Tethered hydroxyl‐radical probing has been used to determine the orientation of binding of polypyrimidine tract‐binding protein (PTB) to the poliovirus type 1 (Mahoney) (PV‐1(M)) internal ribosome ...entry site/segment (IRES)—the question of which RNA‐binding domain (RBD) binds to which sites on the IRES. The results show that under conditions in which PTB strongly stimulates IRES activity, a single PTB is binding to the IRES, a finding which was confirmed by mass spectrometry of PTB/IRES complexes. RBDs1 and 2 interact with the basal part of the Domain V irregular stem loop, very close to the binding site of eIF4G, and RBDs3 and 4 interact with the single‐stranded regions flanking Domain V. The binding of PTB is subtly altered in the presence of the central domain (p50) of eIF4G, and p50 binding is likewise modified if PTB is present. This suggests that PTB stimulates PV‐1(M) IRES activity by inducing eIF4G to bind in the optimal position and orientation to promote internal ribosome entry, which, in PV‐1(M), is at an AUG triplet 30 nt downstream of the base of Domain V.
Internal initiation of translation on picornavirus IRESs requires canonical initiation factors as well as specific IRES trans‐acting factors, such as the pyrimidine tract‐binding protein PTB, whose mode of action has remained largely unclear. Now, Richard Jackson et al elucidate the mechanistic function of PTB in poliovirus type 1 IRES‐mediated translation initiation.
Electronic healthcare records (EHRs) are a rich source of information, with huge potential for secondary research use. The aim of this study was to develop an application to identify instances of ...Adverse Drug Events (ADEs) from free text psychiatric EHRs.
We used the GATE Natural Language Processing (NLP) software to mine instances of ADEs from free text content within the Clinical Record Interactive Search (CRIS) system, a de-identified psychiatric case register developed at the South London and Maudsley NHS Foundation Trust, UK. The tool was built around a set of four movement disorders (extrapyramidal side effects EPSEs) related to antipsychotic therapy and rules were then generalised such that the tool could be applied to additional ADEs. We report the frequencies of recorded EPSEs in patients diagnosed with a Severe Mental Illness (SMI) and then report performance in identifying eight other unrelated ADEs.
The tool identified EPSEs with >0.85 precision and >0.86 recall during testing. Akathisia was found to be the most prevalent EPSE overall and occurred in the Asian ethnic group with a frequency of 8.13%. The tool performed well when applied to most of the non-EPSEs but least well when applied to rare conditions such as myocarditis, a condition that appears frequently in the text as a side effect warning to patients.
The developed tool allows us to accurately identify instances of a potential ADE from psychiatric EHRs. As such, we were able to study the prevalence of ADEs within subgroups of patients stratified by SMI diagnosis, gender, age and ethnicity. In addition we demonstrated the generalisability of the application to other ADE types by producing a high precision rate on a non-EPSE related set of ADE containing documents.
The application can be found at http://git.brc.iop.kcl.ac.uk/rmallah/dystoniaml.
Clozapine can cause severe adverse effects yet it is associated with reduced mortality risk. We test the hypothesis this association is due to increased clinical monitoring and investigate risk of ...premature mortality from natural causes. We identified 14 754 individuals (879 deaths) with serious mental illness (SMI) including schizophrenia, schizoaffective and bipolar disorders aged ≥ 15 years in a large specialist mental healthcare case register linked to national mortality tracing. In this cohort study we modeled the effect of clozapine on mortality over a 5-year period (2007-2011) using Cox regression. Individuals prescribed clozapine had more severe psychopathology and poorer functional status. Many of the exposures associated with clozapine use were themselves risk factors for increased mortality. However, we identified a strong association between being prescribed clozapine and lower mortality which persisted after controlling for a broad range of potential confounders including clinical monitoring and markers of disease severity (adjusted hazard ratio 0.4; 95% CI 0.2-0.7; p = .001). This association remained after restricting the sample to those with a diagnosis of schizophrenia or those taking antipsychotics and after using propensity scores to reduce the impact of confounding by indication. Among individuals with SMI, those prescribed clozapine had a reduced risk of mortality due to both natural and unnatural causes. We found no evidence to indicate that lower mortality associated with clozapine in SMI was due to increased clinical monitoring or confounding factors. This is the first study to report an association between clozapine and reduced risk of mortality from natural causes.
Traditional health information systems are generally devised to support clinical data collection at the point of care. However, as the significance of the modern information economy expands in scope ...and permeates the healthcare domain, there is an increasing urgency for healthcare organisations to offer information systems that address the expectations of clinicians, researchers and the business intelligence community alike. Amongst other emergent requirements, the principal unmet need might be defined as the 3R principle (right data, right place, right time) to address deficiencies in organisational data flow while retaining the strict information governance policies that apply within the UK National Health Service (NHS). Here, we describe our work on creating and deploying a low cost structured and unstructured information retrieval and extraction architecture within King's College Hospital, the management of governance concerns and the associated use cases and cost saving opportunities that such components present.
To date, our CogStack architecture has processed over 300 million lines of clinical data, making it available for internal service improvement projects at King's College London. On generated data designed to simulate real world clinical text, our de-identification algorithm achieved up to 94% precision and up to 96% recall.
We describe a toolkit which we feel is of huge value to the UK (and beyond) healthcare community. It is the only open source, easily deployable solution designed for the UK healthcare environment, in a landscape populated by expensive proprietary systems. Solutions such as these provide a crucial foundation for the genomic revolution in medicine.
Background. Improving human papilloma virus (HPV) vaccination coverage in the US will require healthcare providers to recommend the vaccine more effectively. To inform quality improvement efforts, we ...systematically reviewed studies of dental provider communication about HPV vaccination.
Methods. We searched MEDLINE, CINAHL, ScienceDirect, PsycINFO and JSTOR in August 2018 to identify studies of dental provider knowledge, perceived role and communication about HPV, HPV vaccination and HPV-associated oropharyngeal cancer (HPV-OPC).
Results. We identified 10 qualitative and quantitative studies. Results of the primarily descriptive studies showed that although there were some deficiencies in knowledge about HPV-related outcomes and its effect on the male population, most providers understand HPV as a sexually transmitted infection and know the HPV vaccine is available, yet many are not discussing the HPV-OPC link or recommending vaccination. Providers were less often to recommend HPV vaccination if they were uncomfortable discussing sex, perceived parents as hesitant, or believed patients to be low risk. Studies reported mixed results on providers' perceived role in expanded HPV vaccination and HPV-OPC education, but indicated support for the role of professional organizations in promoting awareness.
Conclusion. Interventions are needed to help dental providers perceive their role to deliver effective recommendations within the complex communication environment surrounding HPV vaccination and HPV-OPC education.
The problem of associating a continuous covariate, or biomarker, against a time‐to‐event outcome, is that it often requires categorisation of the covariate. This can lead to bias, loss of information ...and a poor representation of any underlying relationship. Here, two methods are proposed for estimating the effects of a continuous covariate on a time‐to‐event endpoint using weighted kernel estimators. The first method aims to estimate a density function for a time‐to‐event endpoint conditional on some covariate value whilst the second uses a joint density estimator. The results are visualisations in the form of surface plots that show the effects of a covariate without any need for categorisation. Both methods can aid interpretation and analysis of covariates against a time‐to‐event endpoint.
OBJECTIVESThe objective of this review was to determine the rate and risk factors of paratracheal lymph node (PTLN) involvement during total laryngectomy (TL) or total pharyngolaryngectomy (TPL). In ...addition, we aimed to assess its prognostic significance in terms of survival and peristomal recurrence. METHODSA comprehensive electronic search was performed on PubMed, EMBASE, and CENTRAL databases. We searched for studies reporting outcomes of PTLN dissection during radical laryngeal surgery for squamous cell carcinoma of the larynx, hypopharynx or cervical oesophagus. RESULTSWe included a total of ten studies (838 patients). The overall rate of PTLN dissection positivity was 18.6% (20.7% for primary TL, 8.7% for salvage TL). Random-effects meta-analysis identified T4 stage, N+ stage of the lateral neck, subglottis involvement and primary tumour arising from the hypopharynx or cervical oesophagus as significant risk factors for PTLN involvement. CONCLUSIONSThis meta-analysis allowed to better define the risk of PTLN involvement during TL or TPL, in a bid to guide indication for PTLN dissection. There is a need for further large studies reporting rigorously the outcomes of PTLN dissection in order to establish stronger evidence-based recommendations.
GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome.
is the second most expressed GATA factor in ...the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy.
We analysed PDAC transcriptomic data, stratifying cases according to
and
expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of
knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models.
messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for
and
. Reduced expression of
had a minor transcriptional impact but low expression of
enhanced the effects of
low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival.
and
expression significantly decreased in metastases and negatively correlated with basal markers.
and
cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.
Treatment of juxtarenal and complex neck abdominal aortic aneurysms (AAAs) is now commonly by endovascular rather than open surgical repair (OSR). Published comparisons show poor validity and ...scientific precision. UK-COMPASS is a comparative cohort study of endovascular treatments vs. OSR for patients with an AAA unsuitable for standard on label endovascular aneurysm repair (EVAR).
All procedures for AAA in England (November 2017 to October 2019) were identified, AAA anatomy assessed in a Corelab, peri-operative risk scores determined, and propensity scoring used to identify patients suitable for either endovascular treatment or OSR. Patients were stratified by aneurysm neck length (0 – 4 mm, 5 – 9 mm, or ≥ 10 mm) and operative risk; the highest quartile was considered high risk and the remainder standard risk. Death was the primary outcome measure. Endovascular treatments included fenestrated EVAR (FEVAR) and off label standard EVAR (± adjuncts).
Among 8 994 patients, 2 757 had AAAs that were juxtarenal, short neck, or complex neck in morphology. Propensity score stratification and adjustment method comparisons included 1 916 patients. Widespread off label use of standard EVAR devices was noted (35.6% of patients). The adjusted peri-operative mortality rate was 2.9%, lower for EVAR (1.2%; p = .001) and FEVAR (2.2%; p = .001) than OSR (4.5%). In standard risk patients with a 0 – 4 mm neck, the mortality rate was 7.4% following OSR and 2.3% following FEVAR. Differences were smaller for patients with a neck length ≥ 5 mm: 2.1% OSR vs. 1.0% FEVAR. At 3.5 years of follow up, the overall mortality rate was 20.7% in the whole study population, higher following FEVAR (27.6%) and EVAR (25.2%) than after OSR (14.2%). However, in the 0 – 4 mm neck subgroup, overall survival remained equivalent. The aneurysm related mortality rate was equivalent between treatments, but re-intervention was more common after EVAR and FEVAR than OSR.
FEVAR proves notably safer than OSR in the peri-operative period for juxtarenal aneurysms (0 – 4 mm neck length), with comparable midterm survival. For patients with short neck (5 – 9 mm) and complex neck (≥ 10 mm) AAAs, overall survival was worse in endovascularly treated patients compared with OSR despite relative peri-operative safety. This warrants further research and a re-appraisal of the current clinical application of endovascular strategies, particularly in patients with poor general survival outlook owing to comorbidity and age.
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