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One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.

Lay Abstract: Selective attention to auditory input is reflected in the brain by an electric amplitude called the P3b amplitude, which is measured using electroencephalography. Previous research has shown that children and adolescents with autism have an attenuated P3b amplitude when they have to attend specific sounds while ignoring other sounds. However, it is unknown whether a reduced P3b amplitude in autistic children and adolescents is associated with their autism features, daily functioning and/or cognitive functions. This study aimed to examine these questions. Therefore, we assessed selective attention to auditory input in 57 children with autism aged 7-14 years and 57 neurotypically developing controls while measuring their brain activity with electroencephalography. Participants further underwent cognitive assessment, and parents reported on autistic traits and daily functioning. As expected, children with autism had lower P3b amplitude compared to their neurotypical peers. Importantly, an attenuated P3b amplitude was associated with more parent-reported social-communication problems and difficulties with daily functioning. Children with autism further had reduced processing speed of visual input, which also was coupled to a lower P3b amplitude. In conclusion, we found attenuated P3b amplitude in children with autism performing an auditory selective attention task, which was related to difficulties with processing visual input and allocating attentional resources critical for social and daily functioning. The results suggest that autistic children are more vulnerable to being disturbed when the environment is filled with conflicting sensory input., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Parent-child informant discrepancies on psychopathology provide important knowledge on the parent-child relationship and the child's mental health, but mechanisms underlying parent-child informant discrepancies are largely unknown. Therefore, we investigated the relationship between attachment problems and mentalizing capacity and parent-child informant discrepancies on borderline personality disorder (BPD) severity, internalizing, and externalizing pathology in a clinical sample of 91 adolescent girls with BPD and their parents. Results showed that more attachment problems to parents and peers were related to adolescents reporting more severe BPD than parents. Adolescents who described more internalizing symptoms relative to parents, reported more parental attachment problems, but enhanced peer attachment, suggesting those adolescents who do not feel recognized by their parents might turn to their friends. When parents rated adolescents higher on externalizing behaviors, the adolescent reported more attachment problems to parents and lower mentalizing capacity, indicating that this sub-group of adolescents may reflect less about how their behavior affects others., (© 2024. The Author(s).)

Purpose: The purpose of the study was to investigate the fit of a two-piece pouching system with a concave-shaped skin barrier on people with an outward peristomal body profile and its effect on leakage, wear time, and quality of life (QoL) related to using an ostomy product., Design: Randomized, controlled, open-label, cross-over trial., Subjects and Settings: The sample comprised 53 subjects with outward peristomal body profiles and problems with leakage of ostomy effluent from their pouching system. Participants were randomized to the concave two-piece pouching system or a comparator (two-piece pouching system with a flat skin barrier) for 3 weeks. Subjects were then crossed over to the opposite skin barrier for an additional 3 weeks. The study was conducted in Denmark, Norway, Germany, and the Netherlands; data were collected in multiple ambulatory clinics or during home visits., Methods: The primary end point was the ability of the skin barrier to fit body contours; secondary outcomes were leakage of effluent from the pouching system, wear time, and QoL related to using an ostomy product via the validated Ostomy-Q questionnaire. Primary comparisons between concave and comparator pouching systems were evaluated using proportional odds models and mixed models taking test period into account., Results: Analysis included randomized subjects who had been exposed to at least one product and with information on at least one end point (full-analysis-set, n = 52). The concave pouching system provided a better fit to body contours than the comparator (P< .001) and reduced the degree of leakage underneath the skin barrier (LS mean difference = -1.84, 95% CI -3.31 to -0.37; P = .016). Participants experienced fewer episodes of leakage outside the skin barrier when using concave versus comparator pouching system (13.0% vs. 26.7%, respectively). Participants reported significant improvements in QoL (LS mean difference = 14.3; 95% CI 9.4 to 19.2; P < .001). No significant difference in wear time between skin barrier shapes was reported., Conclusions: Study findings indicate that a pouching system with a concave skin barrier achieved a better body fit on people with an outward peristomal body profile and resulted in fewer leakage incidents and higher QoL compared to using a pouching system with a flat skin barrier., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Wound, Ostomy, and Continence Nurses Society.)

In postweaning calves, it is a challenge to maintain the plasma vitamin E level at or above the recommended level (3 µg/mL), which is linked to a good immune response. It has been unclear until now why the provision of solid feed with concentrations below 200 mg/kg feed of vitamin E is ineffective in maintaining the plasma vitamin E level of calves above the recommended plasma level postweaning. The present study was conducted to investigate if a high fat to vitamin E ratio in the concentrate could protect and improve the delivery of the natural form of vitamin E (RRR-α-tocopherol) to calves postweaning. Thirty calves were included in the experiment from 2 weeks preweaning until 2 weeks postweaning (Weeks -2, -1, 0 [weaning], 1, and 2 relative to weaning) and fed one of three concentrates in which lecithin mixture provided the fat supplement: control (77 mg/kg of vitamin E and 4.9% DM of crude fat; CONT), medium level of vitamin E supplemented (147 mg/kg of vitamin E and 7.7% DM of crude fat; MedVE) or high level of vitamin E supplemented (238 mg/kg of vitamin E and 12.4% DM of fat; HiVE). Thus, there was a comparable ratio of fat to vitamin E (520-630) in the three concentrates. During the 2 weeks postweaning, final body weight (92 ± 2 kg), average daily gain (917 ± 51 g/day) and concentrate intake (2.2 ± 0.09 kg/day; mean of treatment ± standard error) were unaffected by treatment and the interaction between treatment and week. There was an interaction between treatment and week for vitamin E intake pre- (p < 0.001) and postweaning (p < 0.001). There was an interaction between treatment and week (p < 0.001) for plasma vitamin E level postweaning, and it was 2.5, 3.1, and 3.8 µg/mL in CONT, MedVE, and HiVE, respectively, at Week 1 postweaning. In addition, plasma vitamin E levels at Week 2 postweaning were 2.6, 3.6 and 4.8 µg/mL in CONT, MidVE and HiVE respectively. The results show that 147 mg/kg of lecithin-protected vitamin E in the concentrate is needed to secure a plasma vitamin E level well above the recommended level. In addition, lecithin-protected vitamin E elevated the plasma level of triglycerides and nonesterified fatty acids., (© 2024 The Authors. Journal of Animal Physiology and Animal Nutrition published by Wiley‐VCH GmbH.)

Increased schizotypal traits have previously been associated with atypical semantic cognition in community samples. However, no study has yet examined whether adults diagnosed with schizotypal personality disorder (SPD) display atypical semantic fluency and memory. We hypothesized that 24 adults diagnosed with SPD would name more idiosyncratic words on the semantic fluency task and show decreased semantic recall for animal and fruit category words compared with 29 participants with borderline personality disorder (BPD) and a community sample of 96 age-matched controls. We examined whether atypical semantic cognition was specifically associated with disorganized and eccentric speech and thinking, or more broadly with pathological personality traits and personality functioning. Our main hypothesis was confirmed, as the SPD participants named more idiosyncratic words and recalled fewer semantically related words compared with controls. Surprisingly, participants with BPD likewise named more atypical words compared with controls. More idiosyncratic semantic fluency was associated with more eccentric speech and thinking. Increased idiosyncratic semantic fluency and reduced semantic recall were both coupled to increased detachment and lowered personality functioning, while reduced semantic recall further was related to increased interpersonal problems. Our findings suggest that persons with SPD, and to a lesser degree BPD, show atypical semantic cognition, which is associated with eccentric speech and thinking, and more broadly with impaired personality function, social withdrawal, and emotional flatness. The idiosyncratic semantic cognition may worsen difficulties with social reciprocity seen in SPD and BPD.

Background: Qualitative sensory testing (QualST) is a simple, standardised, chairside method for evaluating somatosensory function; however, testing focuses on detection of cold, touch and pain with no recognition of perceptions of pleasantness and unpleasantness., Objectives: The study aimed to utilise the stimuli in QualST, with the addition of a soft brush, to investigate stimulus-evoked perceptions of pleasantness and unpleasantness on the facial skin and if any side-to-side differences. Additional aims were to determine the inter- and intra-rater reliability using the modified QualST protocol and in the side-to-side differences., Methods: Thirty healthy adult female participants underwent three sessions of sensitivity testing as per the modified QualST protocol. Stimuli were applied bilaterally to the facial skin, and participants provided separate yes/no responses for presence of stimulus-evoked pleasantness, unpleasantness and/or differences between sides., Results: The stimuli were able to evoke sensations of pleasantness and unpleasantness with little differences in responses between the Q-tip and goat hair brush for the perceptions. Side-to-side differences in evoked perceptions were observed and greatest, when evaluating for pinprick-evoked unpleasantness (range between sessions = 18-19 participants). Acceptable percentage (≥90%) and excellent Cohen's Kappa (≥0.762) inter- and intra-rater agreements were identified for one or more positive responses for each stimulus modality and the targeted perception., Conclusion: The modified QualST protocol provides a simple, reproducible method for the investigation of perceptions of pleasantness and unpleasantness, with readily accessible instrumentation to dental professionals and allowing for a more holistic approach in somatosensory testing., (© 2024 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)