The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms.

SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive to SUMO availability and SENP2 activity is needed to provide SUMO. SENP2 is amplified as part of the chromosome 3q amplification in many cancers. Increased SENP2 expression prolongs MDC1 focus retention and increases NHEJ and radioresistance. Collectively, our data reveal that deSUMOylation differentially primes cells for responding to DSBs and demonstrates the ability of SENP2 to tune DSB repair responses.

Isomerization of BRCA1-BARD1 promotes replication fork protection.

The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1-PALB2 interaction, is required for fork protection. BRCA1-BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1-BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection.

Simultaneous Hemodynamic and Structural Imaging of Ischemic Stroke With Magnetic Resonance Fingerprinting Arterial Spin Labeling.

BACKGROUND: Perfusion and structural imaging play an important role in ischemic stroke. Magnetic resonance fingerprinting (MRF) arterial spin labeling (ASL) is a novel noninvasive method of ASL perfusion that allows simultaneous estimation of cerebral blood flow (CBF), bolus arrival time (BAT), and tissue T1 map in a single scan of <4 minutes. Here, we evaluated the utility of MRF-ASL in patients with ischemic stroke in terms of detecting hemodynamic and structural damage and predicting neurological deficits and disability. METHODS: A total of 34 patients were scanned on 3T magnetic resonance imaging. MRF-ASL, standard single-delay pseudo-continuous ASL, T2-weighted, and diffusion magnetic resonance imaging were performed. Regions of interest of lesion and contralateral normal tissues were manually delineated. CBF (with 2 different compartmental models), BAT, and tissue T1 parameters were quantified. Cross-sectional linear regression analyses were performed to examine the relationship between MRF-ASL parameters and National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale. Receiver operating characteristic analyses were performed to determine the utility of MRF-ASL in the classification of stroke lesion voxels. RESULTS: MRF-ASL derived parameters revealed a significant difference between stroke lesion and contralateral normal regions of interest, in that lesion regions manifested a lower CBF1-compartment (P<0.001), lower CBF2-compartment (P<0.001), longer BAT (P=0.002), and longer T1 (P<0.001) compared with normal regions of interest. NIHSS scores at acute stage revealed a strong association with lesion-normal differences in CBF1-compartment,diff (ß=-0.11, P=0.008), CBF2-compartment,diff (ß=-0.16, P=0.003), and T1,diff (ß=0.008, P=0.001). MRF-ASL parameters were also predictive of NIHSS score and modified Rankin Scale scale measured at a later stage, although the degree of the associations was weaker. These associations tended to be even stronger when the MRF-ASL data were acquired at the acute/subacute stage. Compared with standard pseudo-continuous ASL, the multiparametric capability of MRF-ASL yielded higher area under curve values in the receiver operating characteristic analyses of stroke voxel classifications. CONCLUSIONS: MRF-ASL may provide a new approach for quantitative hemodynamic and structural imaging in ischemic stroke.

A double dissociation between plural and possessive "s": Evidence from the Morphosyntactic Generation test.

People with aphasia demonstrate impaired production of bound inflectional morphemes, such as noun plurals and possession. They often show greater difficulty in marking possession versus plurality. Using a new tool for eliciting language, the Morphosyntactic Generation test, we assessed people with primary progressive aphasia and those in the acute and chronic phase following left hemisphere stroke. Clinical profiles were associated with different strengths and weaknesses in language production. Performance of the plural was stronger than possessive in group analyses. However, some individuals demonstrated the inverse pattern of performance. These participants provide counter-evidence to the theory that difficulty with marking possessives is purely the result of their greater cognitive-linguistic complexity and support a functional double dissociation between possessives and plurals. The deficits resulted from morphosyntactic impairment. Future work is needed to understand why plural and possessive markers were differently sensitive to neurological disorders of language.

Effects of a topical treatment with spleen tyrosine kinase inhibitor in healthy subjects and patients with cold urticaria or chronic spontaneous urticaria: Results of a phase 1a/b randomised double-blind placebo-controlled study.

AIMS: To explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models. METHODS: Healthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients. RESULTS: Thirty-four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC [0-24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14; 3.5% BSA] or 167 [%CV 120; 10% BSA]). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following 3 applications of GSK2646264 and placebo, a trend towards a greater reduction was seen in ColdU with GSK2646264 compared to placebo. A clinically meaningful reduction in CTT, in ColdU patients treated with GSK2646264, was observed in 4 of 9 patients, who demonstrated either a complete inhibition of ColdU to ≤4°C (n = 2) or partial response (reduction by >4°C, n = 2). Due to the small number of CSU patients recruited, no meaningful conclusions could be drawn from the defined area urticaria activity score PD endpoint. CONCLUSION: This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed. (NCT02424799).

How are social stressors at work related to well-being and health? A systematic review and meta-analysis.

BACKGROUND: Social relationships are crucial for well-being and health, and considerable research has established social stressors as a risk for well-being and health. However, researchers have used many different constructs, and it is unclear if these are actually different or reflect a single overarching construct. Distinct patterns of associations with health/well-being would indicate separate constructs, similar patterns would indicate a common core construct, and remaining differences could be attributed to situational characteristics such as frequency or intensity. The current meta-analysis therefore investigated to what extent different social stressors show distinct (versus similar) patterns of associations with well-being and health. METHODS: We meta-analysed 557 studies and investigated correlations between social stressors and outcomes in terms of health and well-being (e.g. burnout), attitudes (e.g. job satisfaction), and behaviour (e.g. counterproductive work behaviour). Moderator analyses were performed to determine if there were differences in associations depending on the nature of the stressor, the outcome, or both. To be included, studies had to be published in peer-reviewed journals in English or German; participants had to be employed at least 50% of a full-time equivalent (FTE). RESULTS: The overall relation between social stressors and health/well-being was of medium size (r = -.30, p < .001). Type of social stressor and outcome category acted as moderators, with moderating effects being larger for outcomes than for stressors. The strongest effects emerged for job satisfaction, burnout, commitment, and counterproductive work behaviour. Type of stressor yielded a significant moderation, but differences in effect sizes for different stressors were rather small overall. Rather small effects were obtained for physical violence and sexual mistreatment, which is likely due to a restricted range because of rare occurrence and/or underreporting of such intense stressors. CONCLUSIONS: We propose integrating diverse social stressor constructs under the term "relational devaluation" and considering situational factors such as intensity or frequency to account for the remaining variance. Practical implications underscore the importance for supervisors to recognize relational devaluation in its many different forms and to avoid or minimize it as far as possible in order to prevent negative health-related outcomes for employees.

Dynamically Masked Audiograms With Machine Learning Audiometry.

OBJECTIVES: When one ear of an individual can hear significantly better than the other ear, evaluating the worse ear with loud probe tones may require delivering masking noise to the better ear to prevent the probe tones from inadvertently being heard by the better ear. Current masking protocols are confusing, laborious, and time consuming. Adding a standardized masking protocol to an active machine learning audiogram procedure could potentially alleviate all of these drawbacks by dynamically adapting the masking as needed for each individual. The goal of this study is to determine the accuracy and efficiency of automated machine learning masking for obtaining true hearing thresholds. DESIGN: Dynamically masked automated audiograms were collected for 29 participants between the ages of 21 and 83 (mean 43, SD 20) with a wide range of hearing abilities. Normal-hearing listeners were given unmasked and masked machine learning audiogram tests. Listeners with hearing loss were given a standard audiogram test by an audiologist, with masking stimuli added as clinically determined, followed by a masked machine learning audiogram test. The hearing thresholds estimated for each pair of techniques were compared at standard audiogram frequencies (i.e., 0.25, 0.5, 1, 2, 4, 8 kHz). RESULTS: Masked and unmasked machine learning audiogram threshold estimates matched each other well in normal-hearing listeners, with a mean absolute difference between threshold estimates of 3.4 dB. Masked machine learning audiogram thresholds also matched well the thresholds determined by a conventional masking procedure, with a mean absolute difference between threshold estimates for listeners with low asymmetry and high asymmetry between the ears, respectively, of 4.9 and 2.6 dB. Notably, out of 6200 masked machine learning audiogram tone deliveries for this study, no instances of tones detected by the nontest ear were documented. The machine learning methods were also generally faster than the manual methods, and for some listeners, substantially so. CONCLUSIONS: Dynamically masked audiograms achieve accurate true threshold estimates and reduce test time compared with current clinical masking procedures. Dynamic masking is a compelling alternative to the methods currently used to evaluate individuals with highly asymmetric hearing, yet can also be used effectively and efficiently for anyone.

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy.

This corrects the article DOI: 10.1038/bjc.2017.188.

Harnessing citizen science through mobile phone technology to screen for immunohistochemical biomarkers in bladder cancer.

BACKGROUND: Immunohistochemistry (IHC) is often used in personalisation of cancer treatments. Analysis of large data sets to uncover predictive biomarkers by specialists can be enormously time-consuming. Here we investigated crowdsourcing as a means of reliably analysing immunostained cancer samples to discover biomarkers predictive of cancer survival. METHODS: We crowdsourced the analysis of bladder cancer TMA core samples through the smartphone app 'Reverse the Odds'. Scores from members of the public were pooled and compared to a gold standard set scored by appropriate specialists. We also used crowdsourced scores to assess associations with disease-specific survival. RESULTS: Data were collected over 721 days, with 4,744,339 classifications performed. The average time per classification was approximately 15 s, with approximately 20,000 h total non-gaming time contributed. The correlation between crowdsourced and expert H-scores (staining intensity × proportion) varied from 0.65 to 0.92 across the markers tested, with six of 10 correlation coefficients at least 0.80. At least two markers (MRE11 and CK20) were significantly associated with survival in patients with bladder cancer, and a further three markers showed results warranting expert follow-up. CONCLUSIONS: Crowdsourcing through a smartphone app has the potential to accurately screen IHC data and greatly increase the speed of biomarker discovery.

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy.

BACKGROUND: The majority of anal cancers (84-95%) are driven by infection with human papillomavirus (HPV). HPV-positive tumours show significantly better responses to chemo-radiotherapy when compared with HPV-negative tumours. HPV infection is linked to alterations in DNA damage response proteins, including MRE11. MRE11 is a potential predictive biomarker for response to radiotherapy in muscle-invasive bladder cancer and may hold predictive power in other cancers. METHODS: Using a previously reported cohort, we evaluated the levels of MRE11 in anal cancer and assessed its predictive value in this disease. RESULTS: We found no association between the level of MRE11 and relapse-free survival following chemo-radiotherapy. CONCLUSIONS: MRE11 has no predictive value in the analysis of relapse-free survival after chemo-radiotherapy in anal cancer and does not add to the prognostic value of p16 and tumour-infiltrating lymphocyte scores. Further investigation into the role of DNA repair proteins in anal cancer is required.

Comparison of two apheresis systems for autologous stem cell collections in pediatric oncology patients.

BACKGROUND: Peripheral stem cell collections can be challenging in the pediatric population and respective experience is limited. Since February 2015 our institution is utilizing the new Spectra Optia (Optia) apheresis device, which has replaced the former COBE Spectra (COBE) device. As a quality initiative we collected and compared collection efficiency (CE2) and other collection variables between the two devices. STUDY DESIGN AND METHODS: In this retrospective study we collected and compared clinical, laboratory, and technical collection data from stem cell collection procedures done with the Optia and COBE devices. The collected data included patient demographics, precollection peripheral CD34+ cell counts, total CD34+ cells collected, complete blood count, electrolytes before and after collection, side effects attributed to the collection, total blood volumes processed (TBVs), collection times, and calculated CE2 and collection ratios. RESULTS: Forty-one collection procedures performed on 29 pediatric patients with the Optia device were compared to 41 collections performed on 27 patients with the COBE device. The TBVs through the Optia device were significantly smaller than the COBE (3.9 ± 0.2 × TBV vs. 5.5 ± 0.1 × TBV, respectively; p < 0.001), requiring significantly less anticoagulant and providing similar amounts of stem cells while collection times were significantly shorter (mean, 238 ± 9 min vs. 264 ± 9 min, respectively; p < 0.05). Collections on the Optia caused significantly smaller reductions of plasma calcium and magnesium. No significant side effects attributed to the procedure were noted. CONCLUSION: Stem cell apheresis with the Optia device in children is safe and feasible with smaller blood volumes with shorter collection times.

Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair.

Microcephaly with early-onset, intractable seizures and developmental delay (MCSZ) is a hereditary disease caused by mutations in polynucleotide kinase/phosphatase (PNKP), a DNA strand break repair protein with DNA 5'-kinase and DNA 3'-phosphatase activity. To investigate the molecular basis of this disease, we examined the impact of MCSZ mutations on PNKP activity in vitro and in cells. Three of the four mutations currently associated with MCSZ greatly reduce or ablate DNA kinase activity of recombinant PNKP at 30°C (L176F, T424Gfs48X and exon15Δfs4X), but only one of these mutations reduces DNA phosphatase activity under the same conditions (L176F). The fourth mutation (E326K) has little impact on either DNA kinase or DNA phosphatase activity at 30°C, but is less stable than the wild-type enzyme at physiological temperature. Critically, all of the MCSZ mutations identified to date result in ∼ 10-fold reduced cellular levels of PNKP protein, and reduced rates of chromosomal DNA strand break repair. Together, these data suggest that all four known MCSZ mutations reduce the cellular stability and level of PNKP protein, with three mutations likely ablating cellular DNA 5'-kinase activity and all of the mutations greatly reducing cellular DNA 3'-phosphatase activity.

Prevalence, comorbidities, and correlates of challenging behavior among community-dwelling adults with severe traumatic brain injury: a multicenter study.

OBJECTIVE: Investigate the prevalence, comorbidities, and correlates of challenging behaviors among clients of the New South Wales Brain Injury Rehabilitation Program. SETTING: All community-based rehabilitation services of the statewide program. PARTICIPANTS: Five hundred seven active clients with severe traumatic brain injury. DESIGN: Prospective multicenter study. MAIN MEASURES: Eighty-eight clinicians from the 11 services rated clients on the Overt Behaviour Scale, Disability Rating Scale, Sydney Psychosocial Reintegration Scale-2, Care and Needs Scale, and Health of the Nation Outcome Scale-Acquired Brain Injury. RESULTS: Overall prevalence rate of challenging behaviors was 54%. Inappropriate social behavior (33.3%), aggression (31.9%), and adynamia (23.1%) were the 3 most common individual behaviors, with 35.5% of the sample displaying more than 1 challenging behavior. Significant associations were found between increasing levels of challenging behavior and longer duration of posttraumatic amnesia, increasing functional disability, greater restrictions in participation, increased support needs, and greater degrees of psychiatric disturbance, respectively (P < 0.004). Multivariate binomial logistic regression found that premorbid alcohol abuse, postinjury restrictions in participation, and higher levels of postinjury psychiatric disturbance were independent predictors of challenging behavior. CONCLUSIONS: Challenging behaviors are widespread among community-dwelling adults with severe traumatic brain injury. Services need to deliver integrated anger management, social skills, and motivational treatments.

Status of zoonotic disease research in refugees, asylum seekers and internally displaced people, globally: A scoping review of forty clinically important zoonotic pathogens.

BACKGROUND: At the end of 2022, there were over 108 million forcibly displaced people globally, including refugees, asylum seekers (AS) and internally displaced people (IDPs). Forced migration increases the risk of infectious disease transmission, and zoonotic pathogens account for 61% of emerging and re-emerging infectious diseases. Zoonoses create a high burden of disease and have the potential to cause large-scale outbreaks. This scoping review aimed to assess the state of research on a range of clinically relevant zoonotic pathogens in displaced populations in order to identify the gaps in literature and guide future research. METHODOLOGY / PRINCIPAL FINDINGS: Literature was systematically searched to identify original research related to 40 selected zoonotic pathogens of interest in refugees, AS and IDPs. We included only peer-reviewed original research in English, with no publication date restrictions. Demographic data, migration pathways, health factors, associated outbreaks, predictive factors and preventative measures were extracted and synthesized. We identified 4,295 articles, of which 347 were included; dates of publications ranged from 1937 to 2022. Refugees were the most common population investigated (75%). Migration pathways of displaced populations increased over time towards a more complex web, involving migration in dual directions. The most frequent pathogen investigated was Schistosoma spp. (n = 99 articles). Disease outbreaks were reported in 46 publications (13.3%), with viruses being the most commonly reported pathogen type. Limited access to hygiene/sanitation, crowding and refugee status were the most commonly discussed predictors of infection. Vaccination/prophylaxis drug administration, surveillance/screening and improved hygiene/sanitation were the most commonly discussed preventative measures. CONCLUSIONS / SIGNIFICANCE: The current research on zoonoses in displaced populations displays gaps in the spectrum of pathogens studied, as well as in the (sub)populations investigated. Future studies should be more inclusive of One Health approaches to adequately investigate the impact of zoonotic pathogens and identify transmission pathways as a basis for designing interventions for displaced populations.

USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication.

Mammalian DNA replication employs several RecQ DNA helicases to orchestrate the faithful duplication of genetic information. Helicase function is often coupled to the activity of specific nucleases, but how helicase and nuclease activities are co-directed is unclear. Here we identify the inactive ubiquitin-specific protease, USP50, as a ubiquitin-binding and chromatin-associated protein required for ongoing replication, fork restart, telomere maintenance and cellular survival during replicative stress. USP50 supports WRN:FEN1 at stalled replication forks, suppresses MUS81-dependent fork collapse and restricts double-strand DNA breaks at GC-rich sequences. Surprisingly we find that cells depleted for USP50 and recovering from a replication block exhibit increased DNA2 and RECQL4 foci and that the defects in ongoing replication, poor fork restart and increased fork collapse seen in these cells are mediated by DNA2, RECQL4 and RECQL5. These data define a novel ubiquitin-dependent pathway that promotes the balance of helicase: nuclease use at ongoing and stalled replication forks.

Outcomes of surgical treatment with patterns of bacterial culture and antimicrobial susceptibility testing in cases of cervical abscessation in dogs: 82 cases (2018-2021).

OBJECTIVE: The objective of this study was to summarize the presentation, diagnosis, and outcome for dogs surgically treated for chronic cervical abscessation following suspected or reported cervical or oropharyngeal trauma, as well as to report on culture results and antimicrobial susceptibility patterns. RESULTS: Eighty-two dogs were identified by retrospective review. Successful surgical outcome was achieved in 92.7% of dogs. Abscess recurrence was confirmed or suspected in 6/82 (7.3%) cases, and surgical intervention for abscess recurrence was performed in 4/82 (4.9%) cases. Foreign material was identified at surgery in 5/82 (6%) cases. Incisional healing complications were noted in 9/82 (10.9%) cases and required additional surgery in 5/82 (6%) cases. Twenty-three (28%) dogs had negative culture results. The results of antimicrobial sensitivity testing led to a change in antimicrobial treatment in only 9% of cases.Surgically treated cervical abscessation carries a good prognosis with a low incidence of recurrence in this cohort (in contrast to previous reports), despite low frequency of foreign body removal or identification of the underlying cause of the abscess. Excision of chronic inflammatory tissue may not be necessary for a successful outcome, contrary to previous recommendations. Multi-pathogen infections and anaerobic infections are commonly encountered.

Disruptions of the Human Connectome Associated With Hemispatial Neglect.

BACKGROUND AND OBJECTIVES: Hemispatial neglect is a heterogeneous and complex disorder that can be classified by frame of reference for "left" vs "right," including viewer-centered neglect (VCN, affecting the contralesional side of the view), stimulus-centered neglect (SCN, affecting the contralesional side of the stimulus, irrespective of its location with respect to the viewer), or both. We investigated the effect of acute stroke lesions on the connectivity of neural networks that underlie VCN or SCN. METHODS: A total of 174 patients within 48 hours of acute right hemispheric infarct underwent a detailed hemispatial neglect assessment that included oral reading, scene copy, line cancellation, gap detection, horizontal line bisection tests, and MRI. Each patient's connectivity map was generated. We performed a linear association analysis between network connectivity strength and continuous measures of neglect to identify lesion-induced disconnections associated with the presence or severity of VCN and SCN. Results were corrected for multiple comparisons. RESULTS: About 42% of the participants with right hemisphere stroke had at least one type of neglect. The presence of any type of neglect was associated with lesions to tracts connecting the right inferior parietal cortex, orbitofrontal cortex, and right thalamus to other right-hemispheric structures. VCN only was strongly associated with tracts connecting the right putamen to other brain regions and tracts connecting right frontal regions with other brain regions. The presence of both types of neglect was most strongly associated with tracts connecting the right inferior and superior parietal cortex to other brain regions and those connecting left or right mesial temporal cortex to other brain regions. DISCUSSION: Our study provides new evidence for the specific white matter tracts where disruption can cause hemispatial neglect in a relatively large number of participants and homogeneous time after onset. We obtained MRI and behavioral testing acutely, before the opportunity for rehabilitation or substantial recovery. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that damage to specific white matter tracts identified on MRI are associated with the presence of neglect following right hemispheric stroke.

Transcranial Direct Current Stimulation Paired With Verb Network Strengthening Treatment Improves Verb Naming in Primary Progressive Aphasia: A Case Series.

PURPOSE: There are few evidence-based treatments for language deficits in primary progressive aphasia (PPA). PPA treatments are often adopted from the poststroke aphasia literature. The poststroke aphasia literature has shown promising results using Verb Network Strengthening Treatment (VNeST), a behavioral therapy that focuses on improving naming by producing verbs and their arguments in phrases and sentences. Emerging research in poststroke aphasia and PPA has shown promising results pairing behavioral language therapy with transcranial direct current stimulation (tDCS). METHOD: This study used a double-blind, within-subjects, sham-controlled crossover design to study the effect of anodal tDCS applied to left inferior frontal gyrus (IFG) plus VNeST versus VNeST plus sham stimulation in two individuals with nonfluent variant PPA and one individual with logopenic variant PPA. Participants received two phases of treatment, each with 15 1-hr sessions of VNeST. One phase paired VNeST with tDCS stimulation, and one with sham. For each phase, language testing was conducted at baseline, and at 1 week and 8 weeks posttreatment conclusion. For each participant, treatment efficacy was evaluated for each treatment phase by comparing the mean change in accuracy between baseline and the follow-up time points for naming trained verbs (primary outcome measure), untrained verbs, and nouns on the Object and Action Naming Battery. Mean change from baseline was also directly compared between tDCS and sham phases at each time point. RESULTS: Results revealed a different pattern of outcomes for each of the participants. A tDCS advantage was not found for trained verbs for any participant. Two participants with nonfluent variant PPA had a tDCS advantage for generalization to naming of untrained verbs, which was apparent at 1 week and 8 weeks posttreatment. One participant with nonfluent variant also showed evidence of generalization to sentence production in the tDCS phase. CONCLUSION: VNeST plus anodal tDCS stimulation of left IFG shows promising results for improving naming in PPA.

Hyperintense vessels on imaging account for neurological function independent of lesion volume in acute ischemic stroke.

In acute ischemic stroke, reported relationships between lesion metrics and behavior have largely focused on lesion volume and location. However, hypoperfusion has been shown to correlate with deficits in the acute stage. Hypoperfusion is typically identified using perfusion imaging in clinical settings, which requires contrast. Unfortunately, contrast is contraindicated for some individuals. An alternative method has been proposed to identify hypoperfusion using hyperintense vessels on fluid-attenuated inversion recovery (FLAIR) imaging. This study aimed to validate the clinical importance of considering hypoperfusion when accounting for behavior in acute stroke and demonstrate the clinical utility of scoring the presence of hyperintense vessels to quantify it. One hundred and fifty-three participants with acute ischemic stroke completed a battery of commonly-used neurological and behavioral measures. Clinical MRIs were used to determine lesion volume and to score the presence of hyperintense vessels seen on FLAIR images to estimate severity of hypoperfusion in six different vascular regions. National Institutes of Health Stroke Scale (NIHSS) scores, naming accuracy (left hemisphere strokes), and language content produced during picture description were examined in relation to lesion volume, hypoperfusion, and demographic variables using correlational analyses and multivariable linear regression. Results showed that lesion volume and hypoperfusion, in addition to demographic variables, were independently associated with performance on NIHSS, naming, and content production. Specifically, hypoperfusion in the frontal lobe independently correlated with NIHSS scores, while hypoperfusion in parietal areas independently correlated with naming accuracy and content production. These results correspond to previous reports associating hypoperfusion with function, confirming that hypoperfusion is an important consideration-beyond lesion volume-when accounting for behavior in acute ischemic stroke. Quantifying hypoperfusion using FLAIR hyperintense vessels can be an essential clinical tool when other methods of identifying hypoperfusion are unavailable or time prohibitive.

The contribution of white matter pathology, hypoperfusion, lesion load, and stroke recurrence to language deficits following acute subcortical left hemisphere stroke.

Aphasia, the loss of language ability following damage to the brain, is among the most disabling and common consequences of stroke. Subcortical stroke, occurring in the basal ganglia, thalamus, and/or deep white matter can result in aphasia, often characterized by word fluency, motor speech output, or sentence generation impairments. The link between greater lesion volume and acute aphasia is well documented, but the independent contributions of lesion location, cortical hypoperfusion, prior stroke, and white matter degeneration (leukoaraiosis) remain unclear, particularly in subcortical aphasia. Thus, we aimed to disentangle the contributions of each factor on language impairments in left hemisphere acute subcortical stroke survivors. Eighty patients with acute ischemic left hemisphere subcortical stroke (less than 10 days post-onset) participated. We manually traced acute lesions on diffusion-weighted scans and prior lesions on T2-weighted scans. Leukoaraiosis was rated on T2-weighted scans using the Fazekas et al. (1987) scale. Fluid-attenuated inversion recovery (FLAIR) scans were evaluated for hyperintense vessels in each vascular territory, providing an indirect measure of hypoperfusion in lieu of perfusion-weighted imaging. We found that language performance was negatively correlated with acute/total lesion volumes and greater damage to substructures of the deep white matter and basal ganglia. We conducted a LASSO regression that included all variables for which we found significant univariate relationships to language performance, plus nuisance regressors. Only total lesion volume was a significant predictor of global language impairment severity. Further examination of three participants with severe language impairments suggests that their deficits result from impairment in domain-general, rather than linguistic, processes. Given the variability in language deficits and imaging markers associated with such deficits, it seems likely that subcortical aphasia is a heterogeneous clinical syndrome with distinct causes across individuals.