For many years, researchers have sought to understand whether and when stroke survivors with acquired language impairment (aphasia) will recover. There is broad agreement that lesion location information should play some role in these predictions, but still no consensus on the best or right way to encode that information. Here, we address the emerging emphasis on the structural connectome in this work - specifically the claim that disrupted white matter connectivity conveys important, unique prognostic information for stroke survivors with aphasia. Our sample included 818 stroke patients extracted from the PLORAS database, which associates structural MRI from stroke patients with language assessment scores from the Comprehensive Aphasia Test (CAT) and basic demographic. Patients were excluded when their lesions were too diffuse or small (<1 cm3) to be detected by the Automatic Lesion Identification toolbox, which we used to encode patients' lesions as binary lesion images in standard space. Lesions were encoded using the 116 regions defined by the Automatic Anatomical Labelling atlas. We examined prognostic models driven by both "lesion load" in these regions (i.e. the proportion of each region destroyed by each patient's lesion), and by the disconnection of the white matter connections between them which was calculated via the Network Modification toolbox. Using these data, we build a series of prognostic models to predict first one ("naming"), and then all of the language scores defined by the CAT. We found no consistent evidence that connectivity disruption data in these models improved our ability to predict any language score. This may be because the connectivity disruption variables are strongly correlated with the lesion load variables: correlations which we measure both between pairs of variables in their original form, and between principal components of both datasets. Our conclusion is that, while both types of structural brain data do convey useful, prognostic information in this domain, they also appear to convey largely the same variance. We conclude that connectivity disruption variables do not help us to predict patients' language skills more accurately than lesion location (load) data alone.

Central alexia is an acquired reading disorder co-occurring with a generalized language deficit (aphasia). We tested the impact of a novel training app, 'iReadMore', and anodal transcranial direct current stimulation of the left inferior frontal gyrus, on word reading ability in central alexia. The trial was registered at www.clinicaltrials.gov (NCT02062619). Twenty-one chronic stroke patients with central alexia participated. A baseline-controlled, repeated-measures, crossover design was used. Participants completed two 4-week blocks of iReadMore training, one with anodal stimulation and one with sham stimulation (order counterbalanced between participants). Each block comprised 34 h of iReadMore training and 11 stimulation sessions. Outcome measures were assessed before, between and after the two blocks. The primary outcome measures were reading ability for trained and untrained words. Secondary outcome measures included semantic word matching, sentence reading, text reading and a self-report measure. iReadMore training resulted in an 8.7% improvement in reading accuracy for trained words (95% confidence interval 6.0 to 11.4; Cohen's d = 1.38) but did not generalize to untrained words. Reaction times also improved. Reading accuracy gains were still significant (but reduced) 3 months after training cessation. Anodal transcranial direct current stimulation (compared to sham), delivered concurrently with iReadMore, resulted in a 2.6% (95% confidence interval -0.1 to 5.3; d = 0.41) facilitation for reading accuracy, both for trained and untrained words. iReadMore also improved performance on the semantic word-matching test. There was a non-significant trend towards improved self-reported reading ability. However, no significant changes were seen at the sentence or text reading level. In summary, iReadMore training in post-stroke central alexia improved reading ability for trained words, with good maintenance of the therapy effect. Anodal stimulation resulted in a small facilitation (d = 0.41) of learning and also generalized to untrained items.10.1093/brain/awy138_video1awy138media15796149281001.

Mesenchymal stem cells (MSCs) have long been viewed as a promising therapeutic for musculoskeletal repair. However, regulatory concerns including tumorgenicity, inconsistencies in preparation techniques, donor-to-donor variability, and the accumulation of senescence during culture expansion have hindered the clinical application of MSCs. Senescence is a driving mechanism for MSC dysfunction with advancing age. Often characterized by increased reactive oxygen species, senescence-associated heterochromatin foci, inflammatory cytokine secretion, and reduced proliferative capacity, senescence directly inhibits MSCs efficacy as a therapeutic for musculoskeletal regeneration. Furthermore, autologous delivery of senescent MSCs can further induce disease and aging progression through the secretion of the senescence-associated secretory phenotype (SASP) and mitigate the regenerative potential of MSCs. To alleviate these issues, the use of senolytic agents to selectively clear senescent cell populations has become popular. However, their benefits to attenuating senescence accumulation in human MSCs during the culture expansion process have not yet been elucidated. To address this, we analyzed markers of senescence during the expansion of human primary adipose-derived stem cells (ADSCs), a population of fat-resident MSCs commonly used in regenerative medicine applications. Next, we used the senolytic agent fisetin to determine if we can reduce these markers of senescence within our culture-expanded ADSC populations. Our results indicate that ADSCs acquire common markers of cellular senescence including increased reactive oxygen species, senescence-associated β-galactosidase, and senescence-associated heterochromatin foci. Furthermore, we found that the senolytic agent fisetin works in a dose-dependent manner and selectively attenuates these markers of senescence while maintaining the differentiation potential of the expanded ADSCs.

Acquired language disorders after stroke are strongly associated with left hemisphere damage. When language difficulties are observed in the context of right hemisphere strokes, patients are usually considered to have atypical functional anatomy. By systematically integrating behavioural and lesion data from brain damaged patients with functional MRI data from neurologically normal participants, we investigated when and why right hemisphere strokes cause language disorders. Experiment 1 studied right-handed patients with unilateral strokes that damaged the right (n = 109) or left (n = 369) hemispheres. The most frequently impaired language task was: auditory sentence-to-picture matching after right hemisphere strokes; and spoken picture description after left hemisphere strokes. For those with auditory sentence-to-picture matching impairments after right hemisphere strokes, the majority (n = 9) had normal performance on tests of perceptual (visual or auditory) and linguistic (semantic, phonological or syntactic) processing. Experiment 2 found that these nine patients had significantly more damage to dorsal parts of the superior longitudinal fasciculus and the right inferior frontal sulcus compared to 75 other patients who also had right hemisphere strokes but were not impaired on the auditory sentence-to-picture matching task. Damage to these right hemisphere regions caused long-term speech comprehension difficulties in 67% of patients. Experiments 3 and 4 used functional MRI in two groups of 25 neurologically normal individuals to show that within the regions identified by Experiment 2, the right inferior frontal sulcus was normally activated by (i) auditory sentence-to-picture matching; and (ii) one-back matching when the demands on linguistic and non-linguistic working memory were high. Together, these experiments demonstrate that the right inferior frontal cortex contributes to linguistic and non-linguistic working memory capacity (executive function) that is needed for normal speech comprehension. Our results link previously unrelated literatures on the role of the right inferior frontal cortex in executive processing and the role of executive processing in sentence comprehension; which in turn helps to explain why right inferior frontal activity has previously been reported to increase during recovery of language function after left hemisphere stroke. The clinical relevance of our findings is that the detrimental effect of right hemisphere strokes on language is (i) much greater than expected; (ii) frequently observed after damage to the right inferior frontal sulcus; (iii) task dependent; (iv) different to the type of impairments observed after left hemisphere strokes; and (v) can result in long-lasting deficits that are (vi) not the consequence of atypical language lateralization.

The PLORAS Database is a relational repository of anatomical and functional imaging data that has primarily been acquired from stroke survivors, along with standardized scores on a wide range of sensory, motor and cognitive abilities, demographic details and medical history. As of January 2015, we have data from 750 patients with an expected accrual rate of 200 patients per year. Expansion will accelerate as we extend our collaborations. The main aim of the database is to Predict Language Outcome and Recovery After Stroke (PLORAS) on the basis of a single structural (anatomical) brain scan that indexes the stereotactic location and extent of brain damage. Predictions are made for individual patients by indicating how other patients with the most similar brain damage, cognitive abilities and demographic details recovered their language skills over time. Predictions are validated by longitudinal follow-ups of patients who initially presented with speech and language difficulties. The PLORAS Database can also be used to predict recovery of other cognitive abilities on the basis of anatomical brain scans. The functional imaging data can be used to understand the neural mechanisms that support recovery from brain damage; and all the data can be used to understand the main sources of inter-subject variability in structure-function mappings in the human brain. Data will be made available for sharing, subject to: funding, ethical approval and patient consent.

Here, we present and validate a method that lets us predict the severity of cognitive impairments after stroke, and the likely course of recovery over time. Our approach employs (a) a database that records the behavioural scores from a large population of patients who have, collectively, incurred a comprehensive range of focal brain lesions, (b) an automated procedure to convert structural brain scans from those patients into three-dimensional images of their lesions, and (c) a system to learn the relationship between patients' lesions, demographics and behavioural capacities at different times post-stroke. Validation against data collected from 270 stroke patients suggests that our first set of variables yielded predictions that match or exceed the predictive power reported in any comparable work in the available literature. Predictions are likely to improve when other determinants of recovery are included in the system. Many behavioural outcomes after stroke could be predicted using the proposed approach.

Noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting, polarity-dependent changes in neocortical excitability. In a previous concurrent tDCS-fMRI study of overt picture naming, we reported significant behavioural and regionally specific neural facilitation effects in left inferior frontal cortex (IFC) with anodal tDCS applied to left frontal cortex (Holland et al., 2011). Although distributed connectivity effects of anodal tDCS have been modelled at rest, the mechanism by which 'on-line' tDCS may modulate neuronal connectivity during a task-state remains unclear. Here, we used Dynamic Causal Modelling (DCM) to determine: (i) how neural connectivity within the frontal speech network is modulated during anodal tDCS; and, (ii) how individual variability in behavioural response to anodal tDCS relates to changes in effective connectivity strength. Results showed that compared to sham, anodal tDCS elicited stronger feedback from inferior frontal sulcus (IFS) to ventral premotor (VPM) accompanied by weaker self-connections within VPM, consistent with processes of neuronal adaptation. During anodal tDCS individual variability in the feedforward connection strength from IFS to VPM positively correlated with the degree of facilitation in naming behaviour. These results provide an essential step towards understanding the mechanism of 'online' tDCS paired with a cognitive task. They also identify left IFS as a 'top-down' hub and driver for speech change.

The organisational principles of the visual ventral stream are still highly debated, particularly the relative association/dissociation between word and face recognition and the degree of lateralisation of the underlying processes. Reports of dissociations between word and face recognition stem from single case-studies of category selective impairments, and neuroimaging investigations of healthy participants. Despite the historical reliance on single case-studies, more recent group studies have highlighted a greater commonality between word and face recognition. Studying individual patients with rare selective deficits misses (a) important variability between patients, (b) systematic associations between task performance, and (c) patients with mild, severe and/or non-selective impairments; meaning that the full spectrum of deficits is unknown. The Back of the Brain project assessed the range and specificity of visual perceptual impairment in 64 patients with posterior cerebral artery stroke recruited based on lesion localization and not behavioural performance. Word, object, and face processing were measured with comparable tests across different levels of processing to investigate associations and dissociations across domains. We present two complementary analyses of the extensive behavioural battery: (1) a data-driven analysis of the whole patient group, and (2) a single-subject case-series analysis testing for deficits and dissociations in each individual patient. In both analyses, the general organisational principle was of associations between words, objects, and faces even following unilateral lesions. The majority of patients either showed deficits across all domains or in no domain, suggesting a spectrum of visuo-perceptual deficits post stroke. Dissociations were observed, but they were the exception and not the rule: Category-selective impairments were found in only a minority of patients, all of whom showed disproportionate deficits for words. Interestingly, such selective word impairments were found following both left and right hemisphere lesions. This large-scale investigation of posterior cerebral artery stroke patients highlights the bilateral representation of visual perceptual function.

Prior studies have reported inconsistency in the lesion sites associated with verbal short-term memory impairments. Here we asked: How many different lesion sites can account for selective impairments in verbal short-term memory that persist over time, and how consistently do these lesion sites impair verbal short-term memory? We assessed verbal short-term memory impairments using a forward digit span task from the Comprehensive Aphasia Test. First, we identified the incidence of digit span impairments in a sample of 816 stroke survivors (541 males/275 females; age at stroke onset 56 ± 13 years; time post-stroke 4.4 ± 5.2 years). Second, we studied the lesion sites in a subgroup of these patients (n = 39) with left hemisphere damage and selective digit span impairment-defined as impaired digit span with unimpaired spoken picture naming and spoken word comprehension (tests of speech production and speech perception, respectively). Third, we examined how often these lesion sites were observed in patients who either had no digit span impairments or digit span impairments that co-occurred with difficulties in speech perception and/or production tasks. Digit span impairments were observed in 222/816 patients. Almost all (199/222 = 90%) had left hemisphere damage to five small regions in basal ganglia and/or temporo-parietal areas. Even complete damage to one or more of these five regions was not consistently associated with persistent digit span impairment. However, when the same regions were spared, only 5% (23/455) presented with digit span impairments. These data suggest that verbal short-term memory impairments are most consistently associated with damage to left temporo-parietal and basal ganglia structures. Sparing of these regions very rarely results in persistently poor verbal short-term memory. These findings have clinical implications for predicting recovery of verbal short-term memory after stroke.

The COVID-19 pandemic and related social isolation measures are likely to have adverse consequences on community healthcare provision and outcome after acute illnesses treated in hospital, including stroke. We aimed to evaluate the impact of the COVID-19 pandemic on patient-reported health outcomes after hospital admission for acute stroke.

Currently, national training programs do not have the capacity to meet the growing demand for dissemination and implementation (D&I) workforce education and development. The Colorado Research in Implementation Science Program (CRISP) developed and delivered an introductory D&I workshop adapted from national programs to extend training reach and foster a local learning community for D&I.

Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.

Electrophysiological studies in humans and animals suggest that noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting [1], polarity-dependent [2] changes in neocortical excitability. Application of tDCS can have significant and selective behavioral consequences that are associated with the cortical location of the stimulation electrodes and the task engaged during stimulation [3-8]. However, the mechanism by which tDCS affects human behavior is unclear. Recently, functional magnetic resonance imaging (fMRI) has been used to determine the spatial topography of tDCS effects [9-13], but no behavioral data were collected during stimulation. The present study is unique in this regard, in that both neural and behavioral responses were recorded using a novel combination of left frontal anodal tDCS during an overt picture-naming fMRI study. We found that tDCS had significant behavioral and regionally specific neural facilitation effects. Furthermore, faster naming responses correlated with decreased blood oxygen level-dependent (BOLD) signal in Broca's area. Our data support the importance of Broca's area within the normal naming network and as such indicate that Broca's area may be a suitable candidate site for tDCS in neurorehabilitation of anomic patients, whose brain damage spares this region.

Patient-reported outcomes (PROs) have the potential to aid in surgical decision-making, predict surgical outcomes, assess recovery, and evaluate long-term success. We performed a pilot study testing the ability to use PROs in a broad surgical population in preparation for wide spread use.

A new postoperative esophagectomy care pathway was recently implemented at our institution. Practice pattern change among provider teams can prove challenging; therefore, we sought to study the barriers and facilitators toward pathway implementation at the provider level.

Thioredoxin reductase 1 is a key enzyme in cellular redox processes, which are known to play a role in the pathogenesis of familial amyotrophic lateral sclerosis (FALS). The gene TXNRD1 was therefore screened for association with FALS. Resequencing of the exons and flanking regions identified 19 single-nucleotide polymorphisms (SNPs) of which 2, the intronic SNPs rs6539137 and rs4630362, were significantly associated with FALS. However, no association of rs6539137 with sporadic ALS was detected. The TXNRD1 haplotypes were reconstructed using the EH and PHASE 2.1 programs and also showed an association with FALS. Bayesian analysis of these SNP combinations, carried out using the BIMBAM program, indicated that rs10861192 strongly augmented this association. Indeed the haplotypes with minor alleles at both rs10861192 and rs6539137, although present in FALS, were totally absent from controls. Patients with the minor allele of rs6539137 were also associated with an early age at onset, which was decreased by 8 years. Furthermore the shift of onset was more pronounced in males and not significant in females. These results show that TXNRD1 may act as an important modifier gene of FALS and indicate that the additional thiol-redox system genes, thioredoxin and the peroxiredoxins, should also be investigated in FALS and other neurological disorders.

Formal surgical risk assessment tools have been developed to predict risk of adverse postoperative patient outcomes. Such tools accurately predict common postoperative complications, inform patients and providers of likely perioperative outcomes, guide decision making, and improve patient care. However, these are underutilized. We studied the attitudes towards and techniques of how surgeons preoperatively assess risk.

Aging leads to several geriatric conditions including osteoporosis (OP) and associated frailty syndrome. Treatments for these conditions are limited and none target fundamental drivers of pathology, and thus identifying strategies to delay progressive loss of tissue homeostasis and functional reserve will significantly improve quality of life in elderly individuals. A fundamental property of aging is the accumulation of senescent cells. Senescence is a cell state defined by loss of proliferative capacity, resistance to apoptosis, and the release of a proinflammatory and anti-regenerative senescence-associated secretory phenotype (SASP). The accumulation of senescent cells and SASP factors is thought to significantly contribute to systemic aging. Senolytics-compounds which selectively target and kill senescent cells-have been characterized to target and inhibit anti-apoptotic pathways that are upregulated during senescence, which can elicit apoptosis in senescent cells and relieve SASP production. Senescent cells have been linked to several age-related pathologies including bone density loss and osteoarthritis in mice. Previous studies in murine models of OP have demonstrated that targeting senescent cells pharmacologically with senolytic drugs can reduce symptomology of the disease. Here, we demonstrate the efficacy of senolytic drugs (dasatinib, quercetin, and fisetin) to improve age-associated degeneration in bone using the Zmpste24-/- (Z24-/-) progeria murine system for Hutchinson-Gilford progeria syndrome (HGPS). We found that the combination of dasatinib plus quercetin could not significantly mitigate trabecular bone loss although fisetin administration could reduce bone density loss in the accelerated aging Z24-/- model. Furthermore, the overt bone density loss observed in the Z24-/- model reported herein highlights the Z24 model as a translational model to recapitulate alterations in bone density associated with advanced age. Consistent with the "geroscience hypothesis," these data demonstrate the utility of targeting a fundamental driver of systemic aging (senescent cell accumulation) to alleviate a common condition with age, bone deterioration.