Randomized, double-blind, phase 1a single-ascending dose and food effect studies assessing safety and pharmacokinetics of EC5026 in healthy volunteers.

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.

Directing Attention Shapes Learning in Adults but Not Children.

Children sometimes learn distracting information better than adults do, perhaps because of the development of selective attention. To understand this potential link, we ask how the learning of children (aged 7-9 years) and the learning of adults differ when information is the directed focus of attention versus when it is not. Participants viewed drawings of common objects and were told to attend to the drawings (Experiment 1: 42 children, 35 adults) or indicate when shapes (overlaid on the drawings) repeated (Experiment 2: 53 children, 60 adults). Afterward, participants identified fragments of these drawings as quickly as possible. Adults learned better than children when directed to attend to the drawings; however, when drawings were task irrelevant, children showed better learning than adults in the first half of the test. And although directing attention to the drawings improved learning in adults, children learned the drawings similarly across experiments regardless of whether the drawings were the focus of the task or entirely irrelevant.

Quality Improvement Report: Improving Retrieval Time for CT Supplies by Using 5S.

The CT supply room is a critical resource in the imaging workflow. However, the supply room for the two CT scanners at our cancer center, one of which is used for our busy interventional service, was disorganized, and the time spent searching for the appropriate equipment could potentially lead to delays in service and contribute to patient safety risks. The purpose of this project was to reduce the time to find supplies and to increase the satisfaction of CT technologists and medical providers by reorganizing and clearly labeling supplies using "lean" principles. A multidisciplinary team was assembled to reorganize the CT storage using lean 5S methodology (sort, set in order, shine, standardize, and sustain). Baseline and postintervention analysis of the impact of supply reorganization and labeling was performed using three methods: (a) the time recorded for a supply retrieval scavenger hunt, (b) a spaghetti diagram of participant movement during the scavenger hunt, and (c) satisfaction surveys of radiologists and staff. Seven radiology residents participated in the timed supply retrieval scavenger hunt before and after the intervention. Spaghetti diagrams demonstrated a reduction in redundant foot traffic for supply retrieval after the intervention. There was a 61.7% decrease in the average time to retrieve the 10 items in the scavenger hunt (P < .01). Satisfaction surveys after the intervention had statistically significant positive responses compared with those before the intervention. ©RSNA, 2024.

Are Children Performing Better on the Digit Span Backward Task Than the Digit Span Forward Task? An Exploratory Analysis.

PURPOSE: This research note was motivated by community speech-language pathologists (SLPs) who have expressed concerns about how to interpret the unexpected observation of higher performance on the Digit Span Backward task than the Digit Span Forward task on the Test of Integrated Language and Literacy Skills (TILLS). We therefore conducted an exploratory analysis to examine the pattern of digit span performance in children to help clinicians interpret their findings. METHOD: We investigated performance on the Digit Span Forward and Digit Span Backward subtests using the TILLS normative sample (N = 1,262). Raw scores, standard scores, and percentile ranks were systematically compared. In addition, we were able to estimate span length (longest number of items that can be accurately recalled) for 69 participants and evaluated the relation between performance and span length. RESULTS: Our exploratory analyses revealed that "better" performance on the backward than forward task was rare. Instead, the pattern that SLPs are reporting can be explained by three factors: (a) a statistical phenomenon exacerbating small differences, (b) comparing standard scores or percentile ranks instead of raw scores or span length, and (c) better backward scores can still mean longer forward span length. CONCLUSIONS: It is likely that community SLPs tended to report cases of better backward than forward recall because it is the more remarkable and interesting finding, leading to the perception that the pattern is common, when it is not. Overall, we caution clinicians against overinterpreting their own client's performance on the digit span tests.

Taking a second look and zooming out: does this help with abnormality detection in chest radiography?

Purpose: Diagnostic errors are common in radiology. The gestalt impression of an image refers to the rapid holistic understanding one formulates about an image and may facilitate improved diagnostic accuracy. The ability to generate a gestalt impression is typically acquired over time and is generally not explicitly taught. Our study aims to assess whether perceptual training using second look and minification technique (SLMT) can help image interpreters formulate a holistic understanding of an image and become more accurate at evaluating medical images. Approach: Fourteen healthcare trainees voluntarily participated in a perceptual training module, comparing the differences in detection of nodules and other actionable finding (OAF) on chest radiographs before and after perceptual training intervention. The experimental group received SLMT training, and the control group did not. Results: Survey results were positive for all items, with the p-values <0.01. There was improvement in the performance in detection of nodules and OAF in both groups. However, this change was statistically significant only for OAFs in the control group (p-value <0.05) but not the experimental group. Conclusions: SLMT training was viewed by participants as an extremely helpful educational tool. Survey results indicated that participants felt the SLMT was a beneficial educational intervention. The experimental group's detection of nodules and OAF improved after SLMT, though not statistically significantly so, which may be related to the small sample size or lack of training effect. Perceptual training using SLMT may help as a useful educational technique, help radiologists identify abnormalities, and improve workflow.

The Use of Virtual Reality in Teaching Three-Dimensional Anatomy and Pathology on CT.

While radiological imaging is presented as two-dimensional images either on radiography or cross-sectional imaging, it is important for interpreters to understand three-dimensional anatomy and pathology. We hypothesized that virtual reality (VR) may serve as an engaging and effective way for trainees to learn to extrapolate from two-dimensional images to an understanding of these three-dimensional structures. We created a Google Cardboard Virtual Reality application that depicts intracranial vasculature and aneurysms. We then recruited 12 medical students to voluntarily participate in our study. The performance of the students in identifying intracranial aneurysms before and after the virtual reality training was evaluated and compared to a control group. While the experimental group's performance in correctly identifying aneurysms after virtual reality educational intervention was better than the control's (experimental increased by 5.3%, control decreased by 2.1%), the difference was not statistically significant (p-value of 0.06). Significantly, survey data from the medical students was very positive with students noting they preferred the immersive virtual reality training over conventional education and believed that VR would be a helpful educational tool for them in the future. We believe virtual reality can serve as an important tool to help radiology trainees better understand three-dimensional anatomy and pathology.

Lost in descent: Complications of cryptorchidism.

Cryptorchidism is a relatively common and important clinical entity and can lead to an array of downstream complications if it is not corrected in a timely manner, most notably with the development of testicular germ cell tumors. However, beyond the development of malignancy, there are other rare complications associated with cryptorchid testicular germ cell tumors which are more commonly seen in females with ovarian germ cell tumors, including torsion, rupture, and paraneoplastic syndromes. Presented is an instructive case (with literature review) of a patient who presented with NMDA encephalitis due to a torsed mixed germ cell tumor of an undescended testis, which subsequently ruptured leading to growing teratoma syndrome.

Framed and Reframed! The Art of Using Cognitive Behavioral Techniques to Combat Burnout.

The incidence of burnout among radiologists has been increasing exponentially, largely attributed to increased work volumes, expectations for more rapid turn-around times and decreasing interpersonal interactions. While personal wellness activities have been described in the literature, there is little information on the role of cognitive behavioral therapy strategies to mitigate burnout. This manuscript will describe the value of naming automatic negative emotions which can lead to burnout and will provide an overview of strategies that can be used to combat them, using cognitive behavioral therapy techniques.

The role of working memory loads on immediate and long-term sentence recall.

It is well-established that both phonological and semantic knowledge influence verbal working memory. However, the focus has primarily been on understanding phonological effects despite evidence of semantic influences. Articulatory suppression is a well-established task for preventing phonological processing. Methods to prevent semantic processing have rarely been used in the past, highlighting a need for developing a semantic interference task. We, therefore, conceptualised two novel tasks - an animacy categorisation and semantic relatedness judgement task. This study explored the impact of phonological (articulatory suppression) and semantic loads (animacy categorisation and semantic relatedness judgement) on immediate and delayed sentence recall. Additionally, sentence concreteness (concrete vs. abstract sentences) indexed semantic knowledge in verbal working memory. Across two studies, immediate recall revealed that articulatory suppression (preventing phonological processing) increased the size of the concreteness effect, while the novel semantic tasks (preventing semantic processing) reduced it suggesting that our semantic tasks were indeed imposing a semantic load. Further, relative long-term performance showed that more new words were remembered in articulatory suppression, whereas recall was disproportionately impaired in the semantic relatedness task. Our experimental paradigm offers phonological and semantic suppression tasks that can be used in parallel to investigate the interactions between working memory and language.

Evaluating the Modified-Shortened Token Test as a Working Memory and Language Assessment Tool.

PURPOSE: Working memory and linguistic knowledge are highly intertwined in language tasks. Verbal working memory in particular has been studied as a potential constraint on language performance. This, in turn, highlights the need for a clinical assessment tool that will assist clinicians in understanding individual children's performance in relation to working memory and language. In this study, we investigated whether performance on the Token Test could capture differences in verbal working memory and linguistic knowledge given its manipulation of length and syntactic complexity. METHOD: In Experiment 1, 257 children ages 4-7 years completed our Modified-Shortened Token Test, in which they carried out commands of increasing length and complexity. Experiment 2 was an exploratory study that included a separate group of 24 kindergarten-age children who completed our Modified-Shortened Token Test as well as other memory and language measures. RESULTS: The factor analysis in Experiment 1 revealed a three-factor solution with factors corresponding to verbal working memory, linguistic, and basic attention constructs. In Experiment 2, we conducted exploratory correlations between composite scores formed based on identified factors (from Experiment 1) and related measures. Recalling sentences and formulating sentences correlated with the working memory demands of the Token Test, whereas following directions and word structure correlated with Token Test linguistic factor. CONCLUSIONS: A modified Token Test has the potential to be used clinically to understand language performance. In particular, differential performance across sentences could reveal relative verbal working memory and linguistic knowledge abilities. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.19178474.

Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women.

AIMS: GSK3640254 is a next-generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV-positive women. METHODS: This phase I, open-label, 1-way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate-fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration-time curve to the end of the dosing interval (AUC0-t ), maximum observed concentration (Cmax ) and plasma concentration at the end of the dosing interval (Cτ ) for ethinyl oestradiol and levonorgestrel. Serum follicle-stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored. RESULTS: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC0-t , Cmax and Cτ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle-stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver-stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal. CONCLUSION: Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady-state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel.

Marketing strategies used for alternative protein products sold in Australian supermarkets in 2014, 2017, and 2021.

Introduction: Marketing plays an important role in consumers' perceptions and acceptance of new foods. The purpose of this study was to investigate the marketing strategies used for alternative protein products available in Australia in 2014, 2017, and 2021. Methods: Product data were extracted from FoodTrack™, an established database of packaged supermarket products. Marketing strategies investigated included product format descriptors, front of pack (FOP) labeling claims, price, and in-store placement (2021 only). Results: Data from 292 alternative protein products (n = 12 tofu-based products; n = 100 legume-based products; and n = 180 plant-based meats) were analyzed. Across the product range, "burgers" (n = 86), "strips and similar" (n = 51) and "sausages" (n = 42) were the most common product formats, accounting for ∼61% of the product range. Nutrient content claims featured on 273 (93%) products. "Positive" nutrient claims (those highlighting the presence of a nutrient) occurred on FOP labels four times more than "negative" nutrient claims (those highlighting the absence or low levels of a nutrient; 432 versus 101, respectively). Protein-related claims were the most common "positive" nutrient claim (n = 180, 62%). Health claims on FOP labels appeared on 10% of products. Most products (n = 265, 91%) mentioned a dietary pattern (such as "vegetarian" and "plant-based"), or a combination of dietary patterns on their FOP label. The price of alternative products increased over time; between 2014 and 2021, on average, the unit price increased (9% increase, p = 0.035) and the pack size decreased (14% decrease, p < 0.001). There was inconsistency in product placement across the eight stores visited. Occasionally (n = 3 of 13 locations), chilled alternative protein products were positioned near conventional meat products. More commonly, alternative protein products shared space with other vegetarian products (such as non-dairy cheeses and tofu blocks) or alongside convenience products, suggesting these products are promoted as convenience foods, or options for individuals with special dietary needs. Discussion: This study provides a useful evidence base to understand the marketing strategies used for alternative protein products. It appears from this analysis that considerable effort has gone into providing consumers with a level of familiarity and comfort prior to purchasing these alternative protein products.

The role of phonological and semantic representations in verbal short-term memory and delayed retention.

It has been suggested that phonological representations play a central role in verbal short-term memory, but when semantic knowledge has been investigated, it has also been shown to influence verbal short-term memory. Explaining this interaction between verbal short-term memory and the linguistic system has produced different theoretical positions: whether semantic knowledge is used to redintegrate phonological traces or if there is direct activation of both phonological and semantic knowledge upon encountering a word. The present study employed a new paradigm to systematically examine phonological and semantic representations in verbal short-term memory as well as long-term impacts. Across two experiments, a list of words was presented sequentially, followed by a probe word. Participants were to judge whether the probe word rhymed or was synonymous with any items on the list. Delayed memory was also tested. In Experiment 1, we found that immediate performance was better for synonym than rhyme judgements, and this continued to be the case after a brief delay. In Experiment 2, under a fast-encoding, running-span paradigm, we found similar activation of phonological and semantic knowledge. Nevertheless, accuracy was again higher for items probed with the semantic than rhyme cue in the long term. Results showed that indeed there are short-term semantic effects, in addition to phonological effects. Further, semantic processing can occur in a highly automatic and rapid manner, with strong influence on long-term memory. These findings provide a new perspective on viewing verbal short-term memory as operating more dynamically within the context of a complex linguistic system.

Assessment of artificial and natural sweeteners present in packaged non-alcoholic beverages (NABs) sold on the Singapore market.

BACKGROUND: New Nutri-Grade labelling, aimed at reducing Singaporeans' sugar consumption will be implemented for all pre-packaged non-alcoholic beverages (NABs) sold in retail outlets from end 2021 onwards. It is expected such labelling will have a major impact on sugar content of beverages, as well as the replacement of sugar with non-caloric alternatives. METHODS: This study used product label data obtained from in-store surveys to investigate sugar and sweetener composition of NABs present on the Singapore market. Using this data we calculated products prospective Nutri-Grade classification in order to compare the current market composition with relation to sugar and/or sweetener use. RESULTS: Over half of the NABs on market were sweetened with sugar (59%) and were associated with less healthy Nutri-Grades of 'C' and 'D'. The use of natural sweeteners; Stevia and Monk fruit, remains low (6%). CONCLUSION: With continuous efforts by the government in promoting public health nutrition, it is expected that there will be a greater usage of sugar substitutes among NABs in response to the upcoming implementation of Nutri-Grade and ever-fluctuating consumers' demands. The data collected in this study provide a point estimate (July-September 2020) on market composition and use of both sugar and artificial sweeteners in beverages prior to integration of the mandatory labelling requirements.

Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults.

AIMS: GSK3640254, a novel, next-generation maturation inhibitor effective against a range of HIV polymorphisms with no cross-resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2-drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed. METHODS: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1-5 in period 1, GSK3640254 200 mg QD on Days 1-7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1-7 in period 3. All treatments were administered with a moderate-fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored. RESULTS: Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118-1.233), 1.09 (1.044-1.138) and 1.24 (1.160-1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992-1.094), 0.99 (0.923-1.065) and 0.10 (0.939-1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady-state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed. CONCLUSION: Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers.

Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to substantially reduce formation of glucosylceramide-based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism. Therefore, venglustat is under development for substrate reduction therapy in multiple diseases, including Gaucher disease type 3, Parkinson's disease associated with GBA mutations, Fabry disease, GM2 gangliosidosis, and autosomal dominant polycystic kidney disease. Phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability and to assess food effects on pharmacokinetics (single-dose and food-effect studies: NCT01674036; repeated-dose study: NCT01710826). Following a single oral dose of venglustat l-malate (2, 5, 15, 25, 50, 100, or 150 mg), venglustat demonstrated linear pharmacokinetics, rapid absorption (median tmax , 3.00-5.50 hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL/F, 5.18-6.43 L/h), and pooled geometric mean t1/2z of 28.9 hours. Following repeated once-daily oral doses of venglustat l-malate (5, 10, or 20 mg) for 14 days, apparent steady state occurred within 5 days of repeated dosing, with pooled accumulation ratios of 2.10 for Cmax and 2.22 for AUC0-24 , and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe0-24 ) was 26.3% to 33.1%. Plasma GL-1 and GM3 decreased time- and dose-dependently. Venglustat demonstrated a favorable safety and tolerability profile.

Children's use of majority information is influenced by pragmatic inferences and task domain.

Do children always conform to a majority's testimony, or do the pragmatics of that testimony matter? We investigated the influence of pragmatics on conforming to a majority across 2 domains: when learning about object labels and when learning about causal relationships. Four- and 5-year-olds (N = 250) were given a choice between an object endorsed by a 3-person majority, or one endorsed by a single minority informant. Within each domain, there were 4 pragmatic conditions, each with modified testimony so that the majority either explicitly provided an opinion about or pragmatically implied their opinion about the alternative object chosen by the minority. In the unendorsed condition, informants explicitly unendorsed the unchosen object. In the implied condition, informants said nothing about the unchosen object. In the ignorance condition, informants explicitly expressed ignorance about the unchosen object, and in the hidden condition, the chosen object was the only one present at the time of the endorsement. We found that children were most likely to endorse the majority object in the unendorsed condition, in which the majority's opinion was explicitly stated, and least likely in the hidden condition, in which only one object at a time was present, with the other 2 conditions intermediate. Children's preference for majority testimony also depended on the task domain, with a stronger preference for the majority in the language task than causal task. Children might not simply have a majority bias; rather, they use majority information differently depending on the pragmatics and task demands. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

A Phase 1, Randomized, Single-Dose Crossover Pharmacokinetic Study to Investigate the Effect of Food Intake on Absorption of Orteronel (TAK-700) in Healthy Male Subjects.

This study aimed to determine the impact of food on the pharmacokinetics of orteronel, an investigational nonsteroidal, reversible selective inhibitor of 17,20-lyase. In this open-label, randomized crossover study, healthy subjects received single doses of orteronel 400 mg with a low-fat meal, a high-fat meal, and under fasting conditions in a randomized sequence. Plasma concentrations of orteronel and its primary M-I metabolite were determined by ultra-performance liquid chromatography, and pharmacokinetic parameters were evaluated using mixed-effects analysis of variance model. Compared with fasting conditions, the oral bioavailability of orteronel was increased under fed conditions. The least-squares mean ratio for area under the plasma concentration-time curve after a low-fat breakfast was 135% (90% confidence interval [CI], 126%-145%) compared with fasting conditions. Similarly, after a high-fat breakfast, the corresponding value was 142% (90%CI, 132%-152%). No unexpected safety concerns were raised with orteronel 400 mg administered in the fasted state or after either a high-fat or a low-fat meal; mild adverse events were experienced by 36% of the healthy male subjects.