Divergent effects of listening demands and evaluative threat on listening effort in online and laboratory settings.

Objective: Listening effort (LE) varies as a function of listening demands, motivation and resource availability, among other things. Motivation is posited to have a greater influence on listening effort under high, compared to low, listening demands. Methods: To test this prediction, we manipulated the listening demands of a speech recognition task using tone vocoders to create moderate and high listening demand conditions. We manipulated motivation using evaluative threat, i.e., informing participants that they must reach a particular "score" for their results to be usable. Resource availability was assessed by means of working memory span and included as a fixed effects predictor. Outcome measures were indices of LE, including reaction times (RTs), self-rated work and self-rated tiredness, in addition to task performance (correct response rates). Given the recent popularity of online studies, we also wanted to examine the effect of experimental context (online vs. laboratory) on the efficacy of manipulations of listening demands and motivation. We carried out two highly similar experiments with two groups of 37 young adults, a laboratory experiment and an online experiment. To make listening demands comparable between the two studies, vocoder settings had to differ. All results were analysed using linear mixed models. Results: Results showed that under laboratory conditions, listening demands affected all outcomes, with significantly lower correct response rates, slower RTs and greater self-rated work with higher listening demands. In the online study, listening demands only affected RTs. In addition, motivation affected self-rated work. Resource availability was only a significant predictor for RTs in the online study. Discussion: These results show that the influence of motivation and listening demands on LE depends on the type of outcome measures used and the experimental context. It may also depend on the exact vocoder settings. A controlled laboratory settings and/or particular vocoder settings may be necessary to observe all expected effects of listening demands and motivation.

Low-Volume Bowel Preparation Is Associated With Reduced Time to Colonoscopy in Hospitalized Patients: A Propensity-Matched Analysis.

INTRODUCTION: Delays in inpatient colonoscopy are commonly caused by inadequate bowel preparation and result in increased hospital length of stay (LOS) and healthcare costs. Low-volume bowel preparation (LV-BP; sodium sulfate, potassium sulfate, and magnesium sulfate ) has been shown to improve outpatient bowel preparation quality compared with standard high-volume bowel preparations (HV-BP; polyethylene glycol ). However, its efficacy in hospitalized patients has not been well-studied. We assessed the impact of LV-BP on time to colonoscopy, hospital LOS, and bowel preparation quality among inpatients. METHODS: We performed a propensity score-matched analysis of adult inpatients undergoing colonoscopy who received either LV-BP or HV-BP before colonoscopy at a quaternary academic medical center. Multivariate regression models with feature selection were developed to assess the association between LV-BP and study outcomes. RESULTS: Among 1,807 inpatients included in this study, 293 and 1,514 patients received LV-BP and HV-BP, respectively. Among the propensity score-matched population, LV-BP was associated with a shorter time to colonoscopy (ß: -0.43 [95% confidence interval: -0.56 to -0.30]) while having similar odds of adequate preparation (odds ratio: 1.02 [95% confidence interval: 0.71-1.46]; P = 0.92). LV-BP was also significantly associated with decreased hospital LOS among older patients (age ≥ 75 years), patients with chronic kidney disease, and patients who were hospitalized with gastrointestinal bleeding. DISCUSSION: LV-BP is associated with decreased time to colonoscopy in hospitalized patients. Older inpatients, inpatients with chronic kidney disease, and inpatients with gastrointestinal bleeding may particularly benefit from LV-BP. Prospective studies are needed to further establish the role of LV-BP for inpatient colonoscopies.

Quantifying the Effects of Motivation on Listening Effort: A Systematic Review and Meta-Analysis.

Motivation influences the amount of listening effort (LE) exerted or experienced under challenging conditions, such as in high-noise environments. This systematic review and meta-analysis is the first to quantify the effects of motivation on LE. The review was pre-registered in PROSPERO, and performed in accordance with PRISMA guidelines. Eligible studies examined the influence of motivation or individual traits (related to motivation) on LE in adults. Motivational factors, coded as independent variables, included financial reward, evaluative threat, perceived competence, feedback, and individual traits. LE outcomes were categorized as subjective, behavioral, or physiological. The quality of evidence was assessed using an adaptation of the Cochrane Collaboration Risk of Bias Tool. Nested random-effects meta-analyses were performed to quantify and compare the influence of motivational factors across LE outcomes. After assessing 3,532 records, 48 studies met the inclusion criteria and 43 were included in the meta-analyses. Risk of bias was high, for example, many studies lacked sample size justification. Motivational factors had a small-to-medium effect (mean Cohen's d = 0.34, range: 0.11-0.72) on LE. When LE outcomes were considered collectively, an external manipulation of motivation (perceived competence) produced a larger mean effect size compared with individual traits. Some combinations of motivational factors and LE outcomes produced more robust effects than others, for example, evaluative threat and subjective LE outcomes. Although wide prediction intervals and high risk of bias mean that significant positive effects cannot be guaranteed, these findings provide useful guidance on the selection of motivational factors and LE outcomes for future research.

A pilot study of virtual reality as an alternative to pharmacological sedation during colonoscopy.

Background and study aims Conscious sedation is routinely administered for colonoscopy but is associated with risks and inconveniences. We sought to determine whether virtual reality (VR) may be a feasible alternative. Patients and methods Twenty-seven individuals scheduled for screening/surveillance colonoscopy participated. The VR device was activated throughout the colonoscopy, but subjects could opt out and request standard medications. Questionnaires were administered, and variables were assessed on a scale of 1 to 10. Results Cecal intubation was achieved in all cases without adverse events (AEs). Study colonoscopies were completed without pharmacological rescue in 26 of 27 patients (96.3 %) and procedure times were comparable to baseline. Subjects reported minimal pain, high satisfaction, and willingness to use VR for future colonoscopies to avoid narcotics and resume normal activities including driving. Conclusion Replacing pharmacological sedation with VR did not impact colonoscopy completion rates, procedure time, or AEs. Satisfaction was high and only one subject (3.7 %) chose to suspend VR. VR can be an effective alternative for patients undergoing colonoscopy who prefer to avoid narcotics.

Financial reward has differential effects on behavioural and self-report measures of listening effort.

OBJECTIVES: To investigate the effects of listening demands and motivation on listening effort (LE) in a novel speech recognition task. DESIGN: We manipulated listening demands and motivation using vocoded speech and financial reward, respectively, and measured task performance (correct response rate) and indices of LE (response times (RTs), subjective ratings of LE and likelihood of giving up). Effects of inter-individual differences in cognitive skills and personality on task performance and LE were also assessed within the context of the Cognitive Energetics Theory (CET). STUDY SAMPLE: Twenty-four participants with normal-hearing (age range: 19 - 33 years, 6 male). RESULTS: High listening demands decreased the correct response rate and increased RTs, self-rated LE and self-rated likelihood of giving up. High financial reward increased subjective LE ratings only. Mixed-effects modelling showed small fixed effects for competitiveness on LE measured using RTs. Small fixed effects were found for cognitive skills (lexical decision RTs and backwards digit span) on LE measured using RTs and correct response rate, respectively. CONCLUSIONS: The effects of listening demands on LE in the speech recognition task aligned with CET, whereas predictions regarding the influence of motivation, cognitive skills and personality were only partially supported.

Dimensions of self-reported listening effort and fatigue on a digits-in-noise task, and association with baseline pupil size and performance accuracy.

OBJECTIVE: Pupillometry is sensitive to cognitive resource allocation and has been used as a potential measure of listening-related effort and fatigue. We investigated associations between peak pupil diameter, pre-stimulus pupil diameter, performance on a listening task, and the dimensionality of self-reported outcomes (task-related listening effort and fatigue). DESIGN: Pupillometry was recorded while participants performed a speech-in-noise task. Participants rated their experience of listening effort and fatigue using the NASA-Task Load Index (NASA-TLX) and the Visual Analogue Scale of Fatigue (VAS-F), respectively. The dimensionality of the NASA-TLX and the VAS-F was investigated using factor analysis. STUDY SAMPLE: 82 participants with either normal hearing or aided hearing impairment (age range: 55-85 years old, 43 male). RESULTS: Hierarchal linear regression analyses suggested that pre-stimulus pupil diameter predicts a dimension of self-reported fatigue, which we interpreted as tiredness/drowsiness, and listening task performance when controlling for hearing level and age: Larger pre-stimulus pupil diameter was associated with less tiredness/drowsiness and better task performance. CONCLUSION: Pre-stimulus pupil diameter is a potential index of listening fatigue associated with speech processing in challenging listening conditions. To our knowledge, this is the first investigation of the associations between pre-stimulus pupil diameter and self-reported ratings of listening effort and fatigue.

Effect of Low-dose and Standard-dose Aspirin on PGE2 Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial.

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8-12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (-4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (-15%; P = 0.018) or 325 mg/day (-28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.

Physicians' Perspectives on Palliative Care for Patients With End-Stage Liver Disease: A National Survey Study.

Specialty palliative care (PC) is underused for patients with end-stage liver disease (ESLD). We sought to examine attitudes of hepatologists and gastroenterologists about PC for patients with ESLD. We conducted a cross-sectional survey of these specialists who provide care to patients with ESLD. Participants were recruited from the American Association for the Study of Liver Diseases membership directory. Using a questionnaire adapted from prior studies, we examined physicians' attitudes about PC and whether these attitudes varied based on patients' candidacy for liver transplantation. We identified predictors of physicians' attitudes about PC using linear regression. Approximately one-third of eligible physicians (396/1236, 32%) completed the survey. Most (95%) believed that centers providing care to patients with ESLD should have PC services, and 86% trusted PC clinicians to care for their patients. Only a minority reported collaborating frequently with inpatient (32%) or outpatient (11%) PC services. Most believed that when patients hear the term PC, they feel scared (94%) and anxious (87%). Most (83%) believed that patients would think nothing more could be done for their underlying disease if a PC referral was suggested. Physicians who believed that ESLD is a terminal condition (B = 1.09; P = 0.006) reported more positive attitudes about PC. Conversely, physicians with negative perceptions of PC for transplant candidates (B = -0.22; standard error = 0.05; P < 0.001) reported more negative attitudes toward PC. In conclusion, although most hepatologists and gastroenterologists believe that patients with ESLD should have access to PC, they reported rarely collaborating with PC teams and had substantial concerns about patients' perceptions of PC. Interventions are needed to overcome misperceptions of PC and to promote collaboration with PC clinicians for patients with ESLD.

Barriers to Use of Palliative Care and Advance Care Planning Discussions for Patients With End-Stage Liver Disease.

BACKGROUND & AIMS: Despite evidence for the benefits of palliative care (PC) referrals and early advance care planning (ACP) discussions for patients with chronic diseases, patients with end-stage liver disease (ESLD) often do not receive such care. We sought to examine physicians' perceptions of the barriers to PC and timely ACP discussions for patients with ESLD. METHODS: We conducted a cross-sectional survey of hepatologists and gastroenterologists who provide care to adult patients with ESLD, recruited from the American Association for the Study of Liver Diseases 2018 membership registry. Using a questionnaire adapted from prior studies, we assessed physicians' perceptions of barriers to PC use and timely ACP discussions; 396 of 1236 eligible physicians (32%) completed the questionnaire. RESULTS: The most commonly cited barriers to PC use were cultural factors that affect perception of PC (by 95% of respondents), unrealistic expectations from patients about their prognosis (by 93% of respondents), and competing demands for clinicians' time (by 91% of respondents). Most respondents (81%) thought that ACP discussions with patients who have ESLD typically occur too late in the course of illness. The most commonly cited barriers to timely ACP discussions were insufficient communication between clinicians and families about goals of care (by 84% of respondents) and insufficient cultural competency training about end-of-life care (81%). CONCLUSION: There are substantial barriers to use of PC and timely discussions about ACP-most hepatologists and gastroenterologists believe that ACP occurs too late for patients with ESLD. Strategies are needed to overcome barriers and increase delivery of high-quality palliative and end-of-life care to patients with ESLD.

ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial.

BACKGROUND: Although aspirin is recommended for the prevention of colorectal cancer, the specific individuals for whom the benefits outweigh the risks are not clearly defined. Moreover, the precise mechanisms by which aspirin reduces the risk of cancer are unclear. We recently launched the ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED) trial to address these uncertainties. METHODS/DESIGN: ASPIRED is a prospective, double-blind, multidose, placebo-controlled, biomarker clinical trial of aspirin use in individuals previously diagnosed with colorectal adenoma. Individuals (n = 180) will be randomized in a 1:1:1 ratio to low-dose (81 mg/day) or standard-dose (325 mg/day) aspirin or placebo. At two study visits, participants will provide lifestyle, dietary and biometric data in addition to urine, saliva and blood specimens. Stool, grossly normal colorectal mucosal biopsies and cytology brushings will be collected during a flexible sigmoidoscopy without bowel preparation. The study will examine the effect of aspirin on urinary prostaglandin metabolites (PGE-M; primary endpoint), plasma inflammatory markers (macrophage inhibitory cytokine-1 (MIC-1)), colonic expression of transcription factor binding (transcription factor 7-like 2 (TCF7L2)), colonocyte gene expression, including hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and those that encode Wnt signaling proteins, colonic cellular nanocytology and oral and gut microbial composition and function. DISCUSSION: Aspirin may prevent colorectal cancer through multiple, interrelated mechanisms. The ASPIRED trial will scrutinize these pathways and investigate putative mechanistically based risk-stratification biomarkers. TRIAL REGISTRATION: This protocol is registered with the U.S. National Institutes of Health trial registry, ClinicalTrials.gov, under the identifier NCT02394769 . Registered on 16 March 2015.

New findings in pancreatic and intestinal endocrine development to advance regenerative medicine.

PURPOSE OF REVIEW: We highlight some of the major recent advances that have been made towards understanding the mechanisms that control endocrine differentiation and cell identity in the pancreas and intestine. RECENT FINDINGS: Notch signaling plays a complex role in the fate choice between endocrine, duct, and acinar lineages in the developing pancreas. New approaches to dissecting the role of mesenchymal cells in the developing endocrine pancreas reveal inhibitory signals from the endothelium. Epigenetic mechanisms represent another layer of control over pancreatic development and ß cell identity. Further details on the transcriptional control of enteroendocrine cell development have emerged and revealed a surprising role for FoxO1 in restraining insulin expression in the gut. Incremental progress is being made in the field of directed differentiation of embryonic stem cells to pancreatic ß cells and the first reported differentiation of human embryonic stem cells into intestinal organoids containing enteroendocrine cells represents a major breakthrough. SUMMARY: Greater knowledge of the fundamental processes controlling endocrine development in the pancreas and intestine has the potential to advance the field of regenerative medicine by providing a pathway to successfully create cell types of clinical interest.

In vivo screening for secreted proteins that modulate glucose handling identifies interleukin-6 family members as potent hypoglycemic agents.

Diabetes is a disease of abnormal glucose homeostasis characterized by chronic hyperglycemia and a broad array of consequent organ damage. Because normal glucose homeostasis is maintained by a complex interaction between behavior (feeding and physical activity) and metabolic activity that is modulated by inter-organ signaling through secreted factors, disease modeling in vitro is necessarily limited. In contrast, in vivo studies allow complex metabolic phenotypes to be studied but present a barrier to high throughput studies. Here we present the development of a novel in vivo screening platform that addresses this primary limitation of in vivo experimentation. Our platform leverages the large secretory capacity of the liver and the hepatocyte transfection technique of hydrodynamic tail vein injection to achieve supraphysiologic blood levels of secreted proteins. To date, the utility of hydrodynamic transfection has been limited by the deleterious impact of the variable transfection efficiency inherent to this technique. We overcome this constraint by co-transfection of a secreted luciferase cDNA whose product can be easily monitored in the blood of a living animal and used as a surrogate marker for transfection efficiency and gene expression levels. To demonstrate the utility of our strategy, we screened 248 secreted proteins for the ability to enhance glucose tolerance. Surprisingly, interleukin-6 and several of its family members but not other well-recognized insulin sensitizing agents were identified as potent hypoglycemic factors. We propose this experimental system as a powerful and flexible in vivo screening platform for identifying genes that modulate complex behavioral and metabolic phenotypes.

Adenosine kinase inhibition selectively promotes rodent and porcine islet ß-cell replication.

Diabetes is a pathological condition characterized by relative insulin deficiency, persistent hyperglycemia, and, consequently, diffuse micro- and macrovascular disease. One therapeutic strategy is to amplify insulin-secretion capacity by increasing the number of the insulin-producing ß cells without triggering a generalized proliferative response. Here, we present the development of a small-molecule screening platform for the identification of molecules that increase ß-cell replication. Using this platform, we identify a class of compounds [adenosine kinase inhibitors (ADK-Is)] that promote replication of primary ß cells in three species (mouse, rat, and pig). Furthermore, the replication effect of ADK-Is is cell type-selective: treatment of islet cell cultures with ADK-Is increases replication of ß cells but not that of α cells, PP cells, or fibroblasts. Short-term in vivo treatment with an ADK-I also increases ß-cell replication but not exocrine cell or hepatocyte replication. Therefore, we propose ADK inhibition as a strategy for the treatment of diabetes.

LIM homeobox transcription factors integrate signaling events that control three-dimensional limb patterning and growth.

Vertebrate limb development is controlled by three signaling centers that regulate limb patterning and growth along the proximodistal (PD), anteroposterior (AP) and dorsoventral (DV) limb axes. Coordination of limb development along these three axes is achieved by interactions and feedback loops involving the secreted signaling molecules that mediate the activities of these signaling centers. However, it is unknown how these signaling interactions are processed in the responding cells. We have found that distinct LIM homeodomain transcription factors, encoded by the LIM homeobox (LIM-HD) genes Lhx2, Lhx9 and Lmx1b integrate the signaling events that link limb patterning and outgrowth along all three axes. Simultaneous loss of Lhx2 and Lhx9 function resulted in patterning and growth defects along the AP and the PD limb axes. Similar, but more severe, phenotypes were observed when the activities of all three factors, Lmx1b, Lhx2 and Lhx9, were significantly reduced by removing their obligatory co-factor Ldb1. This reveals that the dorsal limb-specific factor Lmx1b can partially compensate for the function of Lhx2 and Lhx9 in regulating AP and PD limb patterning and outgrowth. We further showed that Lhx2 and Lhx9 can fully substitute for each other, and that Lmx1b is partially redundant, in controlling the production of output signals in mesenchymal cells in response to Fgf8 and Shh signaling. Our results indicate that several distinct LIM-HD transcription factors in conjunction with their Ldb1 co-factor serve as common central integrators of distinct signaling interactions and feedback loops to coordinate limb patterning and outgrowth along the PD, AP and DV axes after limb bud formation.

Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation.

Wnts are secreted signaling molecules that can transduce their signals through several different pathways. Wnt-5a is considered a noncanonical Wnt as it does not signal by stabilizing beta-catenin in many biological systems. We have uncovered a new noncanonical pathway through which Wnt-5a antagonizes the canonical Wnt pathway by promoting the degradation of beta-catenin. This pathway is Siah2 and APC dependent, but GSK-3 and beta-TrCP independent. Furthermore, we provide evidence that Wnt-5a also acts in vivo to promote beta-catenin degradation in regulating mammalian limb development and possibly in suppressing tumor formation.