Muddy, muddled, or muffled? Understanding the perception of audio quality in music by hearing aid users.

Introduction: Previous work on audio quality evaluation has demonstrated a developing convergence of the key perceptual attributes underlying judgments of quality, such as timbral, spatial and technical attributes. However, across existing research there remains a limited understanding of the crucial perceptual attributes that inform audio quality evaluation for people with hearing loss, and those who use hearing aids. This is especially the case with music, given the unique problems it presents in contrast to human speech. Method: This paper presents a sensory evaluation study utilising descriptive analysis methods, in which a panel of hearing aid users collaborated, through consensus, to identify the most important perceptual attributes of music audio quality and developed a series of rating scales for future listening tests. Participants (N = 12), with a hearing loss ranging from mild to severe, first completed an online elicitation task, providing single-word terms to describe the audio quality of original and processed music samples; this was completed twice by each participant, once with hearing aids, and once without. Participants were then guided in discussing these raw terms across three focus groups, in which they reduced the term space, identified important perceptual groupings of terms, and developed perceptual attributes from these groups (including rating scales and definitions for each). Results: Findings show that there were seven key perceptual dimensions underlying music audio quality (clarity, harshness, distortion, spaciousness, treble strength, middle strength, and bass strength), alongside a music audio quality attribute and possible alternative frequency balance attributes. Discussion: We outline how these perceptual attributes align with extant literature, how attribute rating instruments might be used in future work, and the importance of better understanding the music listening difficulties of people with varied profiles of hearing loss.

Improving the measurement and acoustic performance of transparent face masks and shields.

Opaque face masks harm communication by preventing speech-reading (lip-reading) and attenuating high-frequency sound. Although transparent masks and shields (visors) with clear plastic inserts allow speech-reading, they usually create more sound attenuation than opaque masks. Consequently, an iterative process was undertaken to create a better design, and the instructions to make it are published. The experiments showed that lowering the mass of the plastic inserts decreases the high-frequency sound attenuation. A shield with a clear thermoplastic polyurethane (TPU) panel had an insertion loss of (2.0 ± 1.1) dB for 1.25-8 kHz, which improves on previous designs that had attenuations of 11.9 dB and above. A cloth mask with a TPU insert was designed and had an insertion loss of (4.6 ± 2.3) dB for 2-8 kHz, which is better than the 9-22 dB reported previously in the literature. The speech intelligibility index was also evaluated. Investigations to improve measurement protocols that use either mannikins or human talkers were undertaken. Manufacturing variability and inconsistency of human speaking were greater sources of experimental error than fitting differences. It was shown that measurements from a mannikin could match those from humans if insertion losses from four human talkers were averaged.

Dataset of British English speech recordings for psychoacoustics and speech processing research: The clarity speech corpus.

This paper presents the Clarity Speech Corpus, a publicly available, forty speaker British English speech dataset. The corpus was created for the purpose of running listening tests to gauge speech intelligibility and quality in the Clarity Project, which has the goal of advancing speech signal processing by hearing aids through a series of challenges. The dataset is suitable for machine learning and other uses in speech and hearing technology, acoustics and psychoacoustics. The data comprises recordings of approximately 10,000 sentences drawn from the British National Corpus (BNC) with suitable length, words and grammatical construction for speech intelligibility testing. The collection process involved the selection of a subset of BNC sentences, the recording of these produced by 40 British English speakers, and the processing of these recordings to create individual sentence recordings with associated transcripts and metadata.

Kernel hazard estimation for visualisation of the effect of a continuous covariates on time-to-event endpoints.

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.

The effects of neoadjuvant chemoradiotherapy and an in-hospital exercise training programme on physical fitness and quality of life in locally advanced rectal cancer patients: a randomised controlled trial (The EMPOWER Trial).

BACKGROUND: The EMPOWER trial aimed to assess the effects of a 9-week exercise prehabilitation programme on physical fitness compared with a usual care control group. Secondary aims were to investigate the effect of (1) the exercise prehabilitation programme on psychological health; and (2) neoadjuvant chemoradiotherapy (NCRT) on physical fitness and psychological health. METHODS: Between October 2013 and December 2016, adults with locally advanced rectal cancer undergoing standardised NCRT and surgery were recruited to a multi-centre trial. Patients underwent cardiopulmonary exercise testing (CPET) and completed HRQoL questionnaires (EORTC-QLQ-C30 and EQ-5D-5L) pre-NCRT and post-NCRT (week 0/baseline). At week 0, patients were randomised to exercise prehabilitation or usual care (no intervention). CPET and HRQoL questionnaires were assessed at week 0, 3, 6 and 9, whilst semi-structured interviews were assessed at week 0 and week 9. Changes in oxygen uptake at anaerobic threshold (VO2 at AT (ml kg-1 min-1)) between groups were compared using linear mixed modelling. RESULTS: Thirty-eight patients were recruited, mean age 64 (10.4) years. Of the 38 patients, 33 were randomised: 16 to usual care and 17 to exercise prehabilitation (26 males and 7 females). Exercise prehabilitation significantly improved VO2 at AT at week 9 compared to the usual care. The change from baseline to week 9, when adjusted for baseline, between the randomised groups was + 2.9 ml kg -1 min -1; (95% CI 0.8 to 5.1), p = 0.011. CONCLUSION: A 9-week exercise prehabilitation programme significantly improved fitness following NCRT. These findings have informed the WesFit trial (NCT03509428) which is investigating the effects of community-based multimodal prehabilitation before cancer surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT01914068 . Registered 1 August 2013.

Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial.

BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit. METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression. FUNDING: European Commission Seventh Framework Programme.

Bioelectrical impedance vector analysis (BIVA) as a method to compare body composition differences according to cancer stage and type.

BACKGROUND & AIMS: Bioelectrical impedance vector analysis (BIVA) is a non-invasive method of measuring human body composition. This offers the potential to evaluate nutritional and hydration states in cancer. Analysis of BIVA data using the z-score method (the number of standard deviations away from the mean value of the reference group) has the potential to facilitate comparisons between different cancer types. The aim of this study was to use the BIVA Reactance (R)/Reactance (Xc) z-score method to evaluate body composition differences in cancer, using data from previously published BIVA studies. METHODS: Previous studies using BIVA in cancer were identified from the literature. Bioimpedance measurements were analysed using the BIVA RXc z-score graph. The mean impedance vectors from the studied populations were transformed into standard deviates (with respect to the mean and standard deviation of the reference populations). Body composition was classified according to vector placement (i.e. normal, athletic, cachectic, oedematous and dehydrated). RESULTS: Seven male and three cancer female populations were evaluated. Body composition was classified as normal for the majority (n = 5), followed by cachexia (n = 4) and athletic (n = 1) respectively. Variation in body composition for the studied populations appeared to be related to gender, disease type and severity. CONCLUSIONS: The BIVA RXc z-score method has potential to evaluate body composition differences between cancer groups. This method can study body composition, according to cancer type, stage, gender and ethnicity. Limitations of the method relate to issues concerning the appropriate use of reference populations and variability between bioimpedance analysers. Better body composition assessment has the potential to personalise therapeutic, nutritional and hydration management. Further work is essential to facilitate in-depth evaluation in these areas, in order to achieve meaningful use of BIVA in clinical practice.

The effects of classroom noise on the reading comprehension of adolescents.

An investigation has been carried out to examine the impact of different levels of classroom noise on adolescents' performance on reading and vocabulary-learning tasks. A total of 976 English high school pupils (564 aged 11 to 13 years and 412 aged 14 to 16 years) completed reading tasks on laptop computers while exposed to different levels of classroom noise played through headphones. The tasks consisted of reading science texts, which were followed by multiple-choice questions probing comprehension and word learning. Number of questions attempted, times taken to read the texts and to answer questions were recorded, as well as correct answers to different types of question. The study consisted of two similar experiments, the first comparing performance in classroom noise at levels of 50 and 70 dB LAeq; and the second at levels of 50 and 64 dB LAeq. The results showed that the performance of all pupils was significantly negatively affected in the 70 dB LAeq condition, for the number of questions attempted and the accuracy of answers to factual and word learning questions. It was harder to discern effects at 64 dB LAeq, this level of noise having a detrimental effect upon the older pupils only.

The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma.

OBJECTIVE AND BACKGROUND: Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies. METHODS: Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial. RESULTS: There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9-27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6-30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2-21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence. CONCLUSIONS: R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

Patient-delivered tDCS on chronic neuropathic pain in prior responders to TMS (a randomized controlled pilot study).

BACKGROUND: Successful response to repetitive transcranial magnetic stimulation (rTMS) of the motor cortex requires continued maintenance treatments. Transcranial Direct Current Stimulation (tDCS) may provide a more convenient alternative. METHODS: This pilot study aimed to examine the feasibility of a randomized, double-blind, double-crossover pilot study for patients to self-administer tDCS motor cortex stimulation for 20 minutes/day over five consecutive days. Primary outcomes were as follows: usability of patient-administered tDCS, compliance with device, recruitment, and retention rates. Secondary outcomes were as follows: effect on overall pain levels and quality of life via Short Form-36 anxiety and depression via Hospital Anxiety and Depression Scale, and Mini-Mental State scores. RESULTS: A total of 24 subjects with neuropathic pain, who had previously experienced rTMS motor cortex stimulation (13 with reduction in pain scores, 11 nonresponders) were recruited at the Pain Research Institute, Fazakerley, UK. A total of 21 subjects completed the study. Recruitment rate was 100% but retention rate was only 87.5%. All patients reported satisfactory usability of the tDCS device. No significant difference was shown between Sham vs Anodal (-0.16, 95% CI: -0.43 to 0.11) P=0.43, Sham vs Cathodal (0.11, 95% CI: -0.16 to 0.37) P=0.94, or Cathodal vs Anodal (-0.27, 95% CI: -0.54 to 0.00) P=0.053 treatments. Furthermore, no significant changes were demonstrated in anxiety, depression, or quality of life measurements. The data collected to estimate sample size for a definitive study suggested that the study's sample size was already large enough to detect a change of 15% in pain levels at 90% power for the overall group of 21 patients. CONCLUSION: This study did not show a beneficial effect of tDCS in this group of patients and does not support the need for a larger definitive study using the same experimental paradigm. TRIAL REGISTRATION: ISRCTN56839387.

Sound Categories: Category Formation and Evidence-Based Taxonomies.

Five evidence-based taxonomies of everyday sounds frequently reported in the soundscape literature have been generated. An online sorting and category-labeling method that elicits rather than prescribes descriptive words was used. A total of N = 242 participants took part. The main categories of the soundscape taxonomy were people, nature, and manmade, with each dividing into further categories. Sounds within the nature and manmade categories, and two further individual sound sources, dogs, and engines, were explored further by repeating the procedure using multiple exemplars. By generating multidimensional spaces containing both sounds and the spontaneously generated descriptive words the procedure allows for the interpretation of the psychological dimensions along which sounds are organized. This reveals how category formation is based upon different cues - sound source-event identification, subjective-states, and explicit assessment of the acoustic signal - in different contexts. At higher levels of the taxonomy the majority of words described sound source-events. In contrast, when categorizing dog sounds a greater proportion of the words described subjective-states, and valence and arousal scores of these words correlated with their coordinates along the first two dimensions of the data. This is consistent with valence and arousal judgments being the primary categorization strategy used for dog sounds. In contrast, when categorizing engine sounds a greater proportion of the words explicitly described the acoustic signal. The coordinates of sounds along the first two dimensions were found to correlate with fluctuation strength and sharpness, consistent with explicit assessment of acoustic signal features underlying category formation for engine sounds. By eliciting descriptive words the method makes explicit the subjective meaning of these judgments based upon valence and arousal and acoustic properties, and the results demonstrate distinct strategies being spontaneously used to categorize different types of sounds.

Metadiffusers: Deep-subwavelength sound diffusers.

We present deep-subwavelength diffusing surfaces based on acoustic metamaterials, namely metadiffusers. These sound diffusers are rigidly backed slotted panels, with each slit being loaded by an array of Helmholtz resonators. Strong dispersion is produced in the slits and slow sound conditions are induced. Thus, the effective thickness of the panel is lengthened introducing its quarter wavelength resonance in the deep-subwavelength regime. By tuning the geometry of the metamaterial, the reflection coefficient of the panel can be tailored to obtain either a custom reflection phase, moderate or even perfect absorption. Using these concepts, we present ultra-thin diffusers where the geometry of the metadiffuser has been tuned to obtain surfaces with spatially dependent reflection coefficients having uniform magnitude Fourier transforms. Various designs are presented where, quadratic residue, primitive root and ternary sequence diffusers are mimicked by metadiffusers whose thickness are 1/46 to 1/20 times the design wavelength, i.e., between about a twentieth and a tenth of the thickness of traditional designs. Finally, a broadband metadiffuser panel of 3 cm thick was designed using optimization methods for frequencies ranging from 250 Hz to 2 kHz.

Time-dependent ROC curve analysis in medical research: current methods and applications.

BACKGROUND: ROC (receiver operating characteristic) curve analysis is well established for assessing how well a marker is capable of discriminating between individuals who experience disease onset and individuals who do not. The classical (standard) approach of ROC curve analysis considers event (disease) status and marker value for an individual as fixed over time, however in practice, both the disease status and marker value change over time. Individuals who are disease-free earlier may develop the disease later due to longer study follow-up, and also their marker value may change from baseline during follow-up. Thus, an ROC curve as a function of time is more appropriate. However, many researchers still use the standard ROC curve approach to determine the marker capability ignoring the time dependency of the disease status or the marker. METHODS: We comprehensively review currently proposed methodologies of time-dependent ROC curves which use single or longitudinal marker measurements, aiming to provide clarity in each methodology, identify software tools to carry out such analysis in practice and illustrate several applications of the methodology. We have also extended some methods to incorporate a longitudinal marker and illustrated the methodologies using a sequential dataset from the Mayo Clinic trial in primary biliary cirrhosis (PBC) of the liver. RESULTS: From our methodological review, we have identified 18 estimation methods of time-dependent ROC curve analyses for censored event times and three other methods can only deal with non-censored event times. Despite the considerable numbers of estimation methods, applications of the methodology in clinical studies are still lacking. CONCLUSIONS: The value of time-dependent ROC curve methods has been re-established. We have illustrated the methods in practice using currently available software and made some recommendations for future research.

Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial.

BACKGROUND: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer. METHODS: The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus gemcitabine (vandetanib group) or placebo plus gemcitabine (placebo group) according to pre-generated sequences produced on the principle of randomly permuted blocks with variable block sizes of two and four. Patients were stratified at randomisation by disease stage and ECOG performance status. All patients received gemcitabine 1000 mg/m2 as a 30-min intravenous infusion, weekly, for 7 weeks followed by a 1-week break, followed by a cycle of 3 weeks of treatment with a 1-week break, until disease progression, and either oral vandetanib 300 mg per day once daily or matching placebo. Patients and investigators were masked to treatment assignment. The primary outcome measure was overall survival (defined as the difference in time between randomisation and death from any cause or the censor date) in the intention-to-treat population. This trial has been completed and the final results are reported. The study is registered at EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Patients were screened and enrolled between Oct 24, 2011, and Oct 7, 2013. Of 381 patients screened, 142 eligible patients were randomly assigned to treatment (72 to the vandetanib group and 70 to the placebo group). At database lock on July 15, 2015, at a median follow-up of 24·9 months (IQR 24·3 to not attainable), 131 patients had died: 70 (97%) of 72 in the vandetanib group and 61 (87%) of 70 in the placebo group. The median overall survival was 8·83 months (95% CI 7·11-11·58) in the vandetanib group and 8·95 months (6·55-11·74) in the placebo group (hazard ratio 1·21, 80·8% CI 0·95-1·53; log rank χ21df 1·1, p=0·303). The most common grade 3-4 adverse events were neutropenia (35 [49%] of 72 patients in the vandetanib group vs 22 [31%] of 70 in the placebo group), thrombocytopenia (20 [28%] vs 16 [23%]), hypertension (nine [13%] vs 11 [16%]), leucopenia (12 [17%] vs 13 [19%]), and fatigue (17 [24%] vs 15 [21%]). No treatment-related deaths occurred during the study. INTERPRETATION: The addition of vandetanib to gemcitabine monotherapy did not improve overall survival in advanced pancreatic cancer. Tyrosine kinase inhibitors might still have potential in the treatment of pancreatic cancer but further development requires the identification of biomarkers to specifically identify responsive cancer subtypes. FUNDING: Cancer Research UK and AstraZeneca.

Dual-focus Magnification, High-Definition Endoscopy Improves Pathology Detection in Direct-to-Test Diagnostic Upper Gastrointestinal Endoscopy.

BACKGROUND: In the UK, the majority of diagnostic upper gastrointestinal (UGI) endoscopies are a result of direct-to-test referral from the primary care physician. The diagnostic yield of these tests is relatively low, and the burden high on endoscopy services. Dual-focus magnification, high-definition endoscopy is expected to improve detection and classification of UGI mucosal lesions and also help minimize biopsies by allowing better targeting. METHODS: This is a retrospective study of patients attending for direct-to-test UGI endoscopy from January 2015 to June 2015. The primary outcome of interest was the identification of significant pathology. Detection of significant pathology was modelled using logistic regression. RESULTS: 500 procedures were included. The mean age of patients was 61.5 (±15.6) years; 60.8% of patients were female. Ninety-four gastroscopies were performed using dual-focus magnification high-definition endoscopy. Increasing age, male gender, type of endoscope, and type of operator were all identified as significant factors influencing the odds of detecting significant mucosal pathology. Use of dual-focus magnification, high-definition endoscopy was associated with an odds ratio of 1.87 (95%CI 1.11-3.12) favouring the detection of significant pathology. Subsequent analysis suggested that the increased detection of pathology during dual-focus magnification, high-definition endoscopy also influenced patient follow-up and led to a 3.0 fold (p=0.04) increase in the proportion of patients entered into an UGI endoscopic surveillance program. CONCLUSION: Dual-focus magnification, high-definition endoscopy improved the diagnostic yield for significant mucosal pathology in patients referred for direct-to-test endoscopy. If this finding is recapitulated elsewhere it will have substantial impact on the provision of UGI endoscopic services.

GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer.

BACKGROUND AND AIMS: The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC. DESIGN: We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy. RESULTS: GATA6 inhibits the epithelial-mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET2) transition. Patients with basal-like GATA6low tumours have a shorter survival and have a distinctly poor response to adjuvant 5-fluorouracil (5-FU)/leucovorin. However, modulation of GATA6 expression in cultured cells does not directly regulate response to 5-FU. CONCLUSIONS: We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy.

New-Generation High-Definition Colonoscopes Increase Adenoma Detection when Screening a Moderate-Risk Population for Colorectal Cancer.

BACKGROUND AND AIM: Adenoma detection rate (ADR) is the most important quality indicator for screening colonoscopy, due to its association with colorectal cancer outcomes. As a result, a number of techniques and technologies have been proposed that have the potential to improve ADR. The aim of this study was to assess the potential impact of new-generation high-definition (HD) colonoscopy on ADR within the Bowel Cancer Screening Programme (BCSP). METHOD: This was a retrospective single-center observational study in patients undergoing an index screening colonoscopy. The examination was performed with either standard-definition colonoscopes (Olympus Q240/Q260 series) or HD colonoscopes (Olympus HQ290 EVIS LUCERA ELITE system) with the primary outcome measures of ADR and mean adenoma per procedure (MAP) between the 2 groups. RESULTS: A total of 395 patients (60.5% male, mean age 66.8 years) underwent screening colonoscopy with 45% performed with HD colonoscopes. The cecal intubation rate was 97.5% on an intention-to-treat basis and ADR was 68.6%. ADR with standard-definition was 63.13%, compared with 75.71% with HD (P = .007). The MAP in the HD group was 2.1 (± 2.0), whereas in the standard-definition group it was 1.6 (± 1.8) (P = .01). There was no significant difference in withdrawal time between the 2 groups. In the multivariate regression model, only HD scopes (P = .03) and male sex (P = .04) independently influenced ADR. CONCLUSION: Olympus H290 LUCERA ELITE HD colonoscopes improved adenoma detection within the moderate-risk population. A 12% improvement in ADR might be expected to increase significantly the protection afforded by colonoscopy against subsequent colorectal cancer mortality.

Neutrophil biomarkers predict response to therapy with tumor necrosis factor inhibitors in rheumatoid arthritis.

Neutrophils are implicated in the pathology of rheumatoid arthritis (RA), but the mechanisms regulating their activation are largely unknown. RA is a heterogeneous disease, and whereas many patients show clinical improvement during TNF inhibitor (TNFi) therapy, a significant proportion fails to respond. In vitro activation of neutrophils with agents, including TNF, results in rapid and selective changes in gene expression, but how neutrophils contribute to TNF signaling in RA and whether TNFi sensitivity involves differential neutrophil responses are unknown. With the use of RNA sequencing (RNA-Seq), we analyzed blood neutrophils from 20 RA patients, pre-TNFi therapy, to identify biomarkers of response, measured by a decrease in disease activity score based on 28 joint count (DAS28), 12 wk post-therapy. Biomarkers were validated by quantitative PCR (qPCR) of blood neutrophils from 2 further independent cohorts of RA patients: 16 pre-TNFi and 16 predisease-modifying anti-rheumatic drugs (DMARDs). Twenty-three neutrophil transcripts predicted a 12-wk response to TNFi: 10 (IFN-regulated) genes predicting a European League against Rheumatism (EULAR) good response and 13 different genes [neutrophil granule protein (NGP) genes] predicting a nonresponse. Statistical analysis indicated a predictive sensitivity and specificity of each gene in the panel of >80%, with some 100% specific. A combination of 3 genes [cytidine monophosphate kinase 2 (CMPK2), IFN-induced protein with tetratricopeptide repeats 1B (IFIT1B), and RNASE3] had the greatest predictive power [area under the curve (AUC) 0.94]. No correlation was found for a response to DMARDs. We conclude that this panel of genes is selective for predicting a response to TNFi and is not a surrogate marker for disease improvement. We also show that in RA, there is great plasticity in neutrophil phenotype, with circulating cells expressing genes normally only expressed in more immature cells.

A metric for predicting binaural speech intelligibility in stationary noise and competing speech maskers.

One criterion in the design of binaural sound scenes in audio production is the extent to which the intended speech message is correctly understood. Object-based audio broadcasting systems have permitted sound editors to gain more access to the metadata (e.g., intensity and location) of each sound source, providing better control over speech intelligibility. The current study describes and evaluates a binaural distortion-weighted glimpse proportion metric-BiDWGP-which is motivated by better-ear glimpsing and binaural masking level differences. BiDWGP predicts intelligibility from two alternative input forms: either binaural recordings or monophonic recordings from each sound source along with their locations. Two listening experiments were performed with stationary noise and competing speech, one in the presence of a single masker, the other with multiple maskers, for a variety of spatial configurations. Overall, BiDWGP with both input forms predicts listener keyword scores with correlations of 0.95 and 0.91 for single- and multi-masker conditions, respectively. When considering masker type separately, correlations rise to 0.95 and above for both types of maskers. Predictions using the two input forms are very similar, suggesting that BiDWGP can be applied to the design of sound scenes where only individual sound sources and their locations are available.

The Association of Hydration Status with Physical Signs, Symptoms and Survival in Advanced Cancer-The Use of Bioelectrical Impedance Vector Analysis (BIVA) Technology to Evaluate Fluid Volume in Palliative Care: An Observational Study.

BACKGROUND: Hydration in advanced cancer is a controversial area; however, current hydration assessments methods are poorly developed. Bioelectrical impedance vector analysis (BIVA) is an accurate hydration tool; however its application in advanced cancer has not been explored. This study used BIVA to evaluate hydration status in advanced cancer to examine the association of fluid status with symptoms, physical signs, renal biochemical measures and survival. MATERIALS AND METHODS: An observational study of 90 adults with advanced cancer receiving care in a UK specialist palliative care inpatient unit was conducted. Hydration status was assessed using BIVA in addition to assessments of symptoms, physical signs, performance status, renal biochemical measures, oral fluid intake and medications. The association of clinical variables with hydration was evaluated using regression analysis. A survival analysis was conducted to examine the influence of hydration status and renal failure. RESULTS: The hydration status of participants was normal in 43 (47.8%), 'more hydrated' in 37 (41.1%) and 'less hydrated' in 10 (11.1%). Lower hydration was associated with increased symptom intensity (Beta = -0.29, p = 0.04) and higher scores for physical signs associated with dehydration (Beta = 10.94, p = 0.02). Higher hydration was associated with oedema (Beta = 2.55, p<0.001). Median survival was statistically significantly shorter in 'less hydrated' patients (44 vs. 68 days; p = 0.049) and in pre-renal failure (44 vs. 100 days; p = 0.003). CONCLUSIONS: In advanced cancer, hydration status was associated with clinical signs and symptoms. Hydration status and pre-renal failure were independent predictors of survival. Further studies can establish the utility of BIVA as a standardised hydration assessment tool and explore its potential research application, in order to inform the clinical management of fluid balance in patients with advanced cancer.