Palliative care needs of people and/or their families with serious and/or chronic health conditions in low- or middle-income country (LMIC) humanitarian settings-a systematic scoping review protocol.

BACKGROUND: Palliative care in low- or middle-income country (LMIC) humanitarian settings is a new area, experiencing a degree of increased momentum over recent years. The review contributes to this growing body of knowledge, in addition to identifying gaps for future research. The overall aim is to systematically explore the evidence on palliative care needs of patients and/or their families in LMIC humanitarian settings. METHODS: Arksey and O'Malley's (Int J Soc Res Methodol. 8:19-32, 2005) scoping review framework forms the basis of the study design, following further guidance from Levac et al. (Implement Sci 5:1-9, 2010), the Joanna Briggs Institute (JBI) Peters et al. (JBI Reviewer's Manual JBI: 406-452, 2020), and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) from Tricco et al. (Ann Intern Med 169:467-73, 2018). This incorporates a five-step approach and the population, concept, and context (PCC) framework. Using already identified key words/terms, searches for both published research and gray literature from January 2012 to October 2022 will be undertaken using databases (likely to include Cumulative Index of Nursing and Allied Health (CINAHL), MEDLINE, Embase, Global Health, Scopus, Applied Social Science Index and Abstracts (ASSIA), Web of Science, Policy Commons, JSTOR, Library Network International Monetary Fund and World Bank, Google Advanced Search, and Google Scholar) in addition to selected pre-print sites and websites. Data selection will be undertaken based on the inclusion and exclusion criteria and will be reviewed at each stage by two reviewers, with a third to resolve any differences. Extracted data will be charted in a table. Ethical approval is not required for this review. DISCUSSION: Findings will be presented in tables and diagrams/charts, followed by a narrative description. The review will run from late October 2022 to early 2023. This is the first systematic scoping review specifically exploring the palliative care needs of patients and/or their family, in LMIC humanitarian settings. The paper from the review findings will be submitted for publication in 2023.

Efficacy of a gamified digital therapy for speech production in people with chronic aphasia (iTalkBetter): behavioural and imaging outcomes of a phase II item-randomised clinical trial.

Background: Aphasia is among the most debilitating of symptoms affecting stroke survivors. Speech and language therapy (SLT) is effective, but many hours of practice are required to make clinically meaningful gains. One solution to this 'dosage' problem is to automate therapeutic approaches via self-supporting apps so people with aphasia (PWA) can amass practice as it suits them. However, response to therapy is variable and no clinical trial has yet identified the key brain regions required to engage with word-retrieval therapy. Methods: Between Sep 7, 2020 and Mar 1, 2022 at University College London in the UK, we carried out a phase II, item-randomised clinical trial in 27 PWA using a novel, self-led app, 'iTalkBetter', which utilises confrontation naming therapy. Unlike previously reported apps, it has a real-time utterance verification system that drives its adaptive therapy algorithm. Therapy items were individually randomised to provide balanced lists of 'trained' and 'untrained' items matched on key psycholinguistic variables and baseline performance. PWA practised with iTalkBetter over a 6-week therapy block. Structural and functional MRI data were collected to identify therapy-related changes in brain states. A repeated-measures design was employed. The trial was registered at ClinicalTrials.gov (NCT04566081). Findings: iTalkBetter significantly improved naming ability by 13% for trained items compared with no change for untrained items, an average increase of 29 words (SD = 26) per person; beneficial effects persisted at three months. PWA's propositional speech also significantly improved. iTalkBetter use was associated with brain volume increases in right auditory and left anterior prefrontal cortices. Task-based fMRI identified dose-related activity in the right temporoparietal junction. Interpretation: Our findings suggested that iTalkBetter significantly improves PWAs' naming ability on trained items. The effect size is similar to a previous RCT of computerised therapy, but this is the first study to show transfer to a naturalistic speaking task. iTalkBetter usage and dose caused observable changes in brain structure and function to key parts of the surviving language perception, production and control networks. iTalkBetter is being rolled-out as an app for all PWA and anomia: https://www.ucl.ac.uk/icn/research/research-groups/neurotherapeutics/projects/digital-interventions-neuro-rehabilitation-0 so that they can increase their dosage of practice-based SLT. Funding: National Institute for Health and Care Research, Wellcome Centre for Human Neuroimaging.

Measurement of synaptic density in Down syndrome using PET imaging: a pilot study.

Down syndrome (DS) is the most prevalent genetic cause of intellectual disability, resulting from trisomy 21. Recently, positron emission tomography (PET) imaging has been used to image synapses in vivo. The motivation for this pilot study was to investigate whether synaptic density in low functioning adults with DS can be evaluated using the PET radiotracer [11C]UCB-J. Data were acquired from low functioning adults with DS (n = 4) and older neurotypical (NT) adults (n = 37). Motion during the scans required the use of a 10-minute acquisition window for the calculation of synaptic density using SUVR50-60,CS which was determined to be a suitable approximation for specific binding in this analysis using dynamic data from the NT group. Of the regions analyzed a large effect was observed when comparing DS and NT hippocampus and cerebral cortex synaptic density as well as hippocampus and cerebellum volumes. In this pilot study, PET imaging of [11C]UCB-J was successfully completed and synaptic density measured in low functioning DS adults. This work provides the basis for studies where synaptic density may be compared between larger groups of NT adults and adults with DS who have varying degrees of baseline cognitive status.

The Web-Based Pain-at-Work Toolkit With Telephone Support for Employees With Chronic or Persistent Pain: Protocol for a Cluster Randomized Feasibility Trial.

BACKGROUND: Chronic or persistent pain affects one's ability to work or be productive at work, generating high societal and economic burden. However, the provision of work-related advice and support for people with chronic pain is variable or lacking. The Pain-at-Work (PAW) Toolkit was cocreated with people who live with pain, health care professionals, and employers. It aims to increase knowledge about employee rights and how to access support for managing a painful chronic condition in the workplace and provides advice on lifestyle behaviors that facilitate the management of chronic pain. OBJECTIVE: We aimed to establish the feasibility of conducting a definitive cluster randomized controlled trial comparing access to the PAW Toolkit and telephone support calls from an occupational therapist (PAW) with treatment as usual (ie, standard support from their employer). Our primary outcomes are establishing parameters of feasibility, acceptability, usability, and safety of this digital workplace health intervention. We will assess the candidate primary and secondary outcomes' feasibility and test research processes for a definitive trial. METHODS: This is an open-label, parallel 2-arm pragmatic feasibility cluster randomized controlled trial with exploratory health economics analysis and a nested qualitative interview study. We aim to recruit 120 participants from at least 8 workplace clusters (any type, >10 employees) in England. The recruitment of workplaces occurs via personal approach, and the recruitment of individual participants is web based. Eligible participants are vocationally active adults aged ≥18 years with internet access and self-reporting chronic pain interfering with their ability to undertake or enjoy productive work. A restricted 1:1 cluster-level randomization is used to allocate employment settings to PAW or treatment as usual; participants are unblinded to group allocation. Following site- and individual-level consent, participants complete a web-based baseline survey (time 0), including measures of work capacity, health and well-being, and health care resource use. Follow-up is performed at 3 months (time 1) and 6 months (time 2). Feasibility outcomes relate to recruitment; intervention fidelity (eg, delivery, reach, uptake, and engagement); retention; and follow-up. Qualitative evaluation (time 2) is mapped to the Capability, Opportunity, Motivation-Behavior model and will explore intervention acceptability to employees and employers, along with individual and contextual factors influencing the delivery and uptake of the intervention. RESULTS: Ethics approval was obtained in March 2023. Trial recruitment began in June 2023. CONCLUSIONS: The PAW Toolkit is the first evidence-based digital health intervention aimed at supporting the self-management of chronic or persistent pain at work. This study will inform the design of a definitive trial, including sample size estimation, approaches to cluster site identification, primary and secondary outcomes' selection, and the final health economic model. Findings will inform approaches for the future delivery of this digital health intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05838677; https://clinicaltrials.gov/study/NCT05838677. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51474.

Prevalence and predictors of shared decision-making in goals-of-care clinician-family meetings for critically ill neurologic patients: a multi-center mixed-methods study.

BACKGROUND: Shared decision-making is a joint process where patients, or their surrogates, and clinicians make health choices based on evidence and preferences. We aimed to determine the extent and predictors of shared decision-making for goals-of-care discussions for critically ill neurological patients, which is crucial for patient-goal-concordant care but currently unknown. METHODS: We analyzed 72 audio-recorded routine clinician-family meetings during which goals-of-care were discussed from seven US hospitals. These occurred for 67 patients with 72 surrogates and 29 clinicians; one hospital provided 49/72 (68%) of the recordings. Using a previously validated 10-element shared decision-making instrument, we quantified the extent of shared decision-making in each meeting. We measured clinicians' and surrogates' characteristics and prognostic estimates for the patient's hospital survival and 6-month independent function using post-meeting questionnaires. We calculated clinician-family prognostic discordance, defined as ≥ 20% absolute difference between the clinician's and surrogate's estimates. We applied mixed-effects regression to identify independent associations with greater shared decision-making. RESULTS: The median shared decision-making score was 7 (IQR 5-8). Only 6% of meetings contained all 10 shared decision-making elements. The most common elements were "discussing uncertainty"(89%) and "assessing family understanding"(86%); least frequent elements were "assessing the need for input from others"(36%) and "eliciting the context of the decision"(33%). Clinician-family prognostic discordance was present in 60% for hospital survival and 45% for 6-month independent function. Univariate analyses indicated associations between greater shared decision-making and younger clinician age, fewer years in practice, specialty (medical-surgical critical care > internal medicine > neurocritical care > other > trauma surgery), and higher clinician-family prognostic discordance for hospital survival. After adjustment, only higher clinician-family prognostic discordance for hospital survival remained independently associated with greater shared decision-making (p = 0.029). CONCLUSION: Fewer than 1 in 10 goals-of-care clinician-family meetings for critically ill neurological patients contained all shared decision-making elements. Our findings highlight gaps in shared decision-making. Interventions promoting shared decision-making for high-stakes decisions in these patients may increase patient-value congruent care; future studies should also examine whether they will affect decision quality and surrogates' health outcomes.

Timing of Alzheimer's Disease by Intellectual Disability Level in Down Syndrome.

BACKGROUND: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimer's disease (AD). OBJECTIVE: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aß and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site. METHODS: Analyses involved adults with DS from the Alzheimer's Biomarkers Consortium-Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was based on IQ or mental age scores prior to dementia concerns. PET was acquired using [11C] PiB for Aß, and [18F] AV-1451 for tau. RESULTS: Cognitive data was available for 361 participants with a mean age of 45.22 (SD = 9.92) and PET biomarker data was available for 154 participants. There was not a significant effect of premorbid ID level by age on cognitive outcomes. There was not a significant effect of premorbid ID by age on PET Aß or on tau PET. There was not a significant difference in age at time of study visit of those with mild cognitive impairment-DS or dementia by premorbid ID level. CONCLUSION: Findings provide robust evidence of a similar time course in AD trajectory across premorbid ID levels, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials.

Weight Loss and Alzheimer's Disease in Down Syndrome.

BACKGROUND: Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. OBJECTIVE: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological age, weight, AD pathology, and AD-related cognitive decline were assessed in a large cohort of adults with DS, and 2) determine if baseline PET amyloid-ß (Aß) and tau PET status (-versus+) and/or decline in memory and mental status were associated with weight loss prior to AD progression. METHODS: Analyses included 261 adults with DS. PET data were acquired using [11C] PiB for Aß and [18F] AV-1451 for tau. Body mass index (BMI) was calculated from weight and height. Direct measures assessed dementia and memory. Clinical AD status was determined using a case consensus process. Percent weight decline across 16-20 months was assessed in a subset of participants (n = 77). RESULTS: Polynomial regressions indicated an 0.23 kg/m2 decrease in BMI per year beginning at age 36.5 years, which occurs alongside the period during which Aß and tau increase and memory and mental status decline. At a within-person level, elevated Aß, decline in memory and mental status were associated with higher percent weight loss across 16-20 months. CONCLUSION: Unintentional weight loss occurs alongside Aß deposition and prior to onset of AD dementia, and thus may be a useful sign of AD in DS.

Neuroprognostication.

Patients with severe acute brain injury are left incapacitated, critically ill, and unable to make their own medical decisions. Surrogate decision-makers must make life-or-death decisions for patients and rely on clinicians' prognostication for guidance. No guidelines currently exist to guide clinicians in how to prognosticate; hence, neuroprognostication is still considered an "art" leaving room for high variability. This review examines the current literature on prognostication in neurocritical care, identifies ongoing challenges that exist in the field, and provides suggestions for future research with the goal to ameliorate variability and focus on scientific and patient-centered, rather than artistic approaches to prognostication.

Physical Activity and Physical and Mental Health in Middle-Aged Adults with Down Syndrome.

Background: Adults with Down syndrome have an increased risk of aging-related physical and mental health conditions and experience them at an earlier age than the general population. There is a need to investigate modifiable lifestyle factors that may reduce risk for these conditions. Method: The present study investigated the associations between physical activity (i.e., sedentary behavior and moderate-to-vigorous activity) assessed via accelerometer across 7 days and caregiver-reported physical and mental health of 66 non-demented middle-aged adults with Down Syndrome aged 25-55 years (52% female). Results: Regression analyses indicated that more time spent in moderate intensity physical activity was associated with less risk of sleep apnea (b = -.031 p = .004) and endocrine/metabolic conditions (b = -.046 p = .009), and lower total number of physical health conditions (b = -.110 p =.016) and anxiety disorders (b = -.021 p =.049) after controlling for relevant sociodemographics. After also adjusting for BMI, the association between time spent in moderate intensity physical activity and sleep apnea (b=-.035, p = .002), endocrine/metabolic conditions (b=-.033, p = .045) and total physical health (b=-.091, p =.026) remained significant Unexpectedly, time spent in sedentary behavior was negatively associated with musculoskeletal conditions (b=-.017, p = .044). Conclusion: Findings indicate important associations between physical activity in everyday life and the physical and mental health of adults with Down syndrome. Social policies and interventions aimed at reducing time spent sitting around (i.e., sedentary behavior) and encouraging moderate-to-vigorous activity may be a low-burden and low-cost mechanism for fostering healthy physical and mental aging in the Down syndrome population.

Physical activity, memory function, and hippocampal volume in adults with Down syndrome.

Higher engagement in moderate-intensity physical activity (PA) is related to better cognitive functioning in neurotypical adults; however, little is known about the effect of PA on cognitive aging in adults with Down syndrome (DS). Individuals with DS have three copies of chromosome 21, which includes the gene involved in the production of the amyloid precursor protein, resulting in an increased risk for an earlier onset of Alzheimer's disease (AD). The goal of this study was to understand the relationship between engagement in moderate PA, memory, and hippocampal volume in adults with DS. Adults with DS participated in an ancillary Lifestyle study linked to the Alzheimer's Biomarkers Consortium for DS (ABC- DS; N = 71). A within-sample z-score memory composite was created from performance on the Cued Recall Test (CRT) and the Rivermead Picture Recognition Test. Participants wore a wrist-worn accelerometer (GT9X) to measure PA. Variables of interest included the average percentage of time spent in moderate PA and average daily steps. Structural MRI data were acquired within 18 months of actigraphy/cognitive data collection for a subset of participants (n = 54). Hippocampal volume was extracted using Freesurfer v5.3. Associations between moderate PA engagement, memory, and hippocampal volume were evaluated with hierarchical linear regressions controlling for relevant covariates [age, body mass index, intellectual disability level, sex, and intracranial volume]. Participants were 37.77 years old (SD = 8.21) and were 55.6% female. They spent 11.1% of their time engaged in moderate PA (SD = 7.5%) and took an average of 12,096.51 daily steps (SD = 4,315.66). After controlling for relevant covariates, higher memory composite score was associated with greater moderate PA engagement (ß = 0.232, p = 0.027) and more daily steps (ß = 0.209, p = 0.037). In a subset of participants, after controlling for relevant covariates, PA variables were not significantly associated with the hippocampal volume (all p-values ≥ 0.42). Greater hippocampal volume was associated with higher memory composite score after controlling for relevant covariates (ß = 0.316, p = 0.017). More PA engagement was related to better memory function in adults with DS. While greater hippocampal volume was related to better memory performance, it was not associated with PA. Greater PA engagement may be a promising lifestyle behavior to preserve memory in adults with DS.

The Gap Between Technology and Ethics, Especially in Low- and Middle-Income Country Health Information Systems: A Bibliometric Study.

Digital health information systems are quickly replacing paper systems worldwide. This study examined scholarly work reflecting how ethical considerations for health information systems (HISs) have evolved over time, with particular interest in the contributions from low- and middle-income country (LMIC) institutions. We systematically searched four research databases for terms related to HISs, ethics, and LMICs; and identified 601 relevant articles published from 1975 through 2019. The included publications were produced by 1,000 authors from more than 700 institutions. However, only 30 publications were co-authored by researchers from both an LMIC and a high-income country (HIC). Most publications pertained to data security. There is an acute need to address a wider array of HIS ethics topics, including those that may be unique to LMIC resource constraints. We recommend more collaborations between LMIC and HIC institutions to address the full range of HIS ethical concerns in LMICs.

Impact of the COVID-19 pandemic on daily life, mood, and behavior of adults with Down syndrome.

BACKGROUND: The Down syndrome population has been disproportionately affected by Coronavirus 2019 (COVID-19) in terms of experiencing severe illness and death. Societal efforts to curb the spread of COVID-19 may also have taken a heavy toll on the daily lives of individuals with Down syndrome. OBJECTIVE/HYPOTHESIS: The goal of the study was to understand how the COVID-19 pandemic has altered daily life (including residence, employment, and participation in adult disability day programs) and influenced the mood and behavior of adults with Down syndrome. METHODS: Between September 2020 and February 2021, caregivers of 171 adults with Down syndrome (aged 22-66 years) located across the United States and in the United Kingdom enrolled in the Alzheimer's Biomarker Research Consortium on Down Syndrome (ABC-DS) completed a survey. RESULTS: The residence of 17% of individuals was altered, and 89% of those who had been employed stopped working during the pandemic. One-third (33%) of individuals were reported to be more irritable or easily angered, 52% were reported to be more anxious, and 41% were reported to be more sad/depressed/unhappy relative to prepandemic. The majority of changes in mood and behavior were of modest severity. CONCLUSIONS: The COVID-19 pandemic has had widespread effects on the daily life and mood and behavior of adults with Down syndrome. In the short term, caregivers and providers should be prepared to help adults with Down syndrome with changes in daily routines, residence, employment, or adult disability day programs as society shifts away from COVID-19 safety protocols.

Cognitive outcome measures for tracking Alzheimer's disease in Down syndrome.

Down syndrome (DS) is now viewed as a genetic type of Alzheimer's disease (AD), given the near-universal presence of AD pathology in middle adulthood and the elevated risk for developing clinical AD in DS. As the field of DS prepares for AD clinical intervention trials, there is a strong need to identify cognitive measures that are specific and sensitive to the transition from being cognitively stable to the prodromal (e.g., Mild Cognitive Impairment-Down syndrome) and clinical AD (e.g., Dementia) stages of the disease in DS. It is also important to determine cognitive measures that map onto biomarkers of early AD pathology during the transition from the preclinical to the prodromal stage of the disease, as this transition period is likely to be targeted and tracked in AD clinical trials. The present chapter discusses the current state of research on cognitive measures that could be used to screen/select study participants and as potential outcome measures in future AD clinical trials with adults with DS. In this chapter, we also identify key challenges that need to be overcome and questions that need to be addressed by the DS field as it prepares for AD clinical trials in the coming years.

Sleep and White Matter in Adults with Down Syndrome.

Adults with Down syndrome are at a high risk for disordered sleep. These sleep problems could have marked effects on aging and Alzheimer's disease, potentially altering white matter integrity. This study examined the associations between disordered sleep assessed via an actigraph accelerometer worn on 7 consecutive nights, presence of diagnosis of obstructive sleep apnea, and diffusion tensor imaging indices of white matter integrity in 29 non-demented adults with Down Syndrome (48% female, aged 33-54 years). Average total sleep time was associated with lower mean diffusivity in the left superior longitudinal fasciculus (r = -0.398, p = 0.040). Average sleep efficiency, length of awakenings, and movement index were related to fractional anisotropy in the right inferior longitudinal fasciculus (r = -0.614 to 0.387, p ≤ 0.050). Diagnosis of obstructive sleep apnea was associated with fractional anisotropy in the right inferior longitudinal fasciculus (r = -0.373, p = 0.050). Findings suggest that more disrupted sleep is associated with lower white matter integrity in the major association tracts in middle-aged adults with Down syndrome. Longitudinal work is needed to confirm the directionally of associations. Sleep interventions could be an important component for promoting optimal brain aging in the Down syndrome population.

NUVA: A Naming Utterance Verifier for Aphasia Treatment.

Anomia (word-finding difficulties) is the hallmark of aphasia, an acquired language disorder most commonly caused by stroke. Assessment of speech performance using picture naming tasks is a key method for both diagnosis and monitoring of responses to treatment interventions by people with aphasia (PWA). Currently, this assessment is conducted manually by speech and language therapists (SLT). Surprisingly, despite advancements in automatic speech recognition (ASR) and artificial intelligence with technologies like deep learning, research on developing automated systems for this task has been scarce. Here we present NUVA, an utterance verification system incorporating a deep learning element that classifies 'correct' versus' incorrect' naming attempts from aphasic stroke patients. When tested on eight native British-English speaking PWA the system's performance accuracy ranged between 83.6% to 93.6%, with a 10-fold cross-validation mean of 89.5%. This performance was not only significantly better than a baseline created for this study using one of the leading commercially available ASRs (Google speech-to-text service) but also comparable in some instances with two independent SLT ratings for the same dataset.

Physical activity and cognitive and imaging biomarkers of Alzheimer's disease in down syndrome.

Adults with Down syndrome (DS) are at risk for Alzheimer's disease. Despite sharing trisomy 21, however, there is variability in the age of disease onset. This variability may mean that other factors, such as lifestyle, influence cognitive aging and disease timing. The present study assessed the association between everyday life physical activity using an actigraph accelerometer and cognitive functioning and early Alzheimer's disease pathology via positron emission tomography amyloid-ß and tau and diffusion tension imaging measures of white matter integrity in 61 non-demented adults with DS. Percent time in sedentary behavior and in moderate-to-vigorous activity were associated (negatively and positively, respectively) with cognitive functioning (r = -.472 to .572, p < 0.05). Neither sedentary behavior nor moderate-to-vigorous activity were associated with amyloid-ß or tau, but both were associated with white matter integrity in the superior and inferior longitudinal fasciculus (Fractional Anisotropy: r = -.397 to -.419, p < 0.05; Mean Diffusivity: r = .400, p < 0.05). Longitudinal studies are needed to determine if physical activity promotes healthy aging in DS.

Caregiver resource utilization: Intellectual and development disability and dementia.

BACKGROUND: Adults with intellectual and developmental disabilities and their families have high need for support services. This study assessed resource utilization among caregivers of intellectual and developmental disabilities and other conditions. METHODS: We assessed 366 caregivers of adults with intellectual and developmental disabilities, dementia or other conditions Regressions assessed group differences in number of agency contacts and frequency of service use. A secondary analysis assessed reasons for underutilization of services. RESULTS: Caregivers of individuals with dementia contacted twice as many agencies as other caregivers and were more likely to report using suggested services. Agency contact and service utilization were similar among caregivers of adults with intellectual and developmental disabilities compared to other caregivers. Caregivers of adults with intellectual and developmental indicated that suggested services were unavailable to them. CONCLUSION: The findings of this study shed light on challenges with access to and utilization of support services.

Efficacy of spoken word comprehension therapy in patients with chronic aphasia: a cross-over randomised controlled trial with structural imaging.

OBJECTIVE: The efficacy of spoken language comprehension therapies for persons with aphasia remains equivocal. We investigated the efficacy of a self-led therapy app, 'Listen-In', and examined the relation between brain structure and therapy response. METHODS: A cross-over randomised repeated measures trial with five testing time points (12-week intervals), conducted at the university or participants' homes, captured baseline (T1), therapy (T2-T4) and maintenance (T5) effects. Participants with chronic poststroke aphasia and spoken language comprehension impairments completed consecutive Listen-In and standard care blocks (both 12 weeks with order randomised). Repeated measures analyses of variance compared change in spoken language comprehension on two co-primary outcomes over therapy versus standard care. Three structural MRI scans (T2-T4) for each participant (subgroup, n=25) were analysed using cross-sectional and longitudinal voxel-based morphometry. RESULTS: Thirty-five participants completed, on average, 85 hours (IQR=70-100) of Listen-In (therapy first, n=18). The first study-specific co-primary outcome (Auditory Comprehension Test (ACT)) showed large and significant improvements for trained spoken words over therapy versus standard care (11%, Cohen's d=1.12). Gains were largely maintained at 12 and 24 weeks. There were no therapy effects on the second standardised co-primary outcome (Comprehensive Aphasia Test: Spoken Words and Sentences). Change on ACT trained words was associated with volume of pretherapy right hemisphere white matter and post-therapy grey matter tissue density changes in bilateral temporal lobes. CONCLUSIONS: Individuals with chronic aphasia can improve their spoken word comprehension many years after stroke. Results contribute to hemispheric debates implicating the right hemisphere in therapy-driven language recovery. Listen-In will soon be available on GooglePlay. TRIAL REGISTRATION NUMBER: NCT02540889.

Alternative splicing of the neurofibromatosis type 1 pre-mRNA is regulated by the muscleblind-like proteins and the CUG-BP and ELAV-like factors.

BACKGROUND: Alternative splicing is often subjected to complex regulatory control that involves many protein factors and cis-acting RNA sequence elements. One major challenge is to identify all of the protein players and define how they control alternative expression of a particular exon in a combinatorial manner. The Muscleblind-like (MBNL) and CUG-BP and ELAV-Like family (CELF) proteins are splicing regulatory proteins, which function as antagonists in the regulation of several alternative exons. Currently only a limited number of common targets of MBNL and CELF are known that are antagonistically regulated by these two groups of proteins. RESULTS: Recently, we identified neurofibromatosis type 1 (NF1) exon 23a as a novel target of negative regulation by CELF proteins. Here we report that MBNL family members are positive regulators of this exon. Overexpression of MBNL proteins promote exon 23a inclusion in a low MBNL-expressing cell line, and simultaneous siRNA-mediated knockdown of MBNL1 and MBNL2 family members in a high MBNL-expressing cell line promotes exon 23a skipping. Importantly, these two groups of proteins antagonize each other in regulating inclusion of exon 23a. Furthermore, we analyzed the binding sites of these proteins in the intronic sequences upstream of exon 23a by UV cross-linking assays. We show that in vitro, in addition to the previously identified preferred binding sequence UGCUGU, the MBNL proteins need the neighboring sequences for optimal binding. CONCLUSION: This study along with our previous work that demonstrated roles for Hu, CELF, and TIA-1 and TIAR proteins in the regulation of NF1 exon 23a establish that this exon is under tight, complex control.

Medical subinternship: student experience on a resident uncovered hospitalist service.

BACKGROUND: Studies demonstrating the value of hospitalists to medical student education have been performed in traditional resident covered ward service settings (RCWS). PURPOSE: To compare medical subinterns' experiences on an RCWS to that on a resident uncovered hospitalist service (RUHS). METHODS: We assessed students' overall experience and knowledge learned on the two services using a 5-point Likert scale. We also assessed learning environment characteristics, workload, and time spent at the hospital on each service. RESULTS: The mean rating for knowledge learned was higher on the RCWS. Subinterns rated the two services equivalent on measures of educational value of patient problems, faculty assessment, supervision, and number and value of teaching sessions. The RCWS received higher ratings on variety of patient problems and frequency of intellectual discussion. CONCLUSIONS: The RCWS provided a superior learning experience for subinterns. Academic medical centers should take these findings into consideration before placing medical students on an RUHS.