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Shea butter is an organic ingredient used in direct consumption, or the manufacture of products in the food, pharmaceutical, and cosmetic industries. Some pre-treatment processes of shea nuts may not favor the high oil recovery and quality attributes, leading to products that may not conform to market standards for quality, stability, importation, and human consumption. This research emphasizes how roasting or boiling shea nuts for shea butter production enhances its quality by lessening its vulnerability to oxidative instability while simultaneously optimizing oil yield. Shea nuts were collected from an agro-processing company in Ghana. Physicochemical parameters such as refractive index, volatile, acid, iodine, saponification, and peroxide values were analyzed using standard analytical methods. Roasted, boiled, and untreated shea nuts produced a maximum oil yield of 53.53, 48.75, and 47.63 %, respectively. The findings of physicochemical properties of the shea butter samples as time increased from 10 to 50 min for roasted, boiled, and untreated shea nuts showed; an acid value from 8.50 to 17.49 mgKOH/g, 19.4 to 26.46 mgKOH/g and 18.20 mgKOH/g, iodine value from 40.91 – 48.23 gI2/100 g, 46.17 – 57.93 gI2/100 g, and 42.9 gI2/100 g, peroxide value from 2.45 to 4.69 meq/kg, 3.05 to 7.08 meq/kg and 2.15 meq/Kg, refractive index from 1.464 to 1.465, 1.464 to 1.469, and 1.463, saponification value from 181.90 to 187.90 mg KOH/g, 177.70 to 181.55 mg KOH/g and 180.60 mg KOH/g. The quality parameters indicate chances of rancidity. Roasting shea nuts was the optimal condition to produce high yield and quality shea butter than boiled shea nuts. The study recommends that regulatory agencies and consumers conduct regular inspections to verify that shea butter satisfies the appropriate quality and safety criteria for consumption and export.

Abstract Pharmacovigilance (PV) systems in many countries in sub-Saharan Africa (SSA) are not fully functional. The spontaneous adverse events (AE) reporting rate in SSA is lower than in any other region of the world, and healthcare professionals (HCPs) in SSA countries have limited awareness of AE surveillance and reporting procedures. The GSK PV enhancement pilot initiative, in collaboration with PATH and national PV stakeholders, aimed to strengthen passive safety surveillance through a training and mentoring program of HCPs in healthcare facilities in three SSA countries: Malawi, Côte d’Ivoire, and Democratic Republic of Congo (DRC). Project implementation was country-driven, led by the Ministry of Health via the national PV center or department, and was adapted to each country’s needs. The implementation phase for each country was scheduled to last 18 months. At project start, low AE reporting rates reflected that awareness of PV practices was very low among HCPs in all three countries, even if a national PV center already existed. Malawi did not have a functional PV system nor a national PV center prior to the start of the initiative. After 18 months of PV training and mentoring of HCPs, passive safety surveillance was enhanced significantly as shown by the increased number of AE reports: from 22 during 2000–2016 to 228 in 18 months to 511 in 30 months in Malawi, and ~ 80% of AE reports from trained healthcare facilities in Côte d’Ivoire. In DRC, project implementation ended after 7 months because of the SARS-CoV-2 pandemic. Main challenges encountered were delayed AE report transmission (1–2 months, due mainly to remoteness of healthcare facilities and complex procedures for transmitting reports to the national PV center), delayed or no causality assessment due to lack of expertise and/or funding, negative perceptions among HCPs toward AE reporting, and difficulties in engaging public health programs with the centralized AE reporting processes. This pilot project has enabled the countries to train more HCPs, increased reporting of AEs and identified KPIs that could be flexibly replicated in each country. Country ownership and empowerment is essential to sustain these improvements and build a stronger AE reporting culture.

Semantic dementia is a neurocognitive disorder characterised by a steady and progressive loss of semantic knowledge in the presence of relatively preserved other cognitive skills. Recent treatment studies have proven that language rehabilitation aimed at anomia in semantic dementia can be successful. The objective of this study was to examine the separate and interactive effects of errorless vs. errorful and active vs. passive learning approaches to anomia and their effects on naming and comprehension of treated items, as well as maintenance and generalisation of treatment gains. Seven participants with semantic dementia re-learned two sets of words (one for which participants retained auditory comprehension, and one for which they did not) in each of four different treatment methods based on those approaches. Errorless learning proved more successful than errorful learning in restoring lexical representations in all but one participant while there was no interaction between effects of errorless and active approaches on treatment success. Maintenance of treatment gains showed an advantage for errorless learning at one but not three months post-treatment, although all overall gains were maintained to a significant degree at both time points. Effects of both treatment and maintenance were stronger for items for which participants showed preserved auditory comprehension. The results are discussed in a framework of progressive language disorders and applicability of errorless methods to language rehabilitation in semantic dementia. [ABSTRACT FROM AUTHOR]

Background: Collaborative research with end-users is an effective way to generate meaningful research applications and support greater impact on practice and knowledge exchange. To address these needs, a Citizen Advisory Group (CAG) of nine older adults (ages 64-80, 67% women) was formed to advise scientists on the development of Brain Health PRO (BHPro), a web-based platform designed to increase dementia prevention literacy and awareness. The current study evaluated if the CAG met its objectives, how inclusion of the CAG aligned with collaborative research approaches, and the CAG's experience and satisfaction throughout the development process., Methods: An anonymous online survey was administered to the CAG members and 30 scientist/trainee authors of the BHPro chapters. The CAG also participated in an online focus group., Results: Most CAG members and chapter authors agreed that the CAG met its primary objectives and added unique value to BHPro. Both groups viewed the CAG's involvement as well-aligned with engaged scholarship, co-production, integrated knowledge translation, and, to a lesser extent, participatory research practices. CAG members reported high satisfaction with personal goal attainment, which included learning, collaborating with others, and making a meaningful impact. Content analyses of the focus group revealed three categories: 1) personal benefits related to learning, connection, and feeling valued, 2) value of a masked peer-review process, and 3) an accessible final product., Conclusions: Findings suggest that collaborating with end-users in the process of aging research confers personal and scientific benefits for both older adults and researchers., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Baycrest Research Ethics Board (REB 22-02). All participants providing online informed consent to participate. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Individuals with amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer's disease and other dementias, show inhibition deficits in addition to episodic memory. How the latent processes of selective attention (i.e., from perception to motor response) contribute to these inhibition deficits remains unclear. Therefore, the present study examined contributions of selective attention to aMCI-related inhibition deficits using computational modeling of attentional dynamics. Two models of selective attention - the dual-stage two-phase model and the shrinking spotlight model - were fitted to individual participant data from a flanker task completed by 34 individuals with single-domain aMCI (sdaMCI, 66-86 years), 20 individuals with multiple-domain aMCI (mdaMCI, 68-88 years), and 52 healthy controls (64-88 years). Findings showed greater commission errors in the mdaMCI group compared to controls. Final-fitting model parameters indicated inhibitory and early perceptual deficits in mdaMCI , and impaired spatial allocation of attention in both MCI groups. Model parameters differentiated mdaMCI from sdaMCI and controls with moderate-to-high sensitivity and specificity. Impairments in perception and selective attention may contribute to inhibition deficits in both aMCI subtypes.

Ten percent of children with cancer harbour a mutation in a predisposition gene. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumourigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukaemias), utilising WGS, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed in children harbouring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumourigenesis, suggesting a variant specific approach to managing children merits consideration.

Positional coding along the anterior-posterior axis is regulated by HOX genes, whose 3' to 5' expression correlates with location along this axis. The precise utilisation of HOX genes in different human cell types is not fully understood. Here, we use single-cell and spatial-transcriptomics, along with in-situ sequencing, to create a developmental atlas of the human fetal spine. We analyse HOX gene expression across cell types during development, finding that neural-crest derivatives unexpectedly retain the anatomical HOX code of their origin while also adopting the code of their destination. This trend is confirmed across multiple organs. In the axial plane of the spinal cord, we find distinct patterns in the ventral and dorsal domains, providing insights into motor pool organisation and loss of collinearity in HOXB genes. Our findings shed new light on HOX gene expression in the developing spine, highlighting a HOX gene 'source code' in neural-crest cell derivatives., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: The "butcher on the bus" is a term describing recognizing someone as familiar but failing to recollect how we know them. Previous studies probing this phenomenon have not used paradigms that mimic real life, and age-related differences have not been adequately addressed., Methods: In two studies, younger and older adults studied faces in scene contexts a variable number of times. In the test phases, studied faces were presented identical to the study phase, new faces were presented with new scenes, or studied faces were presented in a different context. In Study 1, this different context was the face presented with new features (pose, hairstyle, and clothing) and in a new scene. In Study 2, this different context was the same scene, but with new features. Participants made recollect, familiar, or new judgments, as well as source memory judgments for each face., Results: In both studies, younger adults had better recognition discrimination and recollection. The critical finding of both studies was that when faces were presented with new features, in either the same scene or a different scene, older adults did not find these faces as familiar as did younger adults., Discussion: Age-related declines in face recognition when features change may impact social interactions and everyday recognition tasks, highlighting the need for further research and supportive strategies to assist older adults in recognizing people., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Face recognition is a highly developed and specialised human ability, distinct from other cognitive abilities. Previous studies examining individual differences in face recognition have focused on face perception and specialised perceptual mechanisms such as holistic face processing. However, the contribution of specific face memory processes to face recognition ability remains unclear. In 99 neurotypical individuals, we administered validated face perception assessments, three face memory tasks (old/new task, face-scene task, face-name/occupation task), and the Cambridge Face Memory Test (CFMT) to assess face recognition ability. We found that after accounting for face perception ability (which significantly predicted face recognition ability), face-name recall and recollection of faces in the face-scene task predicted unique variance in face recognition ability, with face-name recall being the strongest predictor. This highlights that associative memory mechanisms contribute to face recognition abilities and suggests that the ability to learn and recall proper names is particularly important to face recognition., 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.

Previous studies have found that face perception deficits do not fully account for the severity of face recognition deficits in developmental prosopagnosia (DP). Researchers have begun identifying deficient memory mechanisms such as impaired face recollection, but these findings require replication, and further characterization of additional memory deficits is necessary. Our goals were to replicate prior findings of face recollection impairment in DP and extend these findings to assess different types of face associative memory. We had 69 DPs and 99 controls perform a face perception battery as well as three face memory tasks: 1) Old/New task with confidence ratings to calculate recollection and familiarity using ROC analysis, 2) Face/Scene task to examine remember-know judgments and contextual memory for faces, and 3) Face-Name/Occupation task to assess the ability to learn semantic associations with faces. Compared to controls, DPs showed poorer recollection and familiarity across both Old/New and Face/Scene tasks as well as reduced scene accuracy for correct faces. Of these differences, only Old/New recollection remained significant after controlling for group differences in face perception abilities. In the Face-Name/Occupation task, after controlling for face perception, DPs showed poorer recall of names than controls but performed similarly in recalling occupations. Finally, we found that DPs with major, mild, and no face perception deficits showed consistent impairments in Old/New recollection and face-naming, and larger perceptual deficits were associated with larger memory deficits. Together, these results provide several mechanistic insights into the nature of memory deficits in DPs and have diagnostic and treatment implications., (Published by Elsevier Ltd.)

In this work, we demonstrate a data-driven approach for estimating cerebrovascular reactivity (CVR) amplitude and lag from breathhold (BH) fMRI data alone. Our approach employs a frequency-domain approach that is independent of external recordings. CVR amplitude is estimated from the BOLD frequency spectrum and CVR lag is estimated from the Fourier phase using the global-mean BOLD signal as reference. Unlike referencing to external recordings, these lags are specific to the brain. We demonstrated our method in detecting regional CVR amplitude and lag differences across healthy (CTL), hypertensive (HT) and hypertension-plus-type-2-diabetes (HT + DM) groups of similar ages and sex ratios, with a total N of 49. We found CVR amplitude to be significantly higher in CTL compared to HT + DM, with minimal difference between CTL and HT. Also, voxelwise CVR lag estimated in the Fourier domain is a more sensitive marker of vascular dysfunction than CVR amplitude. CVR lag in HT is significantly shorter than in CTL, with minimal difference between CTL and HT + DM. Our results support the importance of joint CVR amplitude and lag assessments in clinical applications., 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.

Superagers are 80 to 89-year-olds with average or better cognition and memory equivalent to individuals 20 to 30 years younger. As sex and modifiable lifestyle/health factors influence cognitive aging and dementia risk, we examined their impact on superager status. Data from participants (n = 469; 67% female) aged 80-89 years old were analyzed from an online database that included demographic and dementia risk factors, and performance on tasks assessing working memory, cognitive inhibition, associative memory, and set shifting. Cross-sectional comparisons were made between superagers and those with typical-for-age cognitive abilities (typical-agers) to examine relationships between sex, superager status, and dementia risk factors. Females performed better than age-matched males on the associative memory task in the 50-69 years old group used for normative comparisons, and in the 80-89 years old group (ps < .001). More females than males were classified as superagers using non-sex-stratified normative comparisons (p = .009), and in sex-stratified normative comparisons (p = .022). Total weighted dementia risk reduced odds of superager status (OR = 0.199, 95% CI [0.046, 0.829]). Other lifestyle dementia risk factors were unrelated to superager status or could not be tested due to low endorsement. The findings support observations that superaging is more common in females, even when controlling for sex differences in memory performance. Future studies of superagers should account for sex differences. Results support being ambitious about dementia prevention, as having fewer modifiable dementia risk factors may be positively associated with superager status., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Introduction: Pain management for trauma in the extreme environment is vital for both casualty comfort and aiding safe extrication. However, adequate pain management in a resource-limited environment can be challenging and is often limited. We conducted a scoping review of the use of regional anesthesia in the prehospital environment, evaluating which regional anesthetic procedure was performed for various indications, their efficacy, and the type of healthcare provider delivering the anesthetic., Methods: A PRISMA-guided systematic literature review was conducted of Medline, Embase, and Cochrane databases for studies reporting the use of regional anesthesia in the prehospital environment published before June 30, 2022., Results: Thirty studies met the criteria and were included in the review. The most common types of regional anesthesia were fascia-iliaca compartment block ( n  = 317, from 12 studies) and femoral nerve block ( n  = 210, from 8 studies), along with various other blocks for a range of indications. These blocks had good efficacy and a low-risk profile and could be delivered by a wide range of healthcare providers., Conclusions: Regional anesthesia is an effective and non-resource-heavy pain management tool in prehospital environments, which may be applicable to austere settings. It can cover a wide range of injuries and can avoid systemic complications for casualties that may already be challenging to manage in out-of-hospital settings. Additionally, regional anesthesia can be effectively delivered by a wide range of providers. This review provides a holistic summary of pain management using regional anesthesia in the prehospital environment, with a discussion on its potential use in more extreme settings.

Tau pathology accumulates in the perirhinal cortex (PRC) of the medial temporal lobe (MTL) during the earliest stages of the Alzheimer's disease (AD), appearing decades before clinical diagnosis. Here, we leveraged perceptual discrimination tasks that target PRC function to detect subtle cognitive impairment even in nominally healthy older adults. Older adults who did not have a clinical diagnosis or subjective memory complaints were categorized into "at-risk" (score <26; n = 15) and "healthy" (score ≥26; n = 23) groups based on their performance on the Montreal Cognitive Assessment. The task included two conditions known to recruit the PRC: faces and complex objects (greebles). A scene condition, known to recruit the hippocampus, and a size control condition that does not rely on the MTL were also included. Individuals in the at-risk group were less accurate than those in the healthy group for discriminating greebles. Performance on either the face or size control condition did not predict group status above and beyond that of the greeble condition. Visual discrimination tasks that are sensitive to PRC function may detect early cognitive decline associated with AD., (© 2024 The Authors. Hippocampus published by Wiley Periodicals LLC.)

Purpose: Long-term limitations in social participation are common after stroke. Whether these can be attenuated through a tele-rehabilitation approach is unknown. We were particularly interested in examining transfer of learning effects which could result in broader improvements in social participation., Methods: We adapted a strategy training rehabilitation approach ( tele-CO-OP ) for remote delivery. Participants with chronic stroke were randomized to receive the intervention (EXPT) or to a wait list (Control). Feasibility and acceptability were measured via attendance scores, satisfaction with the training and therapist evaluation of engagement with the training. The primary outcome measure was the Canadian Occupational Performance Measure (COPM), a standardized semi-structured interview which elicits difficulties in day-to-day life., Results: Seventeen participants were randomized. Tele-CO-OP was found to be feasible and acceptable: participants reported high satisfaction and engagement, and missed few sessions. Large effect sizes for transfer of learning effects were observed in favor of receiving tele-CO-OP vs being waitlisted. Significant benefits were also conferred to the Control group following receipt of tele-CO-OP . The intervention also appeared to improve mood., Conclusions: This exploratory study demonstrates the feasibility and acceptability of tele-CO-OP and provides preliminary evidence for transfer of learning effects to untrained everyday social participation activities. Trial registration number: NCT02724813.

Background: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) can lead to functional and cognitive decline, increasing dementia risk. There is a pressing need for interventions that prevent this deterioration. The ASPIRE (Adult Strategies Put Into Real-world Environments) intervention was developed to improve performance of daily activities., Objectives: The primary objective was to determine whether ASPIRE was more effective than a Brain Education control intervention in improving performance and satisfaction with daily life activities that were not specifically trained in the intervention. Secondary objectives were to explore: 1) whether ASPIRE was more effective in improving self-reported health and quality of life, and performance on cognitive tests; and 2) maintenance of change over six-months., Design: Double-blind, two-armed, parallel randomized controlled trial, with a six-month follow-up period., Setting: Community based, Greater Toronto Area., Participants: Two-hundred sixty-four older adults (aged 70.8 ± 6.6 years) with SCD or MCI, randomized to ASPIRE (n=131) or a Brain Education active control arm (n= 133)., Intervention: ASPIRE is a 10-week meta-cognitive group intervention focusing on strategy acquisition and application to improve performance of individualized daily activity identified by each participant as important. It involves setting goals, creating tailored plans, and iteratively modifying these plans with support from the group members and facilitator., Measurements: Performance of and satisfaction with daily activities was rated on a 10-point Likert scale using the Canadian Occupational Performance Measure (COPM). Secondary outcome were subjective cognition, depression, anxiety, self-efficacy, quality of life, and cognitive tests of memory and executive functions., Results: Post-intervention, clinically significant improvement of untrained activities (two points or more on the COPM) was found in 32.5% in ASPIRE; and 30.6% in the control arm, with no significant between group differences (Performance: (exp(β ̂) =0.96, z=-0.15, p=.879); Satisfaction: (exp(β ̂) =0.94, z=-0.29, p=.775). The improvements remained stable over six months in both arms. No significant group effects were found on the secondary outcomes, but improvements were found on subjective cognition and self-efficacy in both arms post intervention., Conclusion: Both a meta-cognitive strategy approach and an adult learning activity resulted in positive changes in subjective cognition, self efficacy, and, to a certain extent, engagement in daily activities., Competing Interests: All authors declare that they have no conflicts of interest.

Background/objectives: The Kimel Family Centre for Brain Health and Wellness is a research-driven community centre testing the efficacy of personalized dementia risk reduction programming on dementia risk and cognition. The objective of this protocol is to validate this approach by following people for two years., Design/setting: Participants will receive a comprehensive dementia risk assessment, including nonmodifiable and modifiable risk factors, from which they will receive a Personalized Dementia Risk Report and Program Strategy, indicating their health conditions increasing and their risk level in five modifiable risk domains: physical activity, brain-healthy eating, cognitive engagement, social connections, and mental wellbeing. Equipped with this information, participants will enroll in programs within the Centre to address their risk factors. Changes to their dementia risk, cognition, and Personalized Program Strategy will be communicated through re-assessments of risk factors every six months (risk and cognition) and every year (comprehensive assessment)., Participants: Participants (n = 450) will be 50 years of age or older, without a diagnosis of dementia, and sufficiently fluent in English to complete the assessments and understand program instructors. One goal is that our participant sample will include people of low income (with fundraising providing free community centre membership), and from various ethno-racial backgrounds., Intervention: Participants will select programs to meet their Personalized Program Strategy. For physical activity, they will gradually work toward the Canadian Society for Exercise Physiology guidelines. For brain-healthy eating, they will learn about the Brain Health Food Guide and food label reading, and then take additional programs. For cognitive engagement and mental wellbeing, they will take at least one hour of relevant programming per week. Social connections will be reinforced throughout all programs. All participants will also have access to the Canadian Consortium on Neurodegeneration's CAN-THUMBS Up online, educational program on modifiable dementia risk factors, called Brain Health PRO., Measurements: The comprehensive assessment includes numerous dementia risk factors, but the primary measures are risk in the five domains, health conditions proximal to those five risk domains, and cognition, and how these are affected by adherence and quality of goal-directed future simulation. We hypothesize a reduced risk in the five domains within six months, improvements in health biomarkers within a year, and maintenance of cognition within two years, with these benefits accruing with greater adherence, but only up to a point, at which benefits will plateau, and greater benefits among participants whose goal-directed simulations are more vivid, personally-relevant, achievable, and positive., Conclusions: This innovative approach overcomes a number of limitations present in prior multidomain dementia prevention trials. Adapting a preference clinical trial that is embedded in a community centre, where participants have autonomy to choose programs to address their modifiable dementia risk factors, has real-world applicability in the global effort to reduce dementia risk., Competing Interests: The authors have no conflicts of interest to report.

Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma., (© 2023. Springer Nature Limited.)

Objectives: To adapt the content and functionalities of Brain Health PRO, a web-based multidomain program designed to increase dementia literacy, to the context and needs of users, providers and community organisations across Québec, Canada., Design: Five consecutive qualitative co-creation focus group sessions 30-90 min in duration each, exploring potential barriers and facilitators to usability, accessibility, comprehensibility, participant recruitment and retention., Setting: Virtual meetings., Participants: A 15-member team based in Québec and Ontario, Canada, consisting of 9 researchers (including a graduate student and the project coordinator), representing occupational therapy, sensory rehabilitation, neuropsychology, psychology, health science and research methods, 3 informal caregivers of older adults living with cognitive decline and 3 members of the Federation of Quebec Alzheimer Societies., Data Analysis: Session recordings were summarised through both qualitative description and thematic analysis., Results: The synthesised recommendations included adjustments around diversity, the complexity and presentation styles of the materials, suggestions on refining the web interface and the measurement approaches; it influenced aspects of participant recruitment, retention efforts and engagement with the content of Brain Health PRO ., Conclusions: Co-creation in dementia prevention research is important because it involves collaboration between researchers, community support and service providers, and persons with lived experience as care providers, in the design and implementation of clinical studies. This approach helps to ensure that the content and presentation of educational material is relevant and meaningful to the target population and those involved in its delivery, and it leads to a greater understanding of their needs and perspectives., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists., (© 2023. The Author(s).)

Interest in the gut-brain axis and its implications for neurodegenerative diseases, such as Alzheimer's disease and related dementias, is growing. Microbial imbalances in the gastrointestinal tract, which are associated with impaired cognition, may represent a therapeutic target for lowering dementia risk. Multicomponent lifestyle interventions are a promising dementia risk reduction strategy and most often include diet and exercise, behaviors that are also known to modulate the gut microbiome. A better understanding of the role of the gut microbiome in diet and exercise effects on cognition may help to optimize these lifestyle interventions. The purpose of this review is to summarize findings from diet and exercise interventions that have investigated cognitive changes via effects on the microbiome. We aim to discuss the underlying mechanisms, highlight current gaps in the field, and provide new research directions. There is evidence mainly from rodent studies supporting the notion that microbiota changes mediate the effects of diet and exercise on cognition, with potential mechanisms including end-product metabolites and regulation of local and systemic inflammation. The field lacks whole diet and exercise interventions, especially those involving human participants. It is further limited by heterogeneous rodent models, outcome assessments, and the absence of proper mediation analyses. Trials including older adults with dementia risk factors, factorial designs of diet and exercise, and pre and post measures of microbiota, end-product metabolites, and inflammation would help to elucidate and potentially leverage the role of the microbiome in lowering dementia risk through lifestyle modification., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

The influence of the apolipoprotein E ε4 allele (APOE4) on brain microstructure of cognitively normal older adults remains incompletely understood, in part due to heterogeneity within study populations. In this study, we examined white-matter microstructural integrity in cognitively normal older adults as a function of APOE4 carrier status using conventional diffusion-tensor imaging (DTI) and the novel orthogonal-tensor decomposition (DT-DOME), accounting for the effects of age and sex. Age associations with white-matter microstructure did not significantly depend on APOE4 status, but did differ between sexes, emphasizing the importance of accounting for sex differences in APOE research. Moreover, we found the DT-DOME to be more sensitive than conventional DTI metrics to such age-related and sex effects, especially in crossing WM fiber regions, and suggest their use in further investigation of white matter microstructure across the life span in health and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Srisaikaew, Chad, Mahakkanukrauh, Anderson and Chen.)

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management., (© 2022. The Author(s).)

In a study recently in Nature, Galeano Niño et al. use spatial profiling and single-cell RNA sequencing to delineate the spatial organization of microbiota in cancer. Their findings demonstrate that tumor-associated microbiota coalesce in micro-niches where they may mediate immune and epithelial oncogenic roles., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis., (© 2023. The Author(s).)

Background/objectives: CAN-THUMBS UP is designed as a comprehensive and innovative fully remote program to 1) develop an interactive and compelling online Brain Health Support Program intervention, with potential to positively influence dementia literacy, self-efficacy and lifestyle risk factors; 2) enroll and retain a community-dwelling Platform Trial Cohort of individuals at risk of dementia who will participate in the intervention; 3) support an open platform trial to test a variety of multidomain interventions that might further benefit individuals at risk of dementia. This manuscript presents the Brain Health Support Program Study protocol., Design/setting: Twelve-month prospective multi-center longitudinal study to evaluate a fully remote web-based educational intervention. Participants will subsequently be part of a Platform Trial Cohort and may be eligible to participate in further dementia prevention clinical trials., Participants: Three hundred fifty older adults who are cognitively unimpaired or have mild cognitive impairment, with at least 1 well established dementia risk factor., Intervention: Participants engage in the Brain Health Support Program intervention for 45-weeks and complete pre/post intervention measures. This intervention is designed to convey best available evidence for dementia prevention, consists of 181 chapters within 8 modules that are progressively delivered, and is available online in English and French. The program has been developed as a collaborative effort by investigators with recognized expertise in the program's content areas, along with input from older-adult citizen advisors., Measurements: This study utilizes adapted remote assessments with accessible technologies (e.g. videoconferencing, cognitive testing via computer and mobile phone, wearable devices to track physical activity and sleep, self-administered saliva sample collection). The primary outcome is change in dementia literacy, as measured by the Alzheimer's Disease Knowledge Scale. Secondary outcomes include change in self-efficacy; engagement using the online program; user satisfaction ratings; and evaluation of usability and acceptance. Exploratory outcomes include changes in attitudes toward dementia, modifiable risk factors, performance on the Neuropsychological Test Battery, performance on self-administered online cognitive assessments, and levels of physical activity and sleep; success of the national recruitment plan; and the distribution of age adjusted polygenic hazard scores., Conclusions: This fully remote study provides an accessible approach to research with all study activities being completed in the participants' home environment. This approach may reduce barriers to participation, provide an easier and less demanding participant experience, and reach a broader geography with recruitment from all regions of Canada. CAN-THUMBS UP represents a Canadian contribution to the global World-Wide FINGERS program (alz.org/wwfingers)., Competing Interests: HF reports grant funding from CIHR to the CCNA (CNA-163902) that supported this study. Outside of this study, he also reports grant funding from Annovis (QR Pharma), Vivoryon (Probiodrug), AC Immune, and LuMind; service agreements for consulting activities with LuMind, Genentech (DSMB), Roche/Banner (DMC), Tau Consortium (SAB), Samus Therapeutics, Biosplice Therapeutics, Axon Neurosciences, Novo Nordisk Inc., Janssen Research and Development LLC; and travel funding from World Events Forum (ADDF) with no personal funds received and all payments to UCSD. He also reports a philanthropic donation from the Epstein Family Alzheimer’s Disease Collaboration for therapeutic research in AD with no personal funds received and all payments to UCSD. SB reports grant funding to CCNA from CIHR and ASC that supported this study. Outside of this study, she also reports consulting fees and participation on an advisory board for Lucilab and an unpaid role of scientific advisor for the Quebec Federation of Alzheimer’s Societies. HN reports consulting fees from Hoffman-La Roche and Biogen. AL reports a Centre for Aging Brain Health Innovation Grant (CCNA-1-00295) that helped support this study. NA reports grants from CIHR, Social Sciences and Humanities Research Council of Canada, Natural Sciences and Engineering Research Council of Canada, Centre for Aging + Brain Health Innovation, Canadian Foundation for Innovation, Fonds de Recherché Société et Culture Québec, and ASC. She also reports book royalties from Oxford University Press and consulting fees from the National Eye Institute. JW reports grant funding to her institution from AGE-WELL and MIRI (McMaster Institute for Research in Aging) to support a postdoctoral fellowship and CIHR funding to CCNA Team 18 to support Indigenous research in the CCNA. She also reports unpaid roles as a member of the Federal Ministerial Advisory Committee on Dementia and the Medical and Scientific Advisory Board for Alzheimer’s Disease International. MS reports unpaid roles as a member of the Data Safety and Monitoring Board (DSMB) for Intervention in Parkinson’s Disease and the Chair of the DSMB for Intervention in Depression. As Scientific Director of CCNA, HC reports grants from CIHR, Baycrest Health Sciences Foundation, Women’s Brain Health Initiative, Alzheimer Society of Canada, Brain Canada, Saskatchewan Health Research Foundation, Alberta Innovates, and Weston Foundation (Weston Brain Institute). As a site investigator for clinical trials, he also receives support from Roche, Lilly, Anavex, and Alector. He reports being a member of the Ministerial Advisory Board on Dementia (2019-2022) and part of the membership organizing committee for Canadian Conference on Dementia.

Objectives: Amnestic mild cognitive impairment (aMCI) is associated with cortical thinning in perirhinal and entorhinal cortices, key regions of the brain supporting familiarity. Individuals with aMCI demonstrate familiarity deficits in their behavior, often repeating questions in the same conversation. While familiarity deficits in healthy aging are minimal, past studies measuring familiarity in aMCI have mixed results, perhaps due to the influence of recollection. We therefore used a paradigm that minimized the influence of recollection, and hypothesized that familiarity would be impaired in aMCI relative to age-matched controls, but not in healthy older adults relative to younger adults. We also hypothesized that familiarity deficits in aMCI would be greater for objects than words because the perirhinal cortex plays a significant role in visual discrimination., Methods: A sample of 36 younger adults, 38 cognitively intact older adults, and 30 older adults with aMCI made absolute frequency judgments for words and objects seen a variable number of times in an incidental encoding task. Estimates of familiarity were derived from correlating participants' frequency judgments with the actual frequency of presentation., Results: Familiarity was largely spared in healthy aging, with minor deficits in familiarity for words. Familiarity deficits were evident in aMCI comparably for words and objects., Discussion: The present research underscores the need to study familiarity in contexts minimizing recollection, particularly when comparing groups with different levels of recollection, and adds to our understanding of the phenomenology of aMCI. Familiarity deficits may provide an early biomarker of dementia risk., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A fundamental step of tumour single cell mRNA analysis is separating cancer and non-cancer cells. We show that the common approach to separation, using shifts in average expression, can lead to erroneous biological conclusions. By contrast, allelic imbalances representing copy number changes directly detect the cancer genotype and accurately separate cancer from non-cancer cells. Our findings provide a definitive approach to identifying cancer cells from single cell mRNA sequencing data., (© 2022. The Author(s).)

Purpose: To describe and categorize difficulties in daily activities of older adults with subjective cognitive decline (SCD) compared to individuals with mild cognitive impairment (MCI)., Methods: Deductive quantitative content analysis was used to classify reported issues in the performance of meaningful daily activities, in older adults with SCD ( n  = 67; age= 70 ± 6.3) or MCI ( n  = 42; age= 72 ± 6.6). The occupational performance issues were identified using the Canadian Occupational Performance Measure, a semi-structured interview, and categorised using the International Classification of Functioning, Disability and Health (ICF)., Results: Both groups identified issues in all nine ICF "Activities and Participation" domains, with no significant group effects on seven of them. The most frequently affected "Activities and Participation" domains in both groups were "Self-care" (e.g. exercise and diet); "Community, social and civic life" (e.g. social-leisure activities); and "General tasks and demands" (e.g. time management). Over 90% of the issues in both groups were described in the context of difficulties in "Mental functions" (e.g. memory and higher-level cognitive functions)., Conclusions: Older adults with SCD, although independent, identified a variety of daily activities that they are not performing satisfactorily, remarkably similar in nature to the occupational performance issues described by older adults with MCI.Implications for RehabilitationOlder adults with SCD identified difficulties in performing social and leisure activities, maintaining healthy lifestyle behaviours, and managing multiple daily tasks.The daily challenges described by older adults with SCD are similar in nature to those identified by those with MCI.Older adults with SCD and MCI describe their daily challenges are related not only to memory problems, but also to executive dysfunction.Interventions for older adults with SCD should aim to improve self-identified problems in everyday functioning.

Background: Reversible lifestyle behaviors (modifiable risk factors) can reduce dementia risk by 40%, but their prevalence and association with cognition throughout the adult lifespan is less well understood., Methods: The associations between the number of modifiable risk factors for dementia (low education, hypertension, hearing loss, traumatic brain injury, alcohol or substance abuse, diabetes, smoking, and depression) and cognition were examined in an online sample ( N  = 22,117, ages 18-89)., Findings: Older adults (ages 66-89) had more risk factors than middle-aged (ages 45-65) and younger adults (ages 18-44). Polynomial regression revealed that each additional risk factor was associated with lower cognitive performance (equivalent to 3 years of aging), with a larger association as age increased. People with no risk factors in their forties to seventies showed similar cognitive performance to people 10 or 20 years younger with many risk factors., Interpretation: Modifiable dementia risk factors amplify lifespan age differences in cognitive performance., Competing Interests: None., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: More women than men develop Alzheimer's disease, yet women perform better and show less decline on episodic memory measures, a contradiction that may be accounted for by modifiable risk factors for dementia., Methods: Associations among age, sex, modifiable dementia risk factors, and cognition were measured in a cross-sectional online sample ( n  = 21,840, ages 18 to 89)., Results: Across four tests of associative memory and executive functions, only a Face-Name Association task revealed sex differences in associative memory that varied by age. Men had worse memory than women (the equivalent of performing similar to someone 4 years older) across ages. Men had larger age differences than women (ie, worse memory in older ages) among people with no to one risk factor, but not those with multiple risk factors., Discussion: Because the relationship between dementia risk factors and age-related memory differences varies between men and women, sex-specific dementia prevention approaches are warranted., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Time of day (TOD) influences on executive functions have been widely reported, with greater efficiency demonstrated at optimal relative to non-optimal TOD according to one's chronotype (i.e., synchrony effect). Older adults (OAs) show declines in inhibitory control and are more sensitive to the effects of circadian variation on executive functioning. To date, no studies have investigated the effects of TOD and aging on executive functioning using electrophysiological measures. The present study investigated the effects of aging and TOD on the neural correlates of inhibitory processing (N2 and P3) using event-related potentials (ERPs). Go-NoGo and Flanker tasks were administered to 52 OAs of morning chronotype and 51 younger adults (YAs) of afternoon-to-evening chronotype who were randomly assigned to morning or afternoon test sessions, with the optimal TOD for OAs in the morning and for YAs in the afternoon/evening. While behavioral results demonstrated no TOD effects, ERPs indicated synchrony effects. Both YAs and OAs showed greater modulation of Go-NoGo N2 and greater P3 amplitude during the non-optimal than optimal TOD, consistent with the synchrony effect. For the Flanker task, age differences in P3 amplitude were only apparent during the non-optimal TOD. These results suggest that processes associated with inhibitory control are differentially affected by TOD and aging, with age-related reductions in inhibitory efficiency during off-peak test times on measures of interference control. These findings highlight the sensitivity of ERPs to detect TOD effects in the absence of behavioral differences, confirm more pronounced TOD effects in OAs relative to YAs on ERP measures of interference control, and reinforce the need to assess and control for circadian typology in research studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rabi, Chow, Paracha, Hasher, Gardner, Anderson and Alain.)

Aging is associated with altered brain connectivity within the default mode network (DMN). Although research using functional magnetic resonance imaging has quantified age-related alterations in functional connectivity within this network during resting state, it is less clear how this may be reflected in electrophysiological measures, and how this relates to cognitive performance in older adults. The aim of this study was to quantify age differences in phase synchrony of the DMN during resting state, with particular focus on connectivity between the anterior node (i.e., medial prefrontal cortex, or mPFC) and other associated regions in this network. Electroencephalography was recorded from 55 younger adults (18-30 years, 28 females) and 34 older adults (64-88 years, 16 females) in two resting state conditions (eyes-open and -closed). Source-level functional connectivity was quantified using phase-locking value (PLV) with a spatial filter of six sources of interest, and were subjected to data-driven permutation testing between groups from 1 to 50 Hz. Older adults also completed tests of memory, language, executive functioning, and processing speed. Findings indicated decreased connectivity in the alpha2 range for older than younger adults between the mPFC and other DMN regions including the left angular gyrus and bilateral lateral temporal cortices, the latter of which were associated with lower performance in semantic fluency and executive functioning in older adults. Furthermore, greater PLV in theta and beta bands between the mPFC and posterior cingulate regions were found in older than younger adults. These results suggest age-related changes in DMN functional connectivity are non-uniform and frequency-dependent, and may reflect poorer performance in cognitive domains thought to decline with aging., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Healthy diet and exercise are associated with reduced risk of dementia in older adults. The impact of diet and exercise interventions on brain health is less consistent, especially with dietary interventions which rely on varying approaches. Our objective was to evaluate the feasibility and preliminary efficacy of a 6-month intervention combining exercise with a novel dietary counseling approach to improve hippocampal volume among older adults at-risk for dementia., Methods: Participants with vascular risk factors and subjective cognitive decline or early mild cognitive impairment were cluster randomized in groups of 3-4 to the diet intervention (DIET) or control education (ED) group. All participants engaged in 1 h of supervised exercise per week and additional exercise at home. DIET involved 1 h per week of group-based dietary counseling comprising education, goal setting, and strategy training. ED involved 1 h per week of group-based brain health education classes. Our primary outcome was change in hippocampal volume from baseline to 6 months. Secondary outcomes included changes in cognitive function, blood biomarkers, diet, and fitness. Recruitment challenges and early discontinuation of the trial due to COVID-19 necessitated a revised focus on feasibility and preliminary efficacy., Results: Of 190 older adults contacted, 14 (7%) were eligible and enrolled, constituting 21% of our recruitment target. All participants completed the intervention and attended 90% of exercise and DIET/ED sessions on average. All 6-month assessments prior to COVID-19 were completed but disruptions to in-person testing resulted in incomplete data collection. No serious adverse events occurred and all participants expressed positive feedback about the study. Preliminary findings did not identify any significant changes in hippocampal volume; however, substantial improvements in diet and HbA1c were observed with DIET compared to ED (d = 1.75 and 1.07, respectively)., Conclusions: High adherence and retention rates were observed among participants and preliminary findings illustrate improvements in diet quality and HbA1c. These results indicate that a larger trial is feasible if difficulties surrounding recruitment can be mitigated., Trial Registration: ClinicalTrials.gov identifier: NCT03056508 ., (© 2022. The Author(s).)

In humans, age-related declines in vision, hearing, and touch coincide with changes in amplitude and latency of sensory-evoked potentials. These age-related differences in neural activity may be related to a common deterioration of supra-modal brain areas (e.g., PFC) that mediate activity in sensory cortices or reflect specific sensorineural impairments that may differ between sensory modalities. To distinguish between these two possibilities, we measured neuroelectric brain activity while 37 young adults (18-30 years, 18 males) and 35 older adults (60-88 years, 20 males) were presented with a rapid randomized sequence of lateralized auditory, visual, and somatosensory stimuli. Within each sensory domain, we compared amplitudes and latencies of sensory-evoked responses, source activity, and functional connectivity (via phase-locking value) between groups. We found that older adults' early sensory-evoked responses were greater in amplitude than those of young adults in all three modalities, which coincided with enhanced source activity in auditory, visual, and somatosensory cortices. Older adults also showed stronger neural synchrony than young adults between superior prefrontal and sensory cortices; and in older adults, the degree of phase synchrony was positively correlated with the magnitude of source activity in sensory areas. Critically, older adults who showed enhanced neural activity in one sensory domain also showed enhanced activity in other modalities. Together, these findings support the common cause hypothesis of aging and highlight the role of prefrontal regions in exerting top-down control over sensory cortices. SIGNIFICANCE STATEMENT A prominent theory of aging posits that age-related declines in sensory processing across domains are related to a single common neurobiological mechanism. However, the neural evidence supporting this common cause hypothesis has remained elusive. Our study revealed robust age-related changes in three sensory domains across a range of neural metrics. Importantly, older adults who showed increased neural activity within one sensory domain also showed enhanced neural activity in the other two sensory modalities. No such relation among activity in sensory cortices was observed in young adults. Age-related increases in neural activity in sensory cortices coincided with enhanced neural synchrony between the PFC and sensory cortices, underlining the importance of the PFC in regulating sensory processing., (Copyright © 2022 the authors.)

Objectives: Age-related differences in cognition are typically assessed by comparing groups of older to younger participants, but little is known about the continuous trajectory of cognitive changes across age, or when a shift to older adulthood occurs. We examined the pattern of mean age differences and variability on episodic memory and executive function measures over the adult life span, in a more fine-grained way than past group or life-span comparisons., Method: We used a sample of over 40,000 people aged 18-90 who completed psychometrically validated online tests measuring episodic memory and executive functions (the Cogniciti Brain Health Assessment)., Results: Cognitive performance declined gradually over adulthood, and rapidly later in life on spatial working memory, processing speed, facilitation (but not interference), associative recognition, and set shifting. Both polynomial and segmented regression fit the data well, indicating a nonlinear pattern. Segmented regression revealed a shift from gradual to rapid decline that occurred in the early 60s. Variability between people (interindividual variability or diversity) and variability within a person across tasks (intraindividual variability or dispersion) also increased gradually until the 60s, and rapidly after. Confirmatory factor analysis revealed a single general factor (of variance shared between tasks) offered a good fit for performance across tasks., Discussion: Life-span cognitive performance shows a nonlinear pattern, with gradual decline over early and mid-adulthood, followed by a transition in the 60s to notably accelerated, but more variable, decline. Some people show less decline than others, and some cognitive abilities show less within-person decline than others., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Objectives: Amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer's disease and other dementias, is characterized by episodic memory impairment. Recent evidence has shown inhibitory control deficits in aMCI, but the extent of these deficits across inhibitory domains (i.e., response inhibition and interference control) and aMCI subtypes (i.e., single vs multiple domain) remains unclear. Few studies have included reaction time intraindividual variability (RT IIV) in these efforts. The aim of this study was to compare response inhibition and interference control between aMCI subtypes using measures of accuracy, mean RT, and RT IIV., Methods: We report data from 34 individuals with single-domain aMCI (sdaMCI, 66-86 years), 20 individuals with multiple-domain aMCI (mdaMCI, 68-88 years), and 52 healthy controls (HC, 64-88 years) who completed tasks of response inhibition (Go-NoGo) and interference control (Flanker). Group differences in accuracy, mean RT, and RT IIV were examined for both tasks., Results: Individuals with mdaMCI had higher RT IIV than the other groups on both tasks. In RT IIV, we observed an interference control deficit in mdaMCI and sdaMCI relative to healthy controls, a finding not observed through accuracy or mean RT., Discussion: RT IIV may detect subtle differences in inhibition deficits between aMCI subtypes that may not be evident with conventional behavioral measures. Findings support the supplementary use of RT IIV when assessing early executive function deficits., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Amnestic mild cognitive impairment (aMCI), a prodromal phase of Alzheimer's disease (AD), is characterized by episodic memory dysfunction, but inhibitory deficits have also been commonly reported. Time of day (TOD) effects have been confirmed in 1) healthy aging on cognitive processes such as inhibitory control, and 2) on behavior in AD (termed the sundowning effect), but no such research has addressed aMCI., Objective: The present study examined the impact of TOD on the behavioral and electrophysiological correlates of inhibition in 54 individuals with aMCI and 52 healthy controls (HCs), all of morning chronotype., Methods: Participants were randomly assigned to complete two inhibition tasks (Go-NoGo and Flanker) during their optimal (morning) or non-optimal (evening) TOD, while electroencephalography was recorded., Results: Both tasks elicited changes in N2 and P3 event-related potential (ERP) components, which commonly index inhibitory functioning. Analyses showed that the Go-NoGo difference in P3 amplitude was reduced in individuals with aMCI relative to HCs. Compared to HCs, the Flanker difference in P3 amplitude was also reduced and coincided with more errors in the aMCI group. Notably, these behavioral and ERP differences were exaggerated in the non-optimal TOD relative to the optimal TOD., Conclusion: Findings confirm the presence of inhibition deficits in aMCI and provide novel evidence of sundowning effects on inhibitory control in aMCI. Results reinforce the need to consider the influences of TOD in clinical assessments involving individuals with aMCI.

Disruptions to the central excitatory-inhibitory (E/I) balance are thought to be related to aging and underlie a host of neural pathologies, including Alzheimer's disease. Aging may induce an increase in excitatory signaling, causing an E/I imbalance, which has been linked to shorter lifespans in mice, flies, and worms. In humans, extended longevity correlates to greater repression of genes involved in excitatory neurotransmission. The repressor element-1 silencing transcription factor (REST) is a master regulator in neural cells and is believed to be upregulated with senescent stimuli, whereupon it counters hyperexcitability, insulin/insulin-like signaling pathway activity, oxidative stress, and neurodegeneration. This review examines the putative mechanisms that distort the E/I balance with aging and neurodegeneration, and the putative roles of REST in maintaining neuronal homeostasis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pediatric papillary thyroid carcinoma (PPTC) is clinically distinct from adult-onset disease. Although there are higher rates of metastasis and recurrence in PPTC, prognosis remains highly favorable. Molecular characterization of PPTC has been lacking. Historically, only 40% to 50% of childhood papillary thyroid carcinoma (PTC) were known to be driven by genomic variants common to adult PTC; oncogenic drivers in the remainder were unknown. This contrasts with approximately 90% of adult PTC driven by a discrete number of variants. In this study, 52 PPTCs underwent candidate gene testing, followed in a subset by whole-exome and transcriptome sequencing. Within these samples, candidate gene testing identified variants in 31 (60%) tumors, while exome and transcriptome sequencing identified oncogenic variants in 19 of 21 (90%) remaining tumors. The latter were enriched for oncogenic fusions, with 11 nonrecurrent fusion transcripts, including two previously undescribed fusions, STRN-RET and TG-PBF. Most fusions were associated with 3' receptor tyrosine kinase (RTK) moieties: RET, MET, ALK, and NTRK3. For advanced (distally metastatic) tumors, a driver variant was described in 91%. Gene expression analysis defined three clusters that demonstrated distinct expression of genes involved in thyroid differentiation and MAPK signaling. Among RET-CCDC6-driven tumors, gene expression in pediatric tumors was distinguishable from that in adults. Collectively, these results show that the genomic landscape of pediatric PTC is different from adult PTC. Moreover, they identify genomic drivers in 98% of PPTCs, predominantly oncogenic fusion transcripts involving RTKs, with a pronounced impact on gene expression. Notably, most advanced tumors were driven by a variant for which targeted systemic therapy exists. SIGNIFICANCE: This study highlights important distinctions between the genomes and transcriptomes of pediatric and adult papillary thyroid carcinoma, with implications for understanding the biology, diagnosis, and treatment of advanced disease in children., (©2021 American Association for Cancer Research.)

Introduction: Mean cognitive performance is worse in amnestic mild cognitive impairment (aMCI) compared to control groups. However, studies on variability of cognitive performance in aMCI have yielded inconclusive results, with many differences in variability measures and samples from one study to another., Methods: We examined variability in aMCI using an existing older adult sample ( n = 91; 51 with aMCI, 40 with normal cognition for age), measured with an online self-administered computerized cognitive assessment (Cogniciti's Brain Health Assessment). Our methodology extended past findings by using pure measures of variability (controlling for confounding effects of group performance or practice), and a clinically representative aMCI sample (reflecting the continuum of cognitive performance between normal cognition and aMCI)., Results: Between-group t -tests showed significantly greater between-person variability ( interindividual variability or diversity ) in overall cognitive performance in aMCI than controls, although the effect size was with a small to moderate effect size, d = 0.44. No significant group differences were found in within-person variability ( intraindividual variability ) across cognitive tasks ( dispersion ) or across trials of a response time task ( inconsistency ), which may be because we used a sample measuring the continuum of cognitive performance. Exploratory correlation analyses showed that a worse overall score was associated with greater inter- and intraindividual variability, and that variability measures were correlated with each other, indicating people with worse cognitive performance were more variable., Discussion: The current study demonstrates that self-administered online tests can be used to remotely assess different types of variability in people at risk of Alzheimer`s. Our findings show small but significantly more interindividual differences in people with aMCI. This diversity is considered as "noise" in standard assessments of mean performance, but offers an interesting and cognitively informative "signal" in itself.

Introduction: Sustaining a stroke has a devastating, long-term impact on participation in everyday life. Despite the recognition of participation as a key outcome of stroke rehabilitation, there are few effective interventions that address participation. Occupational performance coaching is a promising intervention designed to improve participation among stroke survivors. Delivery of occupational performance coaching using telerehabilitation could improve access. This study examined the feasibility, acceptability and potential efficacy of telerehabilitation occupational performance coaching., Method: A single-case experimental design was used. Six community-dwelling stroke survivors received 10 sessions of telerehabilitation occupational performance coaching over 16 weeks. We examined the feasibility and acceptability of telerehabilitation occupational performance coaching, improvement in performance and satisfaction with identified goals., Results: Telerehabilitation occupational performance coaching was feasible and acceptable to deliver; participants who started the intervention completed it and reported high satisfaction and a strong therapeutic relationship. All participants experienced technological issues that required resolution. Goal-performance and/or satisfaction improved for five of six participants. Sixty-four percent of goals showed trends for improvement and 43% showed significant improvements., Conclusions: Findings support the feasibility and acceptability of telerehabilitation occupational performance coaching, along with its efficacy for improving performance and satisfaction with performance of goals. Further research is needed to prove the effectiveness of telerehabilitation occupational performance coaching and to determine who may benefit most., Competing Interests: Declaration of conflicting interests: The authors confirm that there is no conflict of interest., (© The Author(s) 2021.)

Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis., (© 2021. The Author(s).)

Benign peripheral nerve tumors include schwannoma, neurofibroma, and perineurioma, as well as a recently recognized group of tumors with dual patterns of differentiation. The molecular pathogenesis of these so-called "hybrid" tumors remains poorly understood. Following identification of a novel CHD7-VGLL3 fusion gene in a hybrid schwannoma-perineurioma, we evaluated an expanded cohort of this tumor-type-as well as tumors with VGLL3 rearrangement identified from a curated molecular database-to characterize the prevalence of fusion genes among these tumors. Eighteen tumors met the inclusion criteria for this study. RNA sequencing identified VGLL3 rearrangement in 14 of these cases; the partner genes included CHD7 (ten cases), CHD9 (two cases), and MAMLD1 (two cases). Two cases possessed altogether unrelated fusions, including: DST-BRAF and SQSTM1-CDX1 fusion genes. Finally, two cases lacked identifiable fusion products. These findings highlight the molecular diversity of these neoplasms, with frequent rearrangement of VGLL3. More importantly, despite their dual pattern of differentiation, our results reveal the pathogenesis of hybrid schwannoma-perineurioma is unrelated to conventional schwannoma and perineurioma, thereby implying this tumor represents an altogether pathologically distinct entity.

Objective: To examine known-groups validity of a telephone administration of the total learning scores of the Rey Auditory Verbal Learning Test (RAVLT) in discriminating between people with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) and convergent validity of the telephone-RAVLT., Method: In total, 83 older adults (age = 71.4 ± 7.0) with SCD or aMCI completed the RAVLT learning trials over the telephone and the Hopkins Verbal Learning Test (HVLT) in-person., Results: Telephone-RAVLT total recall significantly correlated with HVLT total recall (r = .49, p < .001). Significant between group differences were found (effect size = 0.94)., Conclusions: This study provides support for known-groups and convergent validity of the telephone-RAVLT., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction. This article is highlighted in the In This Issue feature, p. 995 ., (©2020 American Association for Cancer Research.)