Antisense Oligonucleotides for Rapid Translation of Gene Therapy in Glioblastoma.

PURPOSE: The limited efficacy of current treatments for malignant brain tumors necessitates novel therapeutic strategies. This study aimed to assess the potential of antisense oligonucleotides (ASOs) as adjuvant therapy for high-grade gliomas, focusing on their CNS penetration and clinical translation prospects. METHODS: A comprehensive review of the existing literature was conducted to evaluate the implications of ASOs in neuro-oncology. Studies that investigated ASO therapy's efficacy, CNS penetration, and safety profile were analyzed to assess its potential as a therapeutic intervention for high-grade gliomas. RESULTS: ASOs present a promising avenue for enhancing targeted gene therapies in malignant gliomas. Their potent CNS penetration, in vivo durability, and efficient transduction offer advantages over conventional treatments. Preliminary in vivo and in vitro studies suggest ASOs as a viable adjuvant therapy for high-grade gliomas, warranting further exploration in clinical trials. CONCLUSIONS: ASOs hold significant promise as adjuvant therapy for high-grade gliomas, offering improved CNS penetration and durability compared with existing treatments. While preliminary studies are encouraging, additional research is needed to establish the safety and efficacy of ASO therapy in clinical settings. Further investigation and clinical trials are warranted to validate ASOs as a transformative approach in neuro-oncology.

HIV-1 RNA in extracellular vesicles is associated with neurocognitive outcomes.

Human immunodeficiency virus type-1 (HIV-1) is responsible for significant mortality and morbidity worldwide. Despite complete control of viral replication with antiretrovirals, cells with integrated HIV-1 provirus can produce viral transcripts. In a cross-sectional study of 84 HIV+ individuals of whom 43 were followed longitudinally, we found that HIV-1 RNAs are present in extracellular vesicles (EVs) derived from cerebrospinal fluid and serum of all individuals. We used seven digital droplet polymerase chain reaction assays to evaluate the transcriptional status of the latent reservoir. EV-associated viral RNA was more abundant in the CSF and correlated with neurocognitive dysfunction in both, the cross-sectional and longitudinal studies. Sequencing studies suggested compartmentalization of defective viral transcripts in the serum and CSF. These findings suggest previous studies have underestimated the viral burden and there is a significant relationship between latent viral transcription and CNS complications of long-term disease despite the adequate use of antiretrovirals.

Autophagy Deregulation in HIV-1-Infected Cells Increases Extracellular Vesicle Release and Contributes to TLR3 Activation.

Human immunodeficiency virus type 1 (HIV-1) infection can result in HIV-associated neurocognitive disorder (HAND), a spectrum of disorders characterized by neurological impairment and chronic inflammation. Combined antiretroviral therapy (cART) has elicited a marked reduction in the number of individuals diagnosed with HAND. However, there is continual, low-level viral transcription due to the lack of a transcription inhibitor in cART regimens, which results in the accumulation of viral products within infected cells. To alleviate stress, infected cells can release accumulated products, such as TAR RNA, in extracellular vesicles (EVs), which can contribute to pathogenesis in neighboring cells. Here, we demonstrate that cART can contribute to autophagy deregulation in infected cells and increased EV release. The impact of EVs released from HIV-1 infected myeloid cells was found to contribute to CNS pathogenesis, potentially through EV-mediated TLR3 (Toll-like receptor 3) activation, suggesting the need for therapeutics to target this mechanism. Three HIV-1 TAR-binding compounds, 103FA, 111FA, and Ral HCl, were identified that recognize TAR RNA and reduce TLR activation. These data indicate that packaging of viral products into EVs, potentially exacerbated by antiretroviral therapeutics, may induce chronic inflammation of the CNS observed in cART-treated patients, and novel therapeutic strategies may be exploited to mitigate morbidity.

Training semantic long-term memory retrieval transfers to executive function and reading fluency.

The retrieval of information from long-term memory is a fundamental cognitive ability, crucial for most aspects of successful human functioning. Whether and how long-term memory retrieval (LTMR) can be improved with training has clear societal importance but also theoretical value for furthering our understanding of underlying mechanisms. Here, we provide electrophysiological evidence for the plasticity of semantic LTMR. Thirty-five university students were randomly assigned to adaptive semantic LTMR training (using a Posner task) or to a non-adaptive version of the training. Before and after training they were assessed on measures of semantic LTMR, working memory, central executive function (interference control, switching), reading fluency, and fluid intelligence. Adaptive LTMR training (relative to non-adaptive training) led to significant improvements in semantic LTMR. The intervention group (in contrast to the control group) also showed a significant reduction in the mean amplitude of the N400 ERP component and 700-1000 ms measured during a semantic LTMR task, suggesting that changes in retrieval occurred at an early/automatic point and retrieval processing in semantic processing. Moreover, transfer effects were observed for switching, working memory and reading fluency, but not for interference control or fluid intelligence. These results point to the plasticity of semantic LTMR, and suggest that improvement in this ability can transfer to other domains for which LTMR is key.

Reliability of the serial reaction time task: If at first you don't succeed, try, try, try again.

Procedural memory is involved in the acquisition and control of skills and habits that underlie rule and procedural learning, including the acquisition of grammar and phonology. The serial reaction time task (SRTT), commonly used to assess procedural learning, has been shown to have poor stability (test-retest reliability). We investigated factors that may affect the stability of the SRTT in adults. Experiment 1 examined whether the similarity of sequences learned in two sessions would impact stability: test-retest correlations were low regardless of sequence similarity (r < .31). Experiment 2 added a third session to examine whether individual differences in learning would stabilise with further training. There was a small (but nonsignificant) improvement in stability for later sessions (Sessions 1 and 2: r = .42; Sessions 2 and 3: r = .60). Stability of procedural learning on the SRTT remained suboptimal in all conditions, posing a serious obstacle to the use of this task as a sensitive predictor of individual differences and ultimately theoretical advance.

The reliability of the serial reaction time task: meta-analysis of test-retest correlations.

The Serial Reaction Time task, one of the most widely used tasks to index procedural memory, has been increasingly employed in individual differences research examining the role of procedural memory in language and other cognitive abilities. Yet, despite consistently producing robust procedural learning effects at the group level (i.e. faster responses to sequenced/probable trials versus random/improbable trials), these effects have recently been found to have poor reliability. In this meta-analysis (N = 7), comprising 719 participants (M = 20.81, s.d. = 7.13), we confirm this 'reliability paradox'. The overall retest reliability of the robust procedural learning effect elicited by the SRTT was found to be well below acceptable psychometric standards (r < 0.40). However, split-half reliability within a session is better, with an overall estimate of 0.66. There were no significant effects of sampling (participants' age), methodology (e.g. number of trials, sequence type) and analytical decisions (whether all trials were included when computing the procedural learning scores; using different indexes of procedural learning). Thus, despite producing robust effects at the group-level, until we have a better understanding of the factors that improve the reliability of this task using the SRTT for individual differences research should be done with caution.

The influence of emotion regulation strategies and sleep quality on depression and anxiety.

Chronic stress is a major risk factor for a number of mental health disorders, including depression and pathological anxiety. Adaptive cognitive emotion regulation (CER) strategies (i.e. positively-focused thought processes) can help to prevent psychiatric disturbance when enduring unpleasant and stressful experiences, but little is known about the inter-individual factors that govern their success. Sleep plays an important role in mental health, and may moderate the effectiveness of adaptive CER strategies by maintaining the executive functions on which they rely. In this study, we carried out a secondary analysis of self-reported mental health and sleep data acquired during a protracted and naturally-occurring stressor - the COVID-19 pandemic - to firstly test the hypothesis that adaptive CER strategy use is associated with positive mental health outcomes and secondly, that the benefits of adaptive CER strategy use for mental health are contingent on high-quality sleep. Using established self-report tools, participants estimated their depression (N = 551) and anxiety (N = 590)2 levels, sleep quality and tendency to engage in adaptive and maladaptive CER strategies during the Spring and Autumn of 2020. Using a linear mixed modelling approach, we found that greater use of adaptive CER strategies and higher sleep quality were independently associated with lower self-reported depression and anxiety. However, adaptive CER strategy use was not a significant predictor of self-reported anxiety when accounting for sleep quality in our final model. The positive influence of adaptive CER strategy use on depression was observed at different levels of sleep quality. These findings highlight the importance of adaptive CER strategy use and good sleep quality in promoting resilience to depression and anxiety when experiencing chronic stress.

Limited Evidence of an Association Between Language, Literacy, and Procedural Learning in Typical and Atypical Development: A Meta-Analysis.

The ability to extract patterns from sensory input across time and space is thought to underlie the development and acquisition of language and literacy skills, particularly the subdomains marked by the learning of probabilistic knowledge. Thus, impairments in procedural learning are hypothesized to underlie neurodevelopmental disorders, such as dyslexia and developmental language disorder. In the present meta-analysis, comprising 2396 participants from 39 independent studies, the continuous relationship between language, literacy, and procedural learning on the Serial Reaction Time task (SRTT) was assessed across children and adults with typical development (TD), dyslexia, and Developmental Language Disorder (DLD). Despite a significant, but very small, relationship between procedural learning and overall language and literacy measures, this pattern was not observed at the group-level when examining TD, dyslexic, and DLD groups separately. Based on the procedural/declarative model, a positive relationship was expected between procedural learning and language and literacy measures for the typically developing group; however, no such relationship was observed. This was also the case for the disordered groups (ps > .05). Also counter to expectations, the magnitude of the relationship between procedural learning and grammar and phonology did not differ between TD and DLD (ps > .05), nor between the TD and dyslexic group on reading, spelling, and phonology (ps > .05). While lending little support to the procedural/declarative model, we consider that these results may be the consequence of poor psychometric properties of the SRTT as a measure of procedural learning.

Stronger Associations Between Sleep and Mental Health in Adults with Autism: A UK Biobank Study.

This study examined sleep and its cognitive and affective correlates in adults with and without autism spectrum disorder (ASD), utilizing UK Biobank data. There were no group differences in subjective sleep duration [n = 220 ASD; n = 2200 general population (GP)]. Accelerometer measures of sleep duration or nighttime activity did not differ by group, but sleep efficiency was marginally lower in ASD (n = 83 ASD; n = 824 GP). Sleep efficiency was associated with wellbeing and mental health, and pathways between accelerometer sleep measures and wellbeing and mental health were significantly stronger for adults with ASD (who also reported substantially poorer wellbeing and > 5 × likelihood of experiencing mental distress). These findings highlight the need to monitor sleep to maintain good mental health in adult ASD.

Sleep health among people with severe mental ill health during the COVID-19 pandemic: Results from a linked UK population cohort study.

Objectives: Sleep problems are a transdiagnostic feature of nearly all psychiatric conditions, and a strong risk factor for initial and recurrent episodes. However, people with severe mental ill health (SMI) are often excluded from general population surveys, and as such the extent and associates of poor sleep in this population are less well understood. This study explores sleep health in an SMI sample during the COVID-19 pandemic, using multiple regression to identify risk factors, including daily routine, wellbeing and demographics. Methods: An existing cohort of people with an SMI diagnosis were sampled. Participants were invited to complete a self-report survey about their health and the impacts of COVID-19 and associated public health measures. Sleep duration, efficiency, and quality were measured using items from the Pittsburgh Sleep Quality Index (PSQI). Results: Two hundred forty-nine adults (aged 21-84 years) completed the survey. Mean sleep duration and efficiency were similar to general population estimates, at 7 h 19 min and 78%, respectively. However, 43% reported "bad" sleep quality that was associated with being younger in age as well as disturbed routine and declined wellbeing. Indeed, 37% reported a disturbed routine during the pandemic. Conclusions: High estimates of perceived poor sleep quality in the SMI population align with previous findings. Supporting people with SMI to maintain routine regularity may work to protect sleep quality and wellbeing. Future research should more closely examine sleep health in people with SMI, using accessible and scalable measures of objective and subjective sleep, examining longitudinal trends.

Neural Responses to Novel and Existing Words in Children with Autism Spectrum and Developmental Language Disorder.

The formation of new phonological representations is key in establishing items in the mental lexicon. Phonological forms become stable with repetition, time and sleep. Atypicality in the establishment of new word forms is characteristic of children with developmental language disorder (DLD) and autism spectrum disorder (ASD), yet neural changes in response to novel word forms over time have not yet been directly compared in these groups. This study measured habituation of event-related-potentials (ERPs) to novel and known words within and between two sessions spaced 24 hours apart in typically developing (TD) children, and their peers with DLD or ASD. We hypothesised that modulation of the auditory N400 amplitude would mark real-time changes in lexical processing with habituation evident within and across sessions in the TD group, while the DLD group would show attenuated habituation within sessions, and the ASD group attenuated habituation between sessions. Twenty-one typically developing children, 19 children with ASD, and 16 children with DLD listened passively to known and novel words on two consecutive days, while ERPs were recorded using dry electrodes. Counter to our hypotheses, no habituation effect emerged within sessions. However, responses did habituate between sessions, with this effect being reduced in the DLD group, indicating less pre-activation of lexical representations in response to words encountered the previous day. No differences in change over time were observed between the TD and ASD groups. These data are in keeping with theories stressing the importance of sleep-related consolidation in word learning.

Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis.

The study of the role of retroviruses in amyotrophic lateral sclerosis (ALS) dates back to the 1960s shortly after transposable elements themselves were first discovered. It was quickly realized that in wild mice both horizontal and vertical transmissions of retroviral elements were key to the development of an ALS-like syndrome leading to the postulate that endogenous retroviruses (ERVs) contribute significantly to the pathogenicity of this disease. Subsequent studies identified retroviral reverse transcriptase activity in brains of individuals with ALS from Guam. However, except for a single study from the former Soviet Union, ALS could not be transmitted to rhesus macaques. The discovery of an ALS-like syndrome in human immunodeficiency virus (HIV) and human T cell leukemia virus infected individuals led to renewed interest in the field and reverse transcriptase activity was found in the blood and cerebrospinal fluid of individuals with sporadic ALS. However, exogenous retroviruses could not be found in individuals with ALS which further reinforced the possibility of involvement of a human ERV (HERV). The first demonstration of the involvement of a HERV was the discovery of the activation of human endogenous retrovirus-K subtype HML-2 in the brains of individuals with ALS. The envelope protein of HML-2 is neurotoxic and transgenic animals expressing the envelope protein develop an ALS-like syndrome. Activation of HML-2 occurs in the context of generalized transposable element activation and is not specific for ALS. Individuals with HIV-associated ALS show a remarkable response to antiretroviral therapy; however, antiretroviral trials in ALS down-regulate HML-2 without ameliorating the disease. This highlights the need for specific drugs to be developed against HML-2 as a novel therapeutic target for ALS. Other approaches might include antisense oligonucleotides, shRNA targeted against the envelope gene or antibodies that can target the extracellular envelope protein. Future clinical trials in ALS should consider combination therapies to control these ERVs.

Animacy interactions with individual variability in sentence production and comprehension reveal similar lexically driven competitive processes.

Sentence production and comprehension both draw on linguistic knowledge, but current research is unclear on whether these fundamental language tasks involve similar or distinct competitive processes. Previous studies suggest that production and comprehension may involve similar conflict resolution processes, but that production may additionally recruit motor-related conflict not necessarily present in comprehension. To examine these possibilities, we combined an experimental animacy-driven manipulation eliciting difficulty in separate production and comprehension tasks with an examination of how this manipulation interacted with individual variability in motor-related and lexicosemantic conflict resolution performance beyond vocabulary measures. We reasoned that a different pattern of interactions for production and comprehension would point to distinct processes across these tasks, whereas interactions with the same individual performance task would indicate similar conflict-related processes. We found that beyond a significant role of vocabulary, only a measure of context-dependent lexical ambiguity resolution interacted with the animacy manipulation in the production and the comprehension task. These findings suggest a role for linguistic knowledge and similar lexically driven competitive processes in both sentence production and comprehension. Alongside current computational models, these results raise the possibility that despite different task demands, some production and comprehension competitive processes are not entirely distinct from one another nor separable from lexical knowledge. Implications for current views on the relationship between sentence production and comprehension are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Introducing and Implementing a Universally Accepted, Readily Accessible, and Actionable End-of-Life Planning Tool for Patients with Advanced Serious Illness or Frailty in Southern New Zealand.

Background: Each health provider/agency in Southland, New Zealand, previously had its own forms and processes to document and communicate the planned scope of treatment; this project attempted to consolidate and streamline these variable processes into one actionable medical order that is valid in all settings. Aim: The hypothesis was that the intervention would reduce unnecessary hospitalizations in the final year of life. Design: The Clinical Order Articulating Scope of Treatment (COAST) form was a single-page medical order designed to document and communicate the resuscitation status and scope of medical treatment for adult patients believed to be in the final year of life, as evidenced by a "no" response to the Surprise Question. This three-phase initiative piloted the use of the COAST form in Southland from May 2019 to January 2020. Results: One hundred eighty-three patients with COAST forms consented to study participation. Sixty-one percent had a malignant primary diagnosis. The average number of emergency department (ED) presentations in the 12 months before COAST form implementation was 1.5 per person, and the average number of hospital admissions per person was 2.2. This was reduced to 0.5 and 0.5, respectively, in the 12 months following COAST implementation (p = 0.00). Three patients had no ED presentations/hospital admissions in the 12 months before COAST implementation, compared with 29 following COAST implementation, and 66.7% of patients died between May 2019 and February 2021. Conclusions: Patients with a COAST form had significantly fewer ED presentations and hospital admissions in the 12 months following implementation.

UK children's sleep and anxiety during the COVID-19 pandemic.

BACKGROUND: Sleep and mental wellbeing are intimately linked. This relationship is particularly important to understand as it emerges over childhood. Here we take the opportunity that the COVID-19 pandemic, and resulting lockdown in the UK, presented to study sleep-related behaviour and anxiety in school-aged children. METHODS: Parents and children were asked to complete questionnaires towards the start of the UK lockdown in April-to-May of 2020, then again in August of that year (when many restrictions had been lifted). We explored children's emotional responses to the pandemic and sleep patterns at both time points, from the perspectives of parents and children themselves. RESULTS: Children's bedtime anxiety increased at the start of the lockdown as compared to a typical week; however, by August, bedtime anxiety had ameliorated along with children's COVID-19 related anxiety. Bedtime anxiety predicted how long it took children to fall asleep at night at both the start and the end of the lockdown. Bedtime and wake-up time shifted at the start of lockdown, but interestingly total sleep time was resilient (likely owing to an absence of early school start times) and was not predicted by child anxiety. CONCLUSIONS: These findings further support calls for sleep quality (in particular, time taken to fall asleep) to be taken as a key indicator of mental health in children, particularly under usual circumstances when schools are open and sleep duration may be less resilient.

Animacy-induced conflict in sentence production and comprehension from late childhood to adolescence.

Some animacy configurations elicit parallel semantic interference in adult production and comprehension; for example, phrases with similar animate nouns like the man that the girl is hugging are more difficult than phrases like the doll that the girl is hugging. Yet little is known about how this interference manifests in development, particularly, beyond early childhood. Because frontal brain maturation and cognitive control improvements are known to occur across late childhood and adolescence, we investigated (a) how animacy-induced difficulty in production and comprehension vary with age throughout this period and (b) whether control processes reflected in the backward digit span (BDS) test uniquely explained these differences besides other language measures. In separate tasks, participants (8- to 15-year-old children; N = 91) heard auditory descriptions of depicted characters, produced characters' descriptions, and completed BDS, vocabulary, and reading experience tests. Results indicated that, as in adults, animacy modulated performance in production and comprehension across all ages. The animacy modulation interacted with age in production but not in comprehension, suggesting age-related animacy differences in production but relatively stable differences in comprehension despite processing speed improvements. Importantly, these age-related production differences were also modulated by the BDS scores; only participants with higher BDS scores displayed age-related animacy differences. Together, these results indicate that comprehension and production develop at different rates and that the development of BDS performance interacts with age-dependent changes in sentence planning from late childhood to adolescence. More generally, the study highlights tasks' disparities to be explained by cognitive and developmental models of language.

Does the maturation of early sleep patterns predict language ability at school entry? A Born in Bradford study.

Children's vocabulary ability at school entry is highly variable and predictive of later language and literacy outcomes. Sleep is potentially useful in understanding and explaining that variability, with sleep patterns being predictive of global trajectories of language acquisition. Here, we looked to replicate and extend these findings. Data from 354 children (without English as an additional language) in the Born in Bradford study were analysed, describing the mean intercepts and linear trends in parent-reported day-time and night-time sleep duration over five time points between 6 and 36 months-of-age. The mean difference between night-time and day-time sleep was predictive of receptive vocabulary at age five, with more night-time sleep relative to day-time sleep predicting better language. An exploratory analysis suggested that socioeconomic status was predictive of vocabulary outcomes, with sleep patterns partially mediating this relationship. We suggest that the consolidation of sleep patterns acts as a driver of early language development.

Retrieval practice transfer effects for multielement event triplets.

Retrieval practice (RP) leads to improved retention relative to re-exposure and is considered a robust phenomenon when the final test conditions are identical to RP conditions. However, the extent to which RP 'transfers' to related material is less clear. Here, we tested for RP transfer effects under conditions known to induce integration of associated material at encoding, which may make transfer more likely. Participants learned multielement triplets (locations, animals and objects) and one pairwise association from each triplet was tested through RP, re-exposed, or not re-exposed (control). Two days later participants completed a final test of all pairwise associations. We found no evidence for an RP effect compared to re-exposure, but both tested/re-exposed pairs were better remembered than the not re-exposed control condition. We also found that transfer occurred from both tested to untested and re-exposed to not re-exposed pairs. Our results highlight that RP and re-exposure can boost retention for directly tested/re-exposed event pairs and associated but untested/not re-exposed event pairs, suggesting re-exposure of integrated information can be of pedagogical value. The results also question the boundary conditions for an increase in retention for RP relative to re-exposure, highlighting the need for a better theoretical understanding of RP effects.

The role of prior lexical knowledge in children's and adults' incidental word learning from illustrated stories.

Children and adults benefit from a new word's phonological neighbors during explicit vocabulary instruction, suggesting that related prior knowledge can support new learning. This study examined the influence of lexical neighborhood structure during incidental word learning-limiting opportunities for strategically engaging prior knowledge-and tested the hypothesis that prior knowledge would provide additional support during subsequent consolidation. Children aged 8-10 years (Experiment 1) and adults (Experiment 2) were presented with 15 pseudowords embedded in a spoken story with illustrations, and were then tested on their recognition and recall of the new word-forms immediately, the next day, and one week later. The pseudowords had either no, one, or many English phonological neighbors, varying the potential connections to existing knowledge. After encountering the pseudowords in this incidental training paradigm, neither children nor adults benefited from phonological neighbors in recall, and children were better at recognizing items without neighbors. The neighbor influence did not change with opportunities for consolidation in either experiment, nor did it relate to learners' existing vocabulary ability. Exploratory analyses revealed that children experienced bigger benefits from offline consolidation overall, with adults outperforming children only for many-neighbor items one week after exposure. We discuss how the neighbor benefit in word learning may be constrained by learning context, and how the enhanced benefits of offline consolidation in childhood extend to vocabulary learning in more naturalistic contexts. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Timing storytime to maximize children's ability to retain new vocabulary.

Shared storybook reading is a key aid to vocabulary acquisition during childhood. However, word learning research has tended to use unnaturalistic (explicit) training regimes. Using a storybook paradigm, we examined whether children (particularly those with weaker vocabularies) are more likely to retain new words if they learn them closer to sleep. Parents read their children (5- to 7-year-olds; N = 237) an alien adventure story that contained 12 novel words with illustrations at one of two training times: at bedtime or 3-5 h before bedtime. Using online tasks, parents tested their children's ability to recall the new words (production) and associate them with pictures (comprehension) immediately after hearing the story and again the following morning. As hypothesized, we replicated two findings. First, children showed overnight improvements in their ability to produce and comprehend new words when tested again the next day. Second, children with better existing vocabulary knowledge showed larger overnight gains in new word comprehension. Counter to expectations, overnight gains in comprehension were larger if the story was read 3-5 h before bedtime rather than at bedtime. These ecologically valid findings are consistent with theories that characterize word learning as a prolonged process supported by mechanisms such as consolidation and retrieval practice, with existing vocabulary knowledge acting as an important source of variability in retention. The findings provide preliminary evidence that encountering new words in stories later in the day (but not too close to sleep) may help to harness vocabulary growth and may be more beneficial than leaving shared storybook reading just for bedtime.