bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical trials in low‐resource settings: the perspectives of caregivers of paediatric participants from Uganda, Tanzania and Kenya
Authors: van den Berg Machteld , Ogutu Bernhards , Sewankambo Nelson K. , Merten Sonja , Biller‐Andorno Nikola , Tanner Marcel 
Published: June 2019

AbstractObjectivesVaccine clinical trials in low‐resource settings have unique challenges due to structural and financial inequities. Specifically, protecting participant and caregiver autonomy to participate in the research study can be a major challenge, so understanding the setting and contextual factors which influence the decision process is necessary. This study investigates the experience of caregivers consenting on behalf of paediatric participants in a malaria vaccine clinical trial where participation enables access to free, high‐quality medical care.MethodsWe interviewed a total of 78 caregivers of paediatric participants previously enrolled in a phase II or III malaria vaccine clinical trial in Uganda, Tanzania and Kenya. Interviews were qualitative and analysed using a thematic framework analysis focusing on the embodied caregiver in the political, economic and social reality.ResultsCaregivers of participants in this study made the decision to enrol their child based on economic, social and political factors that extended beyond the trial into the community and the home. The provision of health care was the dominant reason for participation. Respondents reported how social networks, rumours, hierarchal structures, financial constraints and family dynamics affected their experience with research.ConclusionsThe provision of medical care was a powerful motivator for participation. Caregiver choice was limited by structural constraints and scarce financial resources. The decision to participate in research extended beyond individual consent and was embedded in community and domestic hierarchies. Future research should assess other contexts to determine how the choice to participate in research is affected when free medical care is offered.
Two‐step d‐ononitol epimerization pathway in Medicago truncatula
Authors: Pupel Piotr , Szablińska‐Piernik Joanna , Lahuta Lesław B. 
Published: June 2019

SummaryMethylated inositol, d‐pinitol (3‐O‐methyl‐d‐chiro‐inositol), is a common constituent in legumes. It is synthesized from myo‐inositol in two reactions: the first reaction, catalyzed by myo‐inositol‐O‐methyltransferase (IMT), consists of a transfer of a methyl group from S‐adenosylmethionine to myo‐inositol with the formation of d‐ononitol, while the second reaction, catalyzed by d‐ononitol epimerase (OEP), involves epimerization of d‐ononitol to d‐pinitol. To identify the genes involved in d‐pinitol biosynthesis in a model legume Medicago truncatula, we conducted a BLAST search on its genome using soybean IMT cDNA as a query and found putative IMT (MtIMT) gene. Subsequent co‐expression analysis performed on publicly available microarray data revealed two potential OEP genes: MtOEPA, encoding an aldo‐keto reductase and MtOEPB, encoding a short‐chain dehydrogenase. cDNAs of all three genes were cloned and expressed as recombinant proteins in E. coli. In vitro assays confirmed that putative MtIMT enzyme catalyzes methylation of myo‐inositol to d‐ononitol and showed that MtOEPA enzyme has NAD+‐dependent d‐ononitol dehydrogenase activity, while MtOEPB enzyme has NADP+‐dependent d‐pinitol dehydrogenase activity. Both enzymes are required for epimerization of d‐ononitol to d‐pinitol, which occurs in the presence of NAD+ and NADPH. Introduction of MtIMT, MtOEPA, and MtOEPB genes into tobacco plants resulted in production of d‐ononitol and d‐pinitol in transformants. As this two‐step pathway of d‐ononitol epimerization is coupled with a transfer of reducing equivalents from NADPH to NAD+, we speculate that one of the functions of this pathway might be regeneration of NADP+ during drought stress.
The Two Distinct Types of SecA2-Dependent Export Systems
Authors: Braunstein Miriam , Bensing Barbara A. , Sullam Paul M. 
Published: June 2019

ABSTRACT
In addition to SecA of the general Sec system, many Gram-positive bacteria, including mycobacteria, express SecA2, a second, transport-associated ATPase. SecA2s can be subdivided into two mechanistically distinct types: (i) SecA2s that are part of the accessory Sec (aSec) system, a specialized transporter mediating the export of a family of serine-rich repeat (SRR) glycoproteins that function as adhesins, and (ii) SecA2s that are part of multisubstrate systems, in which SecA2 interacts with components of the general Sec system, specifically the SecYEG channel, to export multiple types of substrates. Found mainly in streptococci and staphylococci, the aSec system also contains SecY2 and novel accessory Sec proteins (Asps) that are required for optimal export. Asp2 also acetylates glucosamine residues on the SRR domains of the substrate during transport. Targeting of the SRR substrate to SecA2 and the aSec translocon is mediated by a specialized signal peptide. Multisubstrate SecA2 systems are present in mycobacteria, corynebacteria, listeriae, clostridia, and some bacillus species. Although most substrates for this SecA2 have canonical signal peptides that are required for export, targeting to SecA2 appears to depend on structural features of the mature protein. The feature of the mature domains of these proteins that renders them dependent on SecA2 for export may be their potential to fold in the cytoplasm. The discovery of aSec and multisubstrate SecA2 systems expands our appreciation of the diversity of bacterial export pathways. Here we present our current understanding of the mechanisms of each of these SecA2 systems.
P003 Intermittent vancomycin in paediatrics: implementation and audit of a new guideline
Authors: Gray Jenny 
Published: June 2019

AimA guideline for the use of intermittent intravenous vancomycin in children was designed and implemented in our Trust in 2016. This introduced the use of a loading dose, increased dosing and increased frequency compared to the BNFC recommendations. The changes were based on the outcomes of a national NPPG project and local focus groups. The aim of this audit was assess compliance with the guideline and to establish if the time taken to reach target vancomycin levels had been reduced as a result of using the new guidance.Methods30 paediatric patients (≥1 month old) prescribed intermittent intravenous infusions of vancomycin were identified by ward pharmacists over a 2 month data collection period. 4 patients required treatment with adult dosing due to their weight. 2 patients were switched onto continuous infusion following pharmacist intervention. The results of the remaining 24 patients were compiled into an excel spreadsheet for analysis.ResultsAudit pre-implementation of the guideline had highlighted the lack of a support for staff to use appropriate dosing and monitoring.1 Overall, usage of the new guideline was positive. The loading dose was used appropriately in 83% patients. Levels were taken at appropriate times in 90% patients. The percentage of levels in therapeutic range at 48 hours increased from 7% to 40%. 100% of patient had a review at this time. Half of the patients out of range at 48 hours had treatment stopped or changed to a more appropriate treatment, reducing the need for unnecessary complex dose adjustment/monitoring plans. At 48 hours, there remained 30% of the total patient group requiring dose adjustment in order continue vancomycin treatment. The main area of concern was that review of these out of range levels was only carried out in accordance with the guideline in 40% of cases. This was improved to 80% with pharmacist intervention. A limitation of this data was the small patient group size. One patient had the level taken at the wrong time so could not be interpreted properly.ConclusionCompliance with the new guideline was good overall. This audit has shown that the use of the new guideline improved the percentage of patients with vancomycin levels in range at 48 hours from 7 to 40%. The main theme from this audit was that pharmacist intervention was the key to directing the medical teams towards prescribing the most appropriate form of treatment. Education can only improve compliance to a certain degree and this drug is not used often enough to be familiar to the average junior doctor. The use of vancomycin in complex and requires an understanding of pharmacokinetics and drug handling unique to the pharmacist skill set. Our aim for the future is that as our pharmacist team acquires more independent prescribers, direct adjustment of treatment plans will become a pharmacist role within the Trust.ReferenceHaylor J. Vancomycin use in paediatrics - prescribing and monitoring. University Hospitals Bristol Foundation Trust Clinical Audit 2014.
P014 An audit assessing the prescribing of naloxone in paediatric patients
Authors: Ntanganika Esther , Patel Bhavee 
Published: June 2019

AimTo assess whether paediatric patients who were prescribed opioids, had also been prescribed naloxone.MethodsThe audit was registered with the Clinical Audit and Effectiveness Department and ethical approval was not required. Patients who were taking weak opioids were excluded from this audit. A data collection sheet was created and data collected prospectively, over a two-month period. Forty-one inpatient medication charts were reviewed, to identify whether naloxone had been prescribed on the PRN section of the chart for patients who had been prescribed opioids, also to see whether the standards set for this audit had been met. The data was analysed with Microsoft excel.ResultsThere were 41 paediatric inpatient charts reviewed in total. Three standards were set for this audit which were derived from local ‘Multidisciplinary Guidelines for Acute Pain Management in Children and Young People’.1 The first standard was that ‘all paediatric patients who are prescribed opioids should have naloxone prescribed’ which was met by 17% (7/41) of the inpatient charts. The second standard was that ‘naloxone should be prescribed on the ‘when required’ PRN section of the drug chart’ which was met by 100% (7/7) of the inpatient charts. The last standard was that ‘the directions for naloxone should include instructions to call a medical practitioner and to immediately commence the administration, if respiratory depression is encountered’,1 2 which was met by 86% (6/7) of the inpatient charts.ConclusionThere is significant lack of naloxone prescribing in paediatric patients who are on opioids. This is reflected from the results showing that only 17% (7/41) of patients on opioids had naloxone prescribed on the PRN section of the chart. The inpatient charts which had naloxone prescribed, did not all have the correct dose and instructions on how it should be administered, only 86% (6/7) did. The results suggest that there is a lack of understanding on the importance of naloxone and how it should be prescribed on inpatient charts. The findings of this audit will be presented at the Paediatric Audit meeting and the Surgical Paediatric meeting, to educate prescribers on the importance of prescribing naloxone in patients who are receiving opioids and to reduce adverse effects that could occur due to opioid toxicity.ReferencesDunn G. Multidisciplinary Guidelines for Acute Pain management in children and young people, COIN, 2016, 55.Committee JF. British National Formulary for Children, 2017–2018. London: BMJ Group and Pharmaceutical Press.
P032  The burden associated with medicines reconciliation in hospitalised children
Authors: Qureshi Tathier , Huynh Chi , Isaac Rhian 
Published: June 2019

AimMedicines reconciliation in children is an important intervention which prevents unintended medication discrepancies and medication errors from occurring when a child moves from one setting to another, e.g. from home to hospital admission. A national study in England across multiple sites has shown that 1/3 of medication discrepancies are prevented from occurring,1 What has not been evaluated however, is the potential burden that medicines reconciliation would have on the resources, in particular on the pharmacy workforce. The overall aim of this project was to investigate the burden that is associated with admissions medicines reconciliation (AMR) in children.MethodsOver a 10 day period spanning over 4 weeks, rotational pharmacists carrying out hospital admission medicines reconciliation at a paediatric hospital in Birmingham, West Midlands were directly observed by a researcher (pharmacy student). This process was timed, and the student recorded the following observations: -The number of AMRs that were initiated within 24 hours of admissionThe number of AMRs that there completed within 24 hours of admissionThe number of completed and incomplete medicines reconciliationsThe reasons for incompletion of medicines reconciliation during the observation period.
Safety of azithromycin in paediatrics: a systematic review protocol
Authors: Xu Peipei , Zeng Linan , Xiong Tao , Choonara Imti , Qazi Shamim , Zhang Lingli 
Published: June 2019

IntroductionAzithromycin is widely used in children not only in the treatment of individual children with infectious diseases, but also as mass drug administration (MDA) within a community to eradicate or control specific tropical diseases. MDA has also been reported to have a beneficial effect on child mortality and morbidity. However, concerns have been raised about the safety of azithromycin, especially in young children. The aim of this review is to systematically identify the safety of azithromycin in children of all ages.Methods and analysisMEDLINE, PubMed, Cochrane Central Register of Controlled Trials, Embase, CINAHL, International Pharmaceutical Abstracts and adverse drug reaction (ADR) monitoring systems will be systematically searched for randomised controlled trials (RCTs), cohort studies, case–control studies, cross-sectional studies, case series and case reports evaluating the safety of azithromycin in children. The Cochrane risk of bias tool, Newcastle-Ottawa and quality assessment tools, and The Joanna Briggs Institute Critical Appraisal tools will be used for quality assessment. Meta-analyses will be conducted to the incidence of ADRs from RCTs if appropriate. Subgroup analyses will be performed in different age and azithromycin dosage groups.Ethics and disseminationFormal ethical approval is not required as no primary data are collected. This systematic review will be disseminated through a peer-reviewed publication.PROSPERO registration numberCRD42018112629
How consultants determine diagnostic competence in histopathology trainees
Authors: Brierley Daniel J , Farthing Paula M , Zijlstra-Shaw Sandra 
Published: June 2019

AimsThis is a qualitative study exploring how consultant histopathologists determine diagnostic competence in their trainees.MethodsSemi-structured interviews were conducted with consultants and trainees and analysed using the Framework Method.ResultsFive major themes emerged from the data: process, person, stage of training, trust and time. Within these major themes, there were multiple subthemes which reflect the complex, longitudinal nature of the judgement, as well as the knowledge, skills and attitudes which are most relevant to diagnostic competence. A conceptual framework is proposed to illustrate the judgement ecology, which is supported by anonymised quotes from interview participants.ConclusionsOur study is the first to explore in depth how consultant histopathologists determine diagnostic competence in their trainees. This is particularly important as histopathology is a unique medical specialty for which there is little evidence to support the current assessment strategies during training. The resulting conceptual model and findings from this study may help to form an evidence base to inform future assessment tools in histopathology.
ExtragenitalMycoplasma genitaliuminfections among men who have sex with men
Authors: Latimer Rosie Louise , Vodstrcil Lenka , De Petra Vesna , Fairley Christopher K , Read Tim RH , Williamson Deborah , Doyle Michelle , Chow Eric PF , Bradshaw Catriona 
Published: June 2019

ObjectivesThere are limited data on the prevalence ofMycoplasma genitalium(Mgen) coinfection with rectal chlamydia (Chlamydia trachomatis(CT)) and rectal gonorrhoea (Neisseria gonorrhoeae(NG)) infections and few studies examining the prevalence of pharyngeal Mgen in men who have sex with men (MSM). Using transcription-mediated amplification assay, this study aimed to determine the proportion of rectal CT and rectal NG infections in MSM who are coinfected with rectal Mgen, and the proportion of MSM with Mgen detected in the pharynx in order to inform clinical practice.MethodsThis was a cross-sectional study conducted at Melbourne Sexual Health Centre in Australia. Consecutively collected rectal swabs from MSM that tested positive for CT (n=212) or NG (n=212), and consecutively collected pharyngeal samples (n=480) from MSM were tested for Mgen using the AptimaMycoplasma genitaliumAssay (Hologic, San Diego). Samples were linked to demographic data and symptom status.ResultsRectal Mgen was codetected in 27 of 212 rectal CT (13%, 95% CI 9 to 18) and in 29 of 212 rectal NG (14%, 95% CI 9 to 19) samples, with no difference in the proportion positive for Mgen. MSM with rectal CT/Mgen coinfection had more sexual partners than those with rectal CT monoinfection (mean 6 vs 11, p=0.06). MSM with rectal NG/Mgen coinfection were more likely to be HIV-positive than those with rectal NG monoinfection (OR=2.96, 95% CI 1.21 to 7.26, p=0.023). MSM with rectal CT/Mgen coinfection were more likely to be using pre-exposure prophylaxis than MSM with rectal NG/Mgen coinfection (OR 0.25, 95% CI 0.10 to 0.65, p=0.002). Pharyngeal Mgen was uncommon and detected in 8 of 464 samples (2%, 95% CI 1% to 3%). Pharyngeal Mgen was associated with having a rectal STI (OR=10.61, 95% CI 2.30 to 48.87, p=0.002), and there was a borderline association with being HIV-positive (p=0.079).ConclusionThese data indicate one in seven MSM treated for rectal CT or rectal NG will have undiagnosed Mgen that is potentially exposed to azithromycin during treatment of these STIs. Rectal Mgen coinfection was associated with specific risk factors which may inform testing practices. Pharyngeal Mgen was uncommon.
Evaluation of Hardware Data Prefetchers on Server Processors
Authors: Bakhshalipour Mohammad , Tabaeiaghdaei Seyedali , Lotfi-Kamran Pejman , Sarbazi-Azad Hamid 
Published: June 2019

Data prefetching, i.e., the act of predicting an application’s future memory accesses and fetching those that are not in the on-chip caches, is a well-known and widely used approach to hide the long latency of memory accesses. The fruitfulness of data prefetching is evident to both industry and academy: Nowadays, almost every high-performance processor incorporates a few data prefetchers for capturing various access patterns of applications; besides, there is a myriad of proposals for data prefetching in the research literature, where each proposal enhances the efficiency of prefetching in a specific way.
In this survey, we evaluate the effectiveness of data prefetching in the context of server applications and shed light on its design trade-offs. To do so, we choose a target architecture based on a contemporary server processor and stack various state-of-the-art data prefetchers on top of it. We analyze the prefetchers in terms of their ability to predict memory accesses and enhance overall system performance, as well as their imposed overheads. Finally, by comparing the state-of-the-art prefetchers with impractical ideal prefetchers, we motivate further work on improving data prefetching techniques.
RETRACTED: KRAS Activation in Gastric Adenocarcinoma Stimulates Epithelial-to-Mesenchymal Transition to Cancer Stem–Like Cells and Promotes Metastasis
Authors: Yoon Changhwan , Till Jacob , Cho Soo-Jeong , Chang Kevin K. , Lin Jian-xian , Huang Chang-ming , Ryeom Sandra , Yoon Sam S. 
Published: June 2019

Abstract

Our previous work showed that in a mouse model of gastric adenocarcinoma with loss of p53 and Cdh1 that adding oncogenic Kras (a.k.a. Tcon mice) accelerates tumorigenesis and metastasis. Here, we sought to examine KRAS activation in epithelial-to-mesenchymal transition (EMT) and generation of cancer stem–like cells (CSC). Transduction of nontransformed HFE-145 gastric epithelial cells with oncogenic KRASG12V significantly decreased expression of the epithelial marker E-cadherin, increased expression of the mesenchymal marker vimentin and the EMT transcription factor Slug, and increased migration and invasion by 15- to 17-fold. KRASG12V also increased expression of self-renewal proteins such as Sox2 and increased spheroid formation by 2.6-fold. In tumor-derived organoids from Tcon mice, Kras knockdown decreased spheroid formation, expression of EMT-related proteins, migration, and invasion; similar effects, as well as reversal of chemoresistance, were observed following KRAS knockdown or MEK inhibition in patient tumor-derived gastric adenocarcinoma cell lines (AGS and KATOIII). KRAS inhibition in gastric adenocarcinoma spheroid cells led to reduced AGS flank xenograft growth, loss of the infiltrative tumor border, fewer lung metastases, and increased survival. In a tissue microarray of human gastric adenocarcinomas from 115 patients, high tumor levels of CD44 (a marker of CSCs) and KRAS activation were independent predictors of worse overall survival. In conclusion, KRAS activation in gastric adenocarcinoma cells stimulates EMT and transition to CSCs, thus promoting metastasis.

Implications:
This study provides rationale for examining inhibitors of KRAS to block metastasis and reverse chemotherapy resistance in gastric adenocarcinoma patients.
Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer
Authors: Gurjao Carino , Liu David , Hofree Matan , AlDubayan Saud H. , Wakiro Isaac , Su Mei-Ju , Felt Kristen , Gjini Evisa , Brais Lauren K. , Rotem Asaf , Rosenthal Michael H. , Rozenblatt-Rosen Orit , Rodig Scott , Ng Kimmie , Van Allen Eliezer M. , Corsello Steven M. , Ogino Shuji , Regev Aviv , Nowak Jonathan A. , Giannakis Marios 
Published: June 2019

Abstract
Immunotherapy with checkpoint inhibitors, such as the programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab, are effective in a variety of tumors, yet not all patients respond. Tumor microsatellite instability-high (MSI-H) has emerged as a biomarker of response to checkpoint blockade, leading to the tissue agnostic approval of pembrolizumab in MSI-H cancers. Here we describe a patient with MSI-H colorectal cancer that was treated with this immune checkpoint inhibitor and exhibited progression of disease. We examined this intrinsic resistance through genomic, transcriptional, and pathologic characterization of the patient's tumor and the associated immune microenvironment. The tumor had typical MSI-H molecular features, including a high neoantigen load. We also identified biallelic loss of the gene for β2-microglobulin (B2M), whose product is critical for antigen presentation. Immune infiltration deconvolution analysis of bulk transcriptome data from this anti-PD-1–resistant tumor and hundreds of other colorectal cancer specimens revealed a high natural killer cell and M2 macrophage infiltration in the patient's cancer. This was confirmed by single-cell transcriptome analysis and multiplex immunofluorescence. Our study provides insight into resistance in MSI-H tumors and suggests immunotherapeutic strategies in additional genomic contexts of colorectal cancer.