 20-40 min after learning did not disrupt memory consolidation. fMRI did not show evidence of altered brain activation after hypoglycaemia. Consolidation may be relatively resistant to hypoglycaemia, or may have been complete before hypoglycaemia was induced. The study was powered to detect a large effect, and provides some reassurance that moderate hypoglycaemia does not cause major disruption of previously learned memories in people with insulin-treated diabetes. Copyright (c) 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE We sought to evaluate the impact of the gluten-free diet on the 5,240 members of the Canadian Celiac Association (CCA). Data are presented on 2,681 adults (>or=16 years) with biopsy-proven celiac disease (CD). METHODS: A mail-out survey was used. Quality of life was evaluated using the 'SF12', and celiac-specific questions. RESULTS: Mean age was 56 years, mean age at diagnosis was 45 years, and 75% were female. The 'SF12' summary scores were similar to normative Canadian data, but were significantly lower for females and newly diagnosed patients. Respondents reported: following a gluten-free (GF) diet (90%), improvement on the diet (83%), and difficulties following the diet (44%), which included: determining if foods were GF (85%), finding GF foods in stores (83%), avoiding restaurants (79%), and avoiding travel (38%). Most common reactions to consumed gluten (among 73%) included pain, diarrhea, bloating, fatigue, nausea, and headache. Excellent information on CD and its treatment was provided by the CCA (64%), gastroenterologists (28%), dietitians (26%) and family doctor (12%). CONCLUSIONS: Quality of life in those with CD could be increased with early diagnosis, increased availability of gluten-free foods, improved food labelling, and better dietary instruction. Education of physicians and dietitians about CD and its treatment is essential. [ABSTRACT FROM AUTHOR]

The Susquehanna Shale Hills Critical Zone Observatory (SSHCZO) was established to investigate the form, function, and dynamics of the critical zone developed on sedimentary rocks in the Appalachian Mountains in central Pennsylvania. When first established, the SSHCZO encompassed only the Shale Hills catchment, a 0.08-km subcatchment within Shaver’s Creek watershed. The SSHCZO has now grown to include 120 km of the Shaver’s Creek watershed. With that growth, the science team designed a strategy to measure a parsimonious set of data to characterize the critical zone in such a large watershed. This parsimonious design includes three targeted subcatchments (including the original Shale Hills), observations along the main stem of Shaver’s Creek, and broad topographic and geophysical observations. Here we describe the goals, the implementation of measurements, and the major findings of the SSHCZO by emphasizing measurements of the main stem of Shaver’s Creek as well as the original Shale Hills subcatchment.

Abstract Background A number of expression systems have been developed where transgene expression can be regulated. They all have specific characteristics making them more suitable for certain applications than for others. Since some applications require the regulation of several genes, there is a need for a variety of independent yet compatible systems. Results We have used the regulatory mechanisms of bacterial operons (cmt and cym) to regulate gene expression in mammalian cells using three different strategies. In the repressor configuration, regulation is mediated by the binding of the repressor (CymR) to the operator site (CuO), placed downstream of a strong constitutive promoter. Addition of cumate, a small molecule, relieves the repression. In the transactivator configuration, a chimaeric transactivator (cTA) protein, formed by the fusion of CymR with the activation domain of VP16, is able to activate transcription when bound to multiple copies of CuO, placed upstream of the CMV minimal promoter. Cumate addition abrogates DNA binding and therefore transactivation by cTA. Finally, an adenoviral library of cTA mutants was screened to identify a reverse cumate activator (rcTA), which activates transcription in the presence rather than the absence of cumate. Conclusion We report the generation of a new versatile inducible expression system.

Abstract Background High throughput sequencing-by-synthesis is an emerging technology that allows the rapid production of millions of bases of data. Although the sequence reads are short, they can readily be used for re-sequencing. By re-sequencing the mRNA products of a cell, one may rapidly discover polymorphisms and splice variants particular to that cell. Results We present the utility of massively parallel sequencing by synthesis for profiling the transcriptome of a human prostate cancer cell-line, LNCaP, that has been treated with the synthetic androgen, R1881. Through the generation of approximately 20 megabases (MB) of EST data, we detect transcription from over 10,000 gene loci, 25 previously undescribed alternative splicing events involving known exons, and over 1,500 high quality single nucleotide discrepancies with the reference human sequence. Further, we map nearly 10,000 ESTs to positions on the genome where no transcription is currently predicted to occur. We also characterize various obstacles with using sequencing by synthesis for transcriptome analysis and propose solutions to these problems. Conclusion The use of high-throughput sequencing-by-synthesis methods for transcript profiling allows the specific and sensitive detection of many of a cell's transcripts, and also allows the discovery of high quality base discrepancies, and alternative splice variants. Thus, this technology may provide an effective means of understanding various disease states, discovering novel targets for disease treatment, and discovery of novel transcripts.

Master regulators of the unfolded protein response (UPR), IRE1α and PERK, promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. Although the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNET) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. Genetic and pharmacologic modulation of IRE1α and PERK in cultured cells, xenograft, and spontaneous genetic (RIP-Tag2) mouse models of PanNETs revealed that UPR signaling was optimized for adaptation and that inhibiting either IRE1α or PERK led to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. These results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers with elevated ER stress. SIGNIFICANCE: The UPR is upregulated in pancreatic neuroendocrine tumors and its inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in these cancers., (©2019 American Association for Cancer Research.)

The Working Party makes more than 100 tabulated recommendations in antimicrobial prescribing for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) and suggest further research, and algorithms for hospital and community antimicrobial usage in urinary infection. The international definition of MDR is complex, unsatisfactory and hinders the setting and monitoring of improvement programmes. We give a new definition of multiresistance. The background information on the mechanisms, global spread and UK prevalence of antibiotic prescribing and resistance has been systematically reviewed. The treatment options available in hospitals using intravenous antibiotics and in primary care using oral agents have been reviewed, ending with a consideration of antibiotic stewardship and recommendations. The guidance has been derived from current peer-reviewed publications and expert opinion with open consultation. Methods for systematic review were NICE compliant and in accordance with the SIGN 50 Handbook; critical appraisal was applied using AGREE II. Published guidelines were used as part of the evidence base and to support expert consensus. The guidance includes recommendations for stakeholders (including prescribers) and antibiotic-specific recommendations. The clinical efficacy of different agents is critically reviewed. We found there are very few good-quality comparative randomized clinical trials to support treatment regimens, particularly for licensed older agents. Susceptibility testing of MDR GNB causing infection to guide treatment needs critical enhancements. Meropenem- or imipenem-resistant Enterobacteriaceae should have their carbapenem MICs tested urgently, and any carbapenemase class should be identified: mandatory reporting of these isolates from all anatomical sites and specimens would improve risk assessments. Broth microdilution methods should be adopted for colistin susceptibility testing. Antimicrobial stewardship programmes should be instituted in all care settings, based on resistance rates and audit of compliance with guidelines, but should be augmented by improved surveillance of outcome in Gram-negative bacteraemia, and feedback to prescribers. Local and national surveillance of antibiotic use, resistance and outcomes should be supported and antibiotic prescribing guidelines should be informed by these data. The diagnosis and treatment of both presumptive and confirmed cases of infection by GNB should be improved. This guidance, with infection control to arrest increases in MDR, should be used to improve the outcome of infections with such strains. Anticipated users include medical, scientific, nursing, antimicrobial pharmacy and paramedical staff where they can be adapted for local use.

Aims: Recurrent severe hypoglycaemia in a patient with diabetes is strongly associated with a crash risk while driving. To help ensure road safety, recent changes were made to European Union driving regulations for patients with diabetes. These included the recommendation that more than one episode of severe hypoglycaemia within 12 months would lead to the loss of a driving licence. This study has assessed the impact of this regulation if applied to patients who participated in the Diabetes Control and Complications Trial., Methods: All patients in the Diabetes Control and Complications Trial were assumed to be drivers. Repeated hypoglycaemic episodes within a year were determined during the mean 6.5 years of the study., Results: Of the 1441 patients in the Diabetes Control and Complications Trial, 439 (30%) had more than one severe hypoglycaemic episode during a 12-month period of their study participation. Amongst the study groups, 312/711 (44%) of intensively treated and 127/730 (17%) of conventionally treated patients would have lost their licence at some point during the trial. The risk of licence loss increased with lower mean HbA1c , longer duration of diabetes and younger age (all P < 0.001)., Conclusions: More than one episode of severe hypoglycaemia within a year was a frequent event in subjects in the Diabetes Control and Complications Trial, especially in intensively treated patients. If applied to current practice, improving road safety through these changes to European Union regulations could have a substantial impact on drivers who have Type 1 diabetes. This emphasizes the need to take into account the potential effects of severe hypoglycaemia in those who rely on a driving licence., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Background: The diagnosis of hypertension is difficult when faced with several different blood pressure measurements in an individual. Using the average of several office measurements is recommended, although considerable uncertainty remains. Twenty-four-hour ambulatory monitoring is often considered the gold standard, but self-monitoring of blood pressure has been proposed as a superior method., Aim: Determination of within-individual variability of blood pressure measured in the office, by ambulatory monitoring, and by a week of self-monitoring., Design of Study: Retrospective analysis of a clinical trial of 163 subjects., Method: Within-patient variability of office and ambulatory blood pressure was determined from measurements at 0 and 6 weeks. Subjects had performed self-monitoring of blood pressure twice each morning and evening, for at least 6 weeks; variability was determined from the means of week 1 and week 6., Results: The within-individual coefficients of variation (CVs) for systolic blood pressure were: office, 8.6%; ambulatory, 5.5%; self, 4.2%. Equivalent values for diastolic blood pressure were 8.6%, 4.9%, and 3.9%. CVs tended to be lower with longer self-monitoring duration, and higher with longer intervals between self-monitoring., Conclusion: Office blood pressure is impractical for precise assessment, as 10-13 measurements are required to give the accuracy required for rational titration of antihypertensive drugs. Twenty-four-hour ambulatory monitoring is better than a single office measurement, but considerable uncertainty remains around the estimate. A week of self-monitoring appears to be the most accurate method of measuring blood pressure, but remains imperfect. Further research may identify superior self-monitoring schedules. Given the inherent accuracy in blood pressure measurement, the importance of considering overall cardiovascular risk is emphasised.

Objectives: The aac(6')-Ib-cr gene has been described in plasmids from CTX-M-15-producing Escherichia coli in the worldwide ST131 lineage, but has not been systematically sought in other quinolone-resistant strains in the UK. A rise in quinolone resistance in bacteraemia isolates in the UK preceded the increased prevalence of CTX-M-producing strains. This study aimed to describe the presence of plasmid-encoded quinolone resistance genes in historical and current strains of E. coli not producing extended-spectrum beta-lactamases (ESBLs)., Methods: Ciprofloxacin-resistant, non-ESBL-producing E. coli isolates included nationally distributed isolates from the BSAC UK bacteraemia surveillance programme between 2001 and 2005, urinary isolates from a regional project in 2000 and local strains in 2006. The aac(6')-Ib-cr gene was detected using PCR followed by restriction fragment length polymorphism analysis. Multiplex PCR was used to detect qnr genes. Isolates with aac(6')-Ib-cr were assessed for aminoglycoside susceptibilities and were serotyped., Results: The prevalence of the aac(6')-Ib-cr gene was 3% and 9% in current local urinary and historic national bacteraemia quinolone-resistant non-ESBL-producing E. coli, respectively. Of 521 regional urinary E. coli isolates from 2000, 14 were norfloxacin-resistant, none of which carried the aac(6')-Ib-cr gene. National positive bacteraemia isolates from 2001/2 were type O102-ST405 and, in 2004/5, types O1-ST645 and O25-ST131. Positive local urinary isolates from 2006 included serotypes O1 and O25., Conclusions: In the UK, aac(6')-Ib-cr occurs in E. coli in the absence of CTX-M-15, but with a restricted serotype distribution. Its presence in widespread bacteraemia isolates of a single type from 2001 to 2002, prior to the spread of CTX-M-15 in Britain, might suggest a lineage from which plasmid recombination occurred in man or other species.

Assessment of the place of daptomycin in the treatment of endocarditis and bacteraemia requires assimilation of data from one open-label randomized comparative clinical trial sized for equivalence, from registry data and from case reports. Selected relevant animal models and in vitro data are also considered in an effort to produce an integrated assessment of the current place of daptomycin in treatment. The evidence for the use of daptomycin is best in Staphylococcus aureus bacteraemia and endocarditis, but also includes some data on infections due to Enterococcus spp., especially if vancomycin-resistant. The emergence of resistance in a minority of patients on current dose regimens may mean that trials have to be repeated with higher doses, or the drug used in a combined therapy where rifampicin may be the best choice. In general, equivalence to comparator antibiotic regimens and a correlation for in vitro and in vivo findings have been demonstrated, but there are important gaps in the clinical data including a comparative equivalence trial in streptococcal and enterococcal endocarditis. Clinical benefit might be anticipated, but has not been proved, over aminoglycoside-containing regimens, and economic assessments are critical in the decision as to when and how daptomycin is deployed.

We present a sequential algorithm for estimating both concentration dependence on range and time and backscatter coefficient spectral dependence of optically thin localized atmospheric aerosols using data from rapidly tuned lidar. The range dependence of the aerosol is modeled as an expansion of the concentration in an orthonormal basis set whose coefficients carry the time dependence. Two estimators are run in parallel: a Kalman filter for the concentration range and time dependence and a maximum-likelihood estimator for the aerosol backscatter wavelength and time dependence. These two estimators exchange information continuously over the data-processing stream. The state model parameters of the Kalman filter are also estimated sequentially together with the concentration and backscatter. Lidar data collected prior to the aerosol release are used to estimate the ambient lidar return. The approach is illustrated on atmospheric backscatter long-wave infrared (CO2) lidar data.

Objective: Recovery times of cognitive functions were examined after exposure to hypoglycemia in people with diabetes with and without impaired hypoglycemia awareness., Research Design and Methods: A total of 36 subjects with type 1 diabetes were studied (20 with normal hypoglycemia awareness [NHA] and 16 with impaired hypoglycemia awareness [IHA]). A hyperinsulinemic glucose clamp was used to lower blood glucose to 2.5 mmol/l (45 mg/dl) (hypoglycemia) for 1 h or to maintain blood glucose at 4.5 mmol/l (81 mg/dl) (euglycemia) on separate occasions. Cognitive tests were applied during each experimental condition and were repeated at 10- to 15-min intervals for 90 min after euglycemia had been restored., Results: In the NHA group, performance was impaired on all cognitive tasks during hypoglycemia and remained impaired for up to 75 min on the choice reaction time (CRT) task (P = 0.03, eta(2) = 0.237). In the IHA group, performance did not deteriorate significantly during hypoglycemia. When all subjects were analyzed within the same general linear model, performance was impaired during hypoglycemia on all tasks. Significant impairment during recovery persisted for up to 40 min on the CRT task (P = 0.04, eta(2) = 0.125) with a significant glycemia-awareness interaction for CRT after one hour of hypoglycemia (P = 0.045, eta(2) = 0.124). Performance on the trail-making B task was impaired for up to 10 min after euglycemia was restored (P = 0.024, eta(2) = 0.158)., Conclusions: Following hypoglycemia, the recovery time for different cognitive tasks varied considerably. In the IHA group, performance was not significantly impaired during hypoglycemia. The state of awareness of hypoglycemia may influence cognitive function during and after hypoglycemia.

Objectives: Escherichia coli producing CTX-M-15 enzyme began to rapidly spread in the UK from around 2003 but other types also occur, notably CTX-M-14. We examined breasts from UK-reared (n = 62) and imported (n = 27) chickens as potential sources of quinolone-resistant E. coli with bla(CTX-M) genes. A further 40 samples for which the country of rearing could not be identified were examined., Methods: During 2006, 129 fresh and frozen chicken breast fillets were purchased from retail outlets in the West Midlands. These were cultured for E. coli on CLED agar containing 8 mg/L ciprofloxacin and carrying a 10 microg cefpodoxime disc. Resistant isolates were identified and typed by RAPD fingerprinting; bla(CTX-M) was identified by PCR and genotyped by reverse-line hybridization., Results: The country of rearing was identified from the packaging for 89 of 129 purchased samples. Only one of the 62 UK-reared chicken samples carried E. coli producing a CTX-M-1 enzyme, whereas 10 of 27 samples reared overseas had E. coli with CTX-M enzymes. Specifically, 4/10 Brazilian, 3/4 Brazilian/Polish/French, and 2/2 Dutch samples had E. coli with CTX-M-2 enzymes. Six of 40 samples for which the country of rearing was not known had producers of CTX-M enzymes, 5 of them with CTX-M-14., Conclusions: Quinolone-resistant E. coli with various CTX-M beta-lactamase genes that are common in human infections worldwide were found in imported chicken breasts, indicating a possible source for gut colonization. Samples from Brazil were commonly positive for E. coli with CTX-M-2, the dominant bla(CTX-M) genotype from human infections in South America, which is currently rare in clinical infections in the UK. CTX-M-15, the dominant CTX-M type in human infections in the UK, was not found in chicken isolates, suggesting that the UK-reared chickens are not a reservoir of CTX-M-15.

Control of infection classically involves hand and healthcare hygiene, reduction of selective and ineffective chemotherapy, reduction of invasive procedures and achlorhydria and adequate staffing, along with appropriate containment and concentration of patients. Investigation and control of any continuing sources of infection in food and water supplies is important also, as is recognition of individuals carrying high-risk strains and species. The onset of infection may be distant from the time of acquisition and may critically affect epidemiological assessment of control points. Carriage may be prolonged, increasing the likelihood of recurrent infection and exacerbating the difficulty of control. Mortality associated with resistance is difficult to assess retrospectively and may not be high, complicating analysis of the success or failure of control measures.

Aims: An association has been described between elevated serum angiotensin-converting enzyme (ACE) and an increased risk of severe hypoglycaemia (SH). To ascertain whether this reported association could be replicated in a different country, it was re-examined in 300 individuals with Type 1 diabetes., Methods: People with Type 1 diabetes, none of whom was taking renin-angiotensin system blocking drugs, were recruited. Participants recorded the frequency with which they had experienced SH. Glycated haemoglobin (HbA(1c)) and serum ACE were measured. The difference in the incidence of SH between different quartiles of ACE activity and the relationship between serum ACE and SH were examined using non-parametric statistical tests and a negative binomial model., Results: Data were obtained from 300 patients [158 male; HbA(1c) median (range) 8.2% (5.2-12.8%), median age 36 years (16-88); duration of diabetes 14.5 years (2-49)]. The incidence of SH was 0.93 episodes per patient year. The mean incidence of SH in the top and bottom quartiles of ACE activity was 0.5 and 1.7 episodes per patient year, respectively, but this difference was not statistically significant (P = 0.075). Spearman's test showed a very weak, although statistically significant, association between serum ACE level and SH incidence (r = 0.115, P = 0.047). The binomial model also showed a statistically significant (P = 0.002), but clinically weak, relationship between serum ACE and SH., Conclusions: The present survey showed a weak relationship between serum ACE and the frequency of SH, the clinical relevance of which is unclear. This limits the proposed role for serum ACE as an index of risk for SH.