Increased Neutrophil H2O2 Production and Enhanced Pulmonary Clearance of Klebsiella pneumoniae in G6PD A- Mice.

The X-linked A- variant (rs1050828, Val68Met) in G6PDX accounts for glucose-6-phosphate (G6PD) deficiency in approximately 11% of African American males. This common, hypomorphic variant may impact pulmonary host defense and phagocyte function during pneumonia by altering levels of reactive oxygen species produced by host leukocytes. We used CRISPR-Cas9 technology to generate novel mouse strain with "humanized" G6PD A- variant containing non-synonymous Val68Met single nucleotide polymorphism. Male hemizygous or littermate wild-type (WT) controls were inoculated intratracheally with K. pneumoniae (KP2 serotype, ATCC 43816 strain,103 CFU inoculum). We examined leukocyte recruitment, organ bacterial burden, bone marrow neutrophil and macrophage (BMDM) phagocytic capacity, and hydrogen peroxide (H2O2) production. Unexpectedly, G6PD-deficient mice showed decreased lung bacterial burden (p=0.05) compared to controls 24-h post-infection. Extrapulmonary dissemination and bacteremia were significantly reduced in G6PD-deficient mice 48-h post-infection. Bronchoalveolar lavage fluid (BALF) IL-10 levels were elevated in G6PD-deficient mice (p=0.03) compared to controls at 24-h but were lower at 48-h (p=0.03). G6PD A- BMDMs show mildly decreased in vitro phagocytosis of pHrodo-labeled KP2 (p=0.03). Baseline, but not stimulated, H2O2 production by G6PD A- neutrophils was greater compared to WT neutrophils. G6PD A- variant demonstrate higher basal neutrophil H2O2 production and are protected against acute Klebsiella intrapulmonary infection.

Reliability of the picture description task of the Western Aphasia Battery - revised in Laurentian French persons without brain injury.

Objective: Limited normative data (including psychometric properties) are currently available on discourse tasks in non-dominant languages such as Laurentian (Quebec) French. The lack of linguistic and cultural adaptation has been identified as a barrier to discourse assessment. The main aim of this study is to document inter-rater and test-retest reliability properties of the picnic scene of the Western Aphasia Battery - Revised (WAB-R), including the cultural adaptation of an information content unit (ICU) list, and provide a normative reference for persons without brain injury (PWBI). Method: To do so, we also aimed to adapt an ICU checklist culturally and linguistically for Laurentian French speakers. Discourse samples were collected from 66 PWBI using the picture description task of the WAB-R. The ICU list was first adapted into Laurentian French. Then, ICUs and thematic units (TUs) were extracted manually, and microstructural variables were extracted using CLAN. Inter-rater reliability and test-retest reliability were determined. Results: Excellent inter-rater reliability was obtained for ICUs and TUs, as well as for all microstructural variables, except for mean length of utterance, which was found to be good. Conversely, test-retest reliability ranged from poor to moderate for all variables. Conclusion: The present study provides a validated ICU checklist for clinicians and researchers working with Laurentian French speakers when assessing discourse with the picnic scene of the WAB-R. It also addresses the gap in available psychometric data regarding inter-rater and test-retest reliability in PWBI.

Functional effects of an African glucose-6-phosphate dehydrogenase (G6PD) polymorphism (Val68Met) on red blood cell hemolytic propensity and post-transfusion recovery.

BACKGROUND: Donor genetic variation is associated with red blood cell (RBC) storage integrity and post-transfusion recovery. Our previous large-scale genome-wide association study demonstrated that the African G6PD deficient A- variant (rs1050828, Val68Met) is associated with higher oxidative hemolysis after cold storage. Despite a high prevalence of X-linked G6PD mutation in African American population (>10%), blood donors are not routinely screened for G6PD status and its importance in transfusion medicine is relatively understudied. STUDY DESIGN AND METHODS: To further evaluate the functional effects of the G6PD A- mutation, we created a novel mouse model carrying this genetic variant using CRISPR-Cas9. We hypothesize that this humanized G6PD A- variant is associated with reduced G6PD activity with a consequent effect on RBC hemolytic propensity and post-transfusion recovery. RESULTS: G6PD A- RBCs had reduced G6PD protein with ~5% residual enzymatic activity. Significantly increased in vitro hemolysis induced by oxidative stressors was observed in fresh and stored G6PD A- RBCs, along with a lower GSH:GSSG ratio. However, no differences were observed in storage hemolysis, osmotic fragility, mechanical fragility, reticulocytes, and post-transfusion recovery. Interestingly, a 14% reduction of 24-h survival following irradiation was observed in G6PD A- RBCs compared to WT RBCs. Metabolomic assessment of stored G6PD A- RBCs revealed an impaired pentose phosphate pathway (PPP) with increased glycolytic flux, decreasing cellular antioxidant capacity. DISCUSSION: This novel mouse model of the common G6PD A- variant has impaired antioxidant capacity like humans and low G6PD activity may reduce survival of transfused RBCs when irradiation is performed.

Myoglobin modulates the Hippo pathway to promote cardiomyocyte differentiation.

The endogenous mechanisms that propagate cardiomyocyte differentiation and prevent de-differentiation remain unclear. While the expression of the heme protein myoglobin increases by over 50% during cardiomyocyte differentiation, a role for myoglobin in regulating cardiomyocyte differentiation has not been tested. Here, we show that deletion of myoglobin in cardiomyocyte models decreases the gene expression of differentiation markers and stimulates cellular proliferation, consistent with cardiomyocyte de-differentiation. Mechanistically, the heme prosthetic group of myoglobin catalyzes the oxidation of the Hippo pathway kinase LATS1, resulting in phosphorylation and inactivation of yes-associated protein (YAP). In vivo, myoglobin-deficient zebrafish hearts show YAP dephosphorylation and accelerated cardiac regeneration after apical injury. Similarly, myoglobin knockdown in neonatal murine hearts shows increased YAP dephosphorylation and cardiomyocyte cycling. These data demonstrate a novel role for myoglobin as an endogenous driver of cardiomyocyte differentiation and highlight myoglobin as a potential target to enhance cardiac development and improve cardiac repair and regeneration.

Shared Neuroanatomical Substrates for Co-occurring Swallowing and Communication Impairments after Acute Stroke.

INTRODUCTION: Post-stroke dysphagia and communication impairments occur in two-thirds of acute stroke survivors. Identifying the shared neuroanatomical substrate for related impairments could facilitate the development of cross-system therapies. Our purpose was to elucidate discrete brain regions predictive of the combined presence of dysphagia alongside dysarthria and/or aphasia post-stroke. METHODS: We included 40 right (RHS) and 67 left hemisphere (LHS) patients from an acute ischemic stroke cohort with lesions demarcated on diffusion weighted imaging. We undertook binary non-parametric voxel-lesion symptom mapping with a false discovery rate of p <0.05 for co-occurring dysphagia, dysarthria, and aphasia (LHS only). If no voxels survived the threshold, a cluster analysis of >20 voxels involving an uncorrected p <0.01 was applied to identify brain regions associated with the co-occurring impairments. RESULTS: Cluster analyses revealed that dysphagia and dysarthria were associated with insular and superior temporal gyrus (STG) involvement after RHS and with basal ganglia (BG), internal capsule, and thalamic involvement after LHS. Co-occurring dysphagia, dysarthria, and aphasia were associated with BG, STG, and insular cortex involvement. DISCUSSION: Our findings highlight the role of the insula and structures of the BG in co-occurrence patterns involving dysphagia, dysarthria, and aphasia. These newly identified biomarkers may inform new rehabilitation therapeutic targets for treating cross-system functions.

Exploring mechanisms of improvement in the Active Brains intervention for older adults with chronic pain and early cognitive decline.

OBJECTIVES: We iteratively developed, optimized, and established the feasibility of a virtual, group-based, mind-body activity program (Active Brains, AB), supported by Fitbit for older adults with chronic pain (CP) and early cognitive decline (ECD). Guided by the principles of the NIH stage model we 1) explore signals of improvement in AB outcomes and hypothesized mechanisms of action and 2) explore relationships between changes in outcomes with changes in mechanisms. METHODS: Participants were N = 15 older adults (age ≥ 60) with CP-ECD from two NIH stage 1 pilot studies of AB. We conducted paired t-tests to explore pre-post improvements, and correlations to investigate associations between changes in outcomes and mechanisms. RESULTS: We observed small to large improvements across co-primary and secondary outcomes (d = 0.24-1.09). We observed small to medium improvements in 4 out of 5 hypothesized mechanisms (d = 0.23-0.47). Overall, improvements in outcomes had moderate to large associations with improvements in hypothesized mechanisms. CONCLUSION: AB was associated with improvements across several co-primary and secondary outcomes, and hypothesized mechanisms. Pain-specific coping and general coping skills are promising treatment targets to address the CP-ECD comorbidity among older adults.

Mindfulness, coping, and optimism as mechanisms of change in the 3RP-NF intervention.

INTRODUCTION: Neurofibromatosis (NF) is chronic neurogenetic condition that increases risk for poor quality of life, depression, and anxiety. Given the lack of biomedical treatments, we developed the "Relaxation Response Resiliency for NF" (3RP-NF) program to improve psychosocial outcomes among adults with NF. OBJECTIVE: To move toward effectiveness testing, we must understand mechanisms that explained treatment effects. We tested whether our hypothesized mechanisms of change-mindfulness, coping, and optimism-mediated improvements in quality of life, depression, and anxiety among adults in the 3RP-NF program (N = 114; ages 18-70; 72.80% female; 81.58% White). METHODS: We conducted mixed-effects models to assess whether these mechanisms uniquely mediated outcomes. RESULTS: Improvements in quality of life were most explained by coping, (b = 0.97, SE = 0.28, CI [0.45, 1.56]), followed by mindfulness (b = 0.46, SE = 0.17, CI [0.15, 0.82]) and optimism (b = 0.39, SE = 0.12, CI [0.17, 0.65]). Improvements in depression and anxiety were most explained by mindfulness (b = -1.52, SE = 0.38, CI [-2.32, -0.85], CSIE = -0.26; b = -1.29, SE = 0.35, CI [-2.04, -0.67], CSIE = -0.23), followed by optimism (b = 0.39, SE = 0.12, CI [0.17, 0.65]; b = -0.49, SE = 0.20, CI [-0.91, -0.13]), but were not explained by coping (b = 0.22, SE = 0.43, CI [-0.62, 1.07]; b = 0.06, SE = 0.46, CI [-0.84, 0.97]), respectively. CONCLUSIONS: Targeting mindfulness, coping, and optimism in psychosocial interventions may be a promising way to improve the lives of adults with NF.

Longitudinal evolution of diffusion metrics after left hemisphere ischaemic stroke.

White matter is often severely affected after human ischaemic stroke. While animal studies have suggested that various factors may contribute to white matter structural damage after ischaemic stroke, the characterization of damaging processes to the affected hemisphere after human stroke remains poorly understood. Thus, the present study aims to thoroughly describe the longitudinal pattern of evolution of diffusion magnetic resonance imaging metrics in different parts of the ipsilesional white matter after stroke. We acquired diffusion and anatomical images in 17 patients who had suffered from a single left hemisphere ischaemic stroke, at 24-72 h, 8-14 days and 6 months post-stroke. For each patient, we created three regions of interest: (i) the white matter lesion; (ii) the perilesional white matter; and (iii) the remaining white matter of the left hemisphere. We extracted diffusion metrics (fractional anisotropy, mean, axial and radial diffusivities) for each region and conducted two-way repeated measures ANOVAs with stage post-stroke (acute, subacute and chronic) × regions of interest (white matter lesion, perilesional white matter and remaining white matter). Fractional anisotropy values stayed consistent across time-points, with significantly lower values in the white matter lesion compared to the perilesional white matter and remaining white matter tissue. Fractional anisotropy values of the perilesional white matter were also significantly lower than that of the remaining white matter. Mean, axial and radial diffusivities in the white matter lesion were all decreased in the acute stage compared to perilesional white matter and remaining white matter, but significantly increased in both the subacute and chronic stages. Significant increases in mean and radial diffusivities in the perilesional white matter were seen in the later stages of stroke. Our findings suggest that various physiological processes are at play in the acute, subacute and chronic stages following ischaemic stroke, with the infarct territory and perilesional white matter affected by ischaemia at different rates and to different extents throughout the stroke recovery stages. The examination of multiple diffusivity metrics may inform us about the mechanisms occurring at different time-points, i.e. focal swelling, axonal damage or myelin loss.

Bio-Experiential Technology to Support Persons With Dementia and Care Partners at Home (TEND): Protocol for an Intervention Development Study.

BACKGROUND: Alzheimer disease and related dementias are debilitating and incurable diseases. Persons with dementia and their informal caregivers (ie, dyads) experience high rates of emotional distress and negative health outcomes. Several barriers prevent dyads from engaging in psychosocial care including cost, transportation, and a lack of treatments that target later stages of dementia and target the dyad together. Technologically informed treatment and serious gaming have been shown to be feasible and effective among persons living with dementia and their care partners. To increase access, there is a need for technologically informed psychosocial interventions which target the dyad, together in the home. OBJECTIVE: This study aims to develop the toolkit for experiential well-being in dementia, a dyadic, "bio-experiential" intervention for persons with dementia and their caregivers. Per our conceptual model, the toolkit for experiential well-being in dementia platform aims to target sustained attention, positive emotions, and active engagement among dyads. In this paper, we outline the protocol and conceptual model for intervention development and partnership with design and development experts. METHODS: We followed the National Institutes of Health (NIH) stage model (stage 1A) and supplemented the model with principles of user-centered design. The first step includes understanding user needs, goals, and strengths. We met this step by engaging in methodology and definition synthesis and conducting focus groups with dementia care providers (N=10) and persons with dementia and caregivers (N=11). Step 2 includes developing and refining the prototype. We will meet this step by engaging dyads in up to 20 iterations of platform ß testing workshops. Step 3 includes observing user interactions with the prototype. We will meet this step by releasing the platform for feasibility testing. RESULTS: Key takeaways from the focus groups include balancing individualization and the dyadic relationship and avoiding confusing stimuli. As of September 2023, we have completed focus groups with providers, persons with dementia, and their caregivers. Additionally, we have conducted 4 iterations of ß testing workshops with dyads. Feedback from focus groups informed the ß testing workshops; data have not yet been formally analyzed and will be reported in future publications. CONCLUSIONS: Technological interventions, particularly "bio-experiential" technology, can be used in dementia care to support emotional health among persons with a diagnosis and caregivers. Here, we outline a collaborative intervention development process of bio-experiential technology through a research, design, and development partnership. Next, we are planning to test the platform's feasibility as well as its impact on clinical outcomes and mechanisms of action. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52799.

Cytoglobin regulates NO-dependent cilia motility and organ laterality during development.

Cytoglobin is a heme protein with unresolved physiological function. Genetic deletion of zebrafish cytoglobin (cygb2) causes developmental defects in left-right cardiac determination, which in humans is associated with defects in ciliary function and low airway epithelial nitric oxide production. Here we show that Cygb2 co-localizes with cilia and with the nitric oxide synthase Nos2b in the zebrafish Kupffer's vesicle, and that cilia structure and function are disrupted in cygb2 mutants. Abnormal ciliary function and organ laterality defects are phenocopied by depletion of nos2b and of gucy1a, the soluble guanylate cyclase homolog in fish. The defects are rescued by exposing cygb2 mutant embryos to a nitric oxide donor or a soluble guanylate cyclase stimulator, or with over-expression of nos2b. Cytoglobin knockout mice also show impaired airway epithelial cilia structure and reduced nitric oxide levels. Altogether, our data suggest that cytoglobin is a positive regulator of a signaling axis composed of nitric oxide synthase-soluble guanylate cyclase-cyclic GMP that is necessary for normal cilia motility and left-right patterning.

A Mindfulness-Based Resiliency Program for Caregivers of Patients With Severe Acute Brain Injury Transitioning Out of Critical Care: Protocol for an Open Pilot Trial.

BACKGROUND: Caregivers of patients with severe acute brain injuries (SABI) that lead to coma and require intensive care unit (ICU) treatment often experience chronic emotional distress. To address this need, we developed the Coma Family (COMA-F) program, a mindfulness-based resiliency intervention for these caregivers. OBJECTIVE: We will conduct an open pilot trial of COMA-F (National Institutes of Health Stage IA). Here we describe our study protocol and proposed intervention content. METHODS: We will enroll 15 caregivers of patients with SABIs during their loved one's hospital course from 3 enrollment centers. A clinical psychologist will deliver the COMA-F intervention (6 sessions) over Zoom (Zoom Video Communications, Inc) or in person. We will iterate COMA-F after each caregiver completes the intervention and an exit interview. English-speaking adults who have emotional distress confirmed by the clinical team and are the primary caregivers of a patient with SABI are eligible. The adult patient must have been admitted to the neuro-ICU for SABI and (1) have had a Glasgow Coma Scale score below 9 while not intubated or an inability to follow meaningful commands while intubated at any point during their hospitalization for >24 hours due to SABI; (2) will be undergoing either tracheostomy or percutaneous endoscopic or surgical gastrostomy tube placement or have already received one or both; and (3) have a prognosis of survival >3 months. We will identify eligible caregivers through screening patients' medical records and through direct referrals from clinicians in the neuro-ICU. During the intervention we will teach caregivers mind-body and resilience skills, including deep breathing, mindfulness, meditation, dialectical thinking, acceptance, cognitive restructuring, effective communication, behavioral activation, and meaning-making. Caregivers will complete self-report assessments (measures of emotional distress and resilience) before and after the intervention. Primary outcomes are feasibility (recruitment, quantitative measures, adherence, and therapist fidelity) and acceptability (treatment satisfaction, credibility, and expectancy). We will conduct brief qualitative exit interviews to gather feedback on refining the program and study procedures. We will examine frequencies and proportions to determine feasibility and acceptability and will analyze qualitative exit interview data using thematic analysis. We will also conduct 2-tailed t tests to explore signals of improvement in emotional distress and treatment targets. We will then conduct an explanatory-sequential mixed methods analysis to integrate quantitative and qualitative data to refine the COMA-F manual and study procedures. RESULTS: This study has been approved by the institutional review board at 1 of the 3 enrollment centers (2023P000536), with approvals at the other 2 centers pending. We anticipate that the study will be completed by late 2024. CONCLUSIONS: We will use our findings to refine the COMA-F intervention and prepare for a feasibility randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05761925; https://clinicaltrials.gov/study/NCT05761925. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/50860.

Adaptation and Reliability of the Cinderella Story Retell Task in Canadian French Persons Without Brain Injury.

PURPOSE: Main concept (MC) analysis is a well-documented method of discourse analysis in adults with and without brain injury. This study aims to develop a MC checklist that is culturally and linguistically adapted for Canadian French speakers and examine its reliability. We also documented microstructural properties and provide a normative reference in persons not brain injured (PNBIs). METHOD: Discourse samples from 43 PNBIs were collected. All participants completed the Cinderella story retell task twice. Manual transcription was performed for all samples. The 34 MCs for the Cinderella story retell task were adapted into Canadian French and used to score all transcripts. In addition, microstructural variables were extracted using Computerized Language Analysis (CLAN). Intraclass correlation coefficients were computed to assess interrater reliability for MC codes and microstructural variables. Test-retest reliability was assessed using intraclass correlations, Spearman's rho correlations, and the Wilcoxon signed-ranks test. Bland-Altman plots were used to examine the agreement of the discourse measures between the two sessions. RESULTS: The MC checklist for the Cinderella story retell task adapted for Canadian French speakers is provided. Good-to-excellent interrater reliability was obtained for most MC codes; however, reliability ranged from poor to excellent for the "inaccurate and incomplete" code. Microstructural variables demonstrated excellent interrater reliability. Test-retest reliability ranged from poor to excellent for all variables, with the majority falling between moderate and excellent. Bland-Altman plots illustrated the limits of agreement between test and retest. CONCLUSIONS: This study provides the MC checklist for clinicians and researchers working with Canadian French speakers when assessing discourse with the Cinderella story retell task. It also addresses the gap in available psychometric data regarding test-retest reliability in PNBIs. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24171087.

Addressing the Chronic Pain-Early Cognitive Decline Comorbidity Among Older Adults: Protocol for the Active Brains Remote Efficacy Trial.

BACKGROUND: Chronic pain and early cognitive decline, which are costly to treat and highly prevalent among older adults, commonly co-occur, exacerbate one another over time, and can accelerate the development and progression of Alzheimer disease and related dementias. We developed the first mind-body activity program (Active Brains [AB]) tailored to the needs of older adults with chronic pain and early cognitive decline. Results from our previous study strongly supported the feasibility of conducting AB remotely and provided evidence for improvements in outcomes. OBJECTIVE: We are conducting a single-blinded, National Institutes of Health stage-2, randomized clinical trial to establish the efficacy of AB versus a time-matched and dose-matched education control (Health Enhancement Program [HEP]) in improving self-reported and objective outcomes of physical, cognitive, and emotional functions in 260 participants. The methodology described in this paper was informed by the lessons learned from the first year of the trial. METHODS: Participants are identified and recruited through multidisciplinary clinician-referred individuals (eg, pain psychologists and geriatricians), the Rally Research platform, social media, and community partnerships. Interested participants complete eligibility screening and electronic informed consent. Baseline assessments include self-report, performance-based measures (eg, 6-min walk test) and objective measures (eg, Repeatable Battery for the Assessment of Neuropsychological Status). Participants are mailed a wrist-worn ActiGraph device (ActiGraph LLC) to passively monitor objective function (eg, steps) during the week between the baseline assessment and the beginning of the programs, which they continue to wear throughout the programs. After baseline assessments, participants are randomized to either AB or HEP and complete 8 weekly, remote, group sessions with a Massachusetts General Hospital psychologist. The AB group receives a Fitbit (Fitbit Inc) to help reinforce increased activity. Assessments are repeated after the intervention and at the 6-month follow-up. Coprimary outcomes include multimodal physical function (self-report, performance based, and objective). Secondary outcomes are cognitive function (self-report and objective), emotional function, and pain. RESULTS: We began recruitment in July 2022 and recruited 37 participants across 4 cohorts. Of them, all (n=37, 100%) have completed the baseline assessment, 26 (70%) have completed the posttest assessment, and 9 (24%) are actively enrolled in the intervention (total dropout: n=2, 5%). In the three cohorts (26/37, 70%) that have completed the AB or HEP, 26 (100%) participants completed all 8 group sessions (including minimal makeups), and watch adherence (1937/2072, 93.48%, average across ActiGraph and Fitbit devices) has been excellent. The fourth cohort is ongoing (9/37, 24%), and we plan to complete enrollment by March 2026. CONCLUSIONS: We aim to establish the efficacy of the AB program over a time-matched and dose-matched control in a live video-based trial and test the mechanisms through theoretically driven mediators and moderators. Findings will inform the development of a future multisite effectiveness-implementation trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05373745; https://classic.clinicaltrials.gov/ct2/show/NCT05373745. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47319.

The longitudinal trajectory of discourse from the hyperacute to the chronic phase in mild to moderate poststroke aphasia recovery: A case series study.

BACKGROUND: Discourse analysis has recently received much attention in the aphasia literature. Even if post-stroke language recovery occurs throughout the longitudinal continuum of recovery, very few studies have documented discourse changes from the hyperacute to the chronic phases of recovery. AIMS: To document a multilevel analysis of discourse changes from the hyperacute phase to the chronic phase of post-stroke recovery using a series of single cases study designs. METHODS & PROCEDURES: Four people with mild to moderate post-stroke aphasia underwent four assessments (hyperacute: 0-24 h; acute: 24-72 h; subacute: 7-14 days; and chronic: 6-12 months post-onset). Three discourse tasks were performed at each time point: a picture description, a personal narrative and a story retelling. Multilevel changes in terms of macro- and microstructural aspects were analysed. The results of each discourse task were combined for each time point. Individual effect sizes were computed to evaluate the relative strength of changes in an early and a late recovery time frame. OUTCOMES & RESULTS: Macrostructural results revealed improvements throughout the recovery continuum in terms of coherence and thematic efficiency. Also, the microstructural results demonstrated linguistic output improvement for three out of four participants. Namely, lexical diversity and the number of correct information units/min showed a greater gain in the early compared with the late recovery phase. CONCLUSIONS & IMPLICATIONS: This study highlights the importance of investigating all discourse processing levels as the longitudinal changes in discourse operate differently at each phase of recovery. Overall results support future longitudinal discourse investigation in people with post-stroke aphasia. WHAT THIS PAPER ADDS: What is already known on the subject Multi-level discourse analysis allows for in-depth analysis of underlying discourse processes. To date, very little is known on the longitudinal discourse changes from aphasia onset through to the chronic stage of recovery. This study documents multi-level discourse features in four people with mild to moderate aphasia in the hyperacute, acute, subacute and chronic stage of post-stroke aphasia recovery. What this paper adds to existing knowledge The study found that most discourse variables demonstrated improvement throughout time. Macrostructural variables of coherence and thematic units improved throughout the continuum whereas microstructural variables demonstrated greater gains in the early compared to the late period of recovery. What are the potential or actual clinical implications of this work? This study suggests that multilevel discourse analysis will allow a better understanding of post-stroke aphasia recovery, although more research is needed to determine the clinical utility of these findings. Future research may wish to investigate longitudinal discourse recovery in a larger sample of people with aphasia with heterogenous aphasia profiles and severities.

Measuring communication as a core outcome in aphasia trials: Results of the ROMA-2 international core outcome set development meeting.

BACKGROUND: Evidence-based recommendations for a core outcome set (COS; minimum set of outcomes) for aphasia treatment research have been developed (the Research Outcome Measurement in Aphasia-ROMA, COS). Five recommended core outcome constructs: communication, language, quality of life, emotional well-being and patient-reported satisfaction/impact of treatment, were identified through three international consensus studies. Constructs were paired with outcome measurement instruments (OMIs) during an international consensus meeting (ROMA-1). Before the current study (ROMA-2), agreement had not been reached on OMIs for the constructs of communication or patient-reported satisfaction/impact of treatment. AIM: To establish consensus on a communication OMI for inclusion in the ROMA COS. METHODS & PROCEDURES: Research methods were based on recommendations from the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. Participants with expertise in design and conduct of aphasia trials, measurement instrument development/testing and/or communication outcome measurement were recruited through an open call. Before the consensus meeting, participants agreed on a definition of communication, identified appropriate OMIs, extracted their measurement properties and established criteria for their quality assessment. During the consensus meeting they short-listed OMIs and participants without conflicts of interest voted on the two most highly ranked instruments. Consensus was defined a priori as agreement by ≥ 70% of participants. OUTCOMES & RESULTS: In total, 40 researchers from nine countries participated in ROMA-2 (including four facilitators and three-panel members who participated in pre-meeting activities only). A total of 20 OMIs were identified and evaluated. Eight short-listed communication measures were further evaluated for their measurement properties and ranked. Participants in the consensus meeting (n = 33) who did not have conflicts of interest (n = 29) voted on the top two ranked OMIs: The Scenario Test (TST) and the Communication Activities of Daily Living-3 (CADL-3). TST received 72% (n = 21) of 'yes' votes and the CADL-3 received 28% (n = 8) of 'yes' votes. CONCLUSIONS & IMPLICATIONS: Consensus was achieved that TST was the preferred communication OMI for inclusion in the ROMA COS. It is currently available in the original Dutch version and has been adapted into English, German and Greek. Further consideration must be given to the best way to measure communication in people with mild aphasia. Development of a patient-reported measure for satisfaction with/impact of treatment and multilingual versions of all OMIs of the COS is still required. Implementation of the ROMA COS would improve research outcome measurement and the quality, relevance, transparency, replicability and efficiency of aphasia treatment research. WHAT THIS PAPER ADDS: What is already known on this subject International consensus has been reached on five core constructs to be routinely measured in aphasia treatment studies. International consensus has also been established for OMIs for the three constructs of language, quality of life and emotional well-being. Before this study, OMIs for the constructs of communication and patient-reported satisfaction/impact of treatment were not established. What this paper adds to existing knowledge We gained international consensus on an OMI for the construct of communication. TST is recommended for inclusion in the ROMA COS for routine use in aphasia treatment research. What are the potential or actual clinical implications of this work? The ROMA COS recommends OMIs for a minimum set of outcomes for adults with post-stroke aphasia within phases I-IV aphasia treatment research. Although not intended for clinical use, clinicians may employ the instruments of the ROMA COS, considering the quality of their measurement properties. The systematic inclusion of a measure of communication, such as TST, in clinical practice could ultimately support the implementation of research evidence and best practices.

Cognitive Training to Enhance Aphasia Therapy (Co-TrEAT): A Feasibility Study.

Persons with aphasia (PWA) often have deficits in cognitive domains such as working memory (WM), which are negatively correlated with recovery, and studies have targeted WM deficits in aphasia therapy. To our knowledge, however, no study has examined the efficacy of multi-modal training which includes both WM training and targeted language therapy. This pilot project examined the feasibility and preliminary efficacy of combining WM training and naming therapy to treat post-stroke PWA. Chronic PWA were randomly assigned to either the a) Phonological Components Analysis (PCA) and WM intervention (WMI) condition (i.e., a computerized adaptive dual n-back task), or b) PCA and active control condition (WMC). Participants received face-to-face PCA therapy 3 times/week for 5 weeks, and simultaneously engaged in WM training or the active control condition five times/week, independently at home. Six PWA were enrolled, 3 in each condition. Feasibility metrics were excellent for protocol compliance, retention rate and lack of adverse events. Recruitment was less successful, with insufficient participants for group analyses. Participants in the WMI (but not the WMC) condition demonstrated a clinically significant (i.e., > 5 points) improvement on the Western Aphasia Battery- Aphasia Quotient (WAB-R AQ) and Boston Naming Test after therapy. Given the small sample size, the performance of two individuals, matched on age, education, naming accuracy pre-treatment, WAB-R AQ and WM abilities was compared. Participant WMI-3 demonstrated a notable increase in WM training performance over the course of therapy; WMC-2 was the matched control. After therapy, WMI-3's naming accuracy for the treated words improved from 30 to 90% (compared to 30-50% for WMC-2) with a 7-point WAB-R AQ increase (compared to 3 for WMC-2). Improvements were also found for WMI-3 but not for WMC-2 on ratings of communicative effectiveness, confidence and some conversation parameters in discourse. This feasibility study demonstrated excellent results for most aspects of Co-TrEAT. Recruitment rate, hampered by limited resources, must be addressed in future trials; remotely delivered aphasia therapy may be a possible solution. Although no firm conclusions can be drawn, the case studies suggest that WM training has the potential to improve language and communication outcomes when combined with aphasia therapy.

Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation.

White matter hyperintensities (WMHs) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D convolutional neural network with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control, and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. Four hundred thirty-two subjects were recruited to train the CNNs from four multisite imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multisite study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 ± 0.08 and the lowest modified Hausdorff distance of 2.98 ± 4.40 mm. We further validated our models highlighting their robustness on "clinical adversarial cases" simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io.

Word-finding in confrontation naming and picture descriptions produced by individuals with early post-stroke aphasia.

Objective: The present study aims to assess the relationship between quantitative measures of connected speech production and performance in confrontation naming in early post-stroke aphasia (8-14 days post-stroke). Method: We collected connected speech samples elicited by a picture description task and administered a confrontation naming task to 20 individuals with early post-stroke aphasia and 20 healthy controls. Transcriptions were made in compliance with the CHAT format guidelines. Several micro- (i.e. duration, total number of words, words per minute, mean length of utterances, ratio of open- to closed-class words and noun-to-verb ratio, VOC-D, repetitions, self-corrections, and phonological and semantic errors) and macrolinguistic (i.e. informativeness and efficiency) measures were extracted. Results: We provide evidence for the presence of impairments in an array of micro- and macrolinguistic measures of speech in individuals with early post-stroke aphasia. We show that in the patient group, confrontation naming abilities most strongly relate to informativeness in a picture description task. Conclusion: Our findings contribute to a better understanding of the relationship between performance in confrontation naming and in connected speech production in the first days after stroke onset and also suggest that discourse analysis may provide unique, possibly more complex information.

Simultaneous Normalization and Compensatory Changes in Right Hemisphere Connectivity during Aphasia Therapy.

Changes in brain connectivity during language therapy were examined among participants with aphasia (PWA), aiming to shed light on neural reorganization in the language network. Four PWA with anomia following left hemisphere stroke and eight healthy controls (HC) participated in the study. Two fMRI scans were administered to all participants with a 3.5-month interval. The fMRI scans included phonological and semantic tasks, each consisting of linguistic and perceptual matching conditions. Between the two fMRI scans, PWA underwent Phonological Components Analysis treatment. Changes in effective connectivity during the treatment were examined within right hemisphere (RH) architecture. The results illustrate that following the treatment, the averaged connectivity of PWA across all perceptual and linguistic conditions in both tasks increased resemblance to HC, reflecting the normalization of neural processes associated with silent object name retrieval. In contrast, connections that were specifically enhanced by the phonological condition in PWA decreased in their resemblance to HC, reflecting emerging compensatory reorganization in RH connectivity to support phonological processing. These findings suggest that both normalization and compensation play a role in neural language reorganization at the chronic stage, occurring simultaneously in the same brain.