[Features of aphasic disorders in patients with acute cerebrovascular disorder in the posterior cerebral artery basin]. / Osobennosti afaticheskikh rasstroistv u patsientov s ostrym narusheniem mozgovogo krovoobrashcheniya v basseine zadnei mozgovoi arterii.

Aphasia is a systemic disorder of formed speech that develops as a result of local brain lesions. Most aphasias are characterized by damage to secondary cortical fields, which in turn are responsible for the performance of the functions of gnosis and praxis, which explains the variability in the manifestations of speech disorders in patients with acute cerebrovascular accidents. However, it is necessary in each case to diagnose the central pathological mechanism, which underlies the development of the entire syndrome and determines the entire clinical picture. The most important task of a speech therapist-aphasiologist is to qualify the defect, namely to isolate the mechanism and analyze the syndrome in order to select individual methods of corrective restoration. This article presents a case of a patient with an ischemic stroke in the left posterior cerebral artery with the development of amnestic aphasia in combination with alexia without agraphia.

The non-paretic-hand-to-opposite-ear test: A simple test to detect aphasia and neglect and an indicator of large anterior vessel occlusion in patients with suspected acute stroke.

INTRODUCTION: Aphasia and neglect in combination with hemiparesis are reliable indicators of large anterior vessel occlusion (LAVO). Prehospital identification of these symptoms is generally considered difficult by emergency medical service (EMS) personnel. Therefore, we evaluated the simple non-paretic-hand-to-opposite-ear (NPE) test to identify aphasia and neglect with a single test. As the NPE test includes a test for arm paresis, we also evaluated the diagnostic ability of the NPE test to detect LAVO in patients with suspected stroke. METHODS: In this prospective observational study, we performed the NPE test in 1042 patients with suspected acute stroke between May 2021 and May 2022. We analyzed the correlation between the NPE test and the aphasia/neglect items of the National Institutes of Health Stroke Scale. Additionally, the predictive values of the NPE test for LAVO detection were calculated. RESULTS: The NPE test showed a strong, significant correlation with both aphasia and neglect. A positive NPE test result predicted LAVO with a sensitivity of 0.70, a specificity of 0.88, and an accuracy of 0.85. Logistic regression analysis showed an odds ratio of 16.14 (95% confidence interval 10.82-24.44) for predicting LAVO. CONCLUSION: The NPE test is a simple test for the detection of both aphasia and neglect. With its predictive values for LAVO detection being comparable to the results of LAVO scores in the prehospital setting, this simple test might be a promising test for prehospital LAVO detection by EMS personnel. Further prospective prehospital validation is needed.

Resting-state brain network connectivity is an independent predictor of responsiveness to language therapy in chronic post-stroke aphasia.

Post-stroke aphasia recovery, especially in the chronic phase, is challenging to predict. Functional integrity of the brain and brain network topology have been suggested as biomarkers of language recovery. This study sought to investigate functional connectivity in four predefined brain networks (i.e., language, default mode, dorsal attention, and salience networks), in relation to aphasia severity and response to language therapy. Thirty patients with chronic post-stroke aphasia were recruited and received a treatment targeting word finding. Structural and functional brain scans were acquired at baseline and resting state functional connectivity for each network was calculated. Additionally, graph measures quantifying network properties were calculated for each network. These included global efficiency for all networks and average strength and clustering coefficient for the language network. Linear mixed effects models showed that mean functional connectivity in the default mode, dorsal attention, and salience networks as well as graph measures of all four networks are independent predictors of response to therapy. While greater mean functional connectivity and global efficiency of the dorsal attention and salience networks predicted greater treatment response, greater mean functional connectivity and global efficiency in the default mode network predicted poorer treatment response. Results for the language network were more nuanced with more efficient network configurations (as reflected in graph measures), but not mean functional connectivity, predicting greater treatment response. These findings highlight the prognostic value of resting-state functional connectivity in chronic treatment-induced aphasia recovery.

Digital Avatars and Personalized Voices-How AI Is Helping to Restore Speech to Patients.

In this Medical News article, Edward Chang, MD, chair of the department of neurological surgery at the University of California, San Francisco Weill Institute for Neurosciences joins JAMA Editor in Chief Kirsten Bibbins-Domingo, PhD, MD, MAS, to discuss the potential for AI to revolutionize communication for those unable to speak due to aphasia.

A Review of Poststroke Aphasia Recovery and Treatment Options.

Poststroke aphasia, which impacts expressive and receptive communication, can have detrimental effects on the psychosocial well-being and the quality of life of those affected. Aphasia recovery is multidimensional and can be influenced by several baseline, stroke-related, and treatment-related factors, including preexisting cerebrovascular conditions, stroke size and location, and amount of therapy received. Importantly, aphasia recovery can continue for many years after aphasia onset. Behavioral speech and language therapy with a speech-language pathologist is the most common form of aphasia therapy. In this review, the authors also discuss augmentative treatment methodologies, collaborative goal setting frameworks, and recommendations for future research.

Meta-analysis and systematic review of the relationship between sex and the risk or incidence of poststroke aphasia and its types.

OBJECTIVE: To analyse and discuss the association of gender differences with the risk and incidence of poststroke aphasia (PSA) and its types, and to provide evidence-based guidance for the prevention and treatment of poststroke aphasia in clinical practice. DATA SOURCES: Embase, PubMed, Cochrane Library and Web of Science were searched from January 1, 2002, to December 1, 2023. STUDY SELECTION: Including the total number of strokes, aphasia, the number of different sexes or the number of PSA corresponding to different sex. DATA EXTRACTION: Studies with missing data, aphasia caused by nonstroke and noncompliance with the requirements of literature types were excluded. DATA SYNTHESIS: 36 papers were included, from 19 countries. The analysis of 168,259 patients with stroke and 31,058 patients with PSA showed that the risk of PSA was 1.23 times higher in female than in male (OR = 1.23, 95% CI = 1.19-1.29, P < 0.001), with a prevalence of PSA of 31% in men and 36% in women, and an overall prevalence of 34% (P < 0.001). Analysis of the risk of the different types of aphasia in 1,048 patients with PSA showed a high risk in females for global, broca and Wenicke aphasia, and a high risk in males for anomic, conductive and transcortical aphasia, which was not statistically significant by meta-analysis. The incidence of global aphasia (males vs. females, 29% vs. 32%) and broca aphasia (17% vs 19%) were higher in females, and anomic aphasia (19% vs 14%) was higher in males, which was statistically significant (P < 0.05). CONCLUSIONS: There are gender differences in the incidence and types of PSA. The risk of PSA in female is higher than that in male.

Situating word deafness within aphasia recovery: A case report.

Word deafness is a rare neurological disorder often observed following bilateral damage to superior temporal cortex and canonically defined as an auditory modality-specific deficit in word comprehension. The extent to which word deafness is dissociable from aphasia remains unclear given its heterogeneous presentation, and some have consequently posited that word deafness instead represents a stage in recovery from aphasia, where auditory and linguistic processing are affected to varying degrees and improve at differing rates. Here, we report a case of an individual (Mr. C) with bilateral temporal lobe lesions whose presentation evolved from a severe aphasia to an atypical form of word deafness, where auditory linguistic processing was impaired at the sentence level and beyond. We first reconstructed in detail Mr. C's stroke recovery through medical record review and supplemental interviewing. Then, using behavioral testing and multimodal neuroimaging, we documented a predominant auditory linguistic deficit in sentence and narrative comprehension-with markedly reduced behavioral performance and absent brain activation in the language network in the spoken modality exclusively. In contrast, Mr. C displayed near-unimpaired behavioral performance and robust brain activations in the language network for the linguistic processing of words, irrespective of modality. We argue that these findings not only support the view of word deafness as a stage in aphasia recovery but also further instantiate the important role of left superior temporal cortex in auditory linguistic processing.

Circulatory shock associated with left insular stroke and chronic steroid treatment.

BACKGROUND: Damage to the insula has been associated with various types of cardiovascular dysfunction, including arrhythmias and blood pressure imbalances. Acute neuroendocrine disturbances following insular damage have also been described. CASE PRESENTATION: A 50-year-old right-handed man with a left insular ischemic lesion exhibited aphasia and right central VII nerve palsy. Five days after the stroke, the patient exhibited severe bradycardia and hypotension. He had been treated for ocular trauma with prednisone for the preceding 3 weeks. Cortisol and adrenocorticotropic hormone levels indicated secondary adrenal insufficiency. Despite adequate fluid intake, the patient's blood pressure dropped, requiring norepinephrine administration. Midodrine was also initiated, leading to clinical improvement. The therapy was gradually discontinued as vital signs normalized. By Day 24, electrocardiogram monitoring was unremarkable, hormonal levels normalized, and the neurological examination revealed only mild residual speech fluency impairment. Computed tomography scans confirmed a recovering ischemic lesion of the left insula. CONCLUSIONS: This case reveals the inhibitory effect exerted by a left-sided insular stroke on the autonomic system. It also highlights the still largely unexplored neuroendocrine complications of damage to this brain region.

High-Intensity Aphasia Therapy Is Cost-Effective in People With Poststroke Aphasia: Evidence From the COMPARE Trial.

BACKGROUND: Evidence from systematic reviews confirms that speech and language interventions for people with aphasia during the chronic phase after stroke (>6 months) improve word retrieval, functional communication, and communication-related quality of life. However, there is limited evidence of their cost-effectiveness. We aimed to estimate the cost per quality-adjusted life year gained from 2 speech and language therapies compared with usual care in people with aphasia during the chronic phase (median, 2.9 years) after stroke. METHODS: A 3-arm, randomized controlled trial compared constraint-induced aphasia therapy plus (CIAT-Plus) and multimodality aphasia therapy (M-MAT) with usual care in 216 people with chronic aphasia. Participants were administered a standardized questionnaire before intervention and at 12 weeks after the 2-week intervention/control period to ascertain health service utilization, employment changes, and informal caregiver burden. Unit prices from Australian sources were used to estimate costs in 2020. Quality-adjusted life years were estimated using responses to the EuroQol-5 Dimension-3 Level questionnaire. To test uncertainty around the differences in costs and outcomes between groups, bootstrapping was used with the cohorts resampled 1000 times. RESULTS: Overall 201/216 participants were included (mean age, 63 years, 29% moderate or severe aphasia, 61 usual care, 70 CIAT-Plus, 70 M-MAT). There were no statistically significant differences in mean total costs ($13 797 usual care, $17 478 CIAT-Plus, $11 113 M-MAT) and quality-adjusted life years (0.19 usual care, 0.20 CIAT-Plus, 0.20 M-MAT) between groups. In bootstrapped analysis of CIAT-Plus, 21.5% of iterations were likely to result in better outcomes and be cost saving (dominant) compared with usual care. In contrast, 72.4% of iterations were more favorable for M-MAT than usual care. CONCLUSIONS: We observed that both treatments, but especially M-MAT, may result in better outcomes at an acceptable additional cost, or potentially with cost savings. These findings are relevant in advocating for the use of these therapies for chronic aphasia after stroke.

Disentangling neuroplasticity mechanisms in post-stroke language recovery.

A major objective in post-stroke aphasia research is to gain a deeper understanding of neuroplastic mechanisms that drive language recovery, with the ultimate goal of enhancing treatment outcomes. Subsequent to recent advances in neuroimaging techniques, we now have the ability to examine more closely how neural activity patterns change after a stroke. However, the way these neural activity changes relate to language impairments and language recovery is still debated. The aim of this review is to provide a theoretical framework to better investigate and interpret neuroplasticity mechanisms underlying language recovery in post-stroke aphasia. We detail two sets of neuroplasticity mechanisms observed at the synaptic level that may explain functional neuroimaging findings in post-stroke aphasia recovery at the network level: feedback-based homeostatic plasticity and associative Hebbian plasticity. In conjunction with these plasticity mechanisms, higher-order cognitive control processes dynamically modulate neural activity in other regions to meet communication demands, despite reduced neural resources. This work provides a network-level neurobiological framework for understanding neural changes observed in post-stroke aphasia and can be used to define guidelines for personalized treatment development.

Focal Brain Lesions Causing Acquired Amusia Map to a Common Brain Network.

Music is a universal human attribute. The study of amusia, a neurologic music processing deficit, has increasingly elaborated our view on the neural organization of the musical brain. However, lesions causing amusia occur in multiple brain locations and often also cause aphasia, leaving the distinct neural networks for amusia unclear. Here, we utilized lesion network mapping to identify these networks. A systematic literature search was carried out to identify all published case reports of lesion-induced amusia. The reproducibility and specificity of the identified amusia network were then tested in an independent prospective cohort of 97 stroke patients (46 female and 51 male) with repeated structural brain imaging, specifically assessed for both music perception and language abilities. Lesion locations in the case reports were heterogeneous but connected to common brain regions, including bilateral temporoparietal and insular cortices, precentral gyrus, and cingulum. In the prospective cohort, lesions causing amusia mapped to a common brain network, centering on the right superior temporal cortex and clearly distinct from the network causally associated with aphasia. Lesion-induced longitudinal structural effects in the amusia circuit were confirmed as reduction of both gray and white matter volume, which correlated with the severity of amusia. We demonstrate that despite the heterogeneity of lesion locations disrupting music processing, there is a common brain network that is distinct from the language network. These results provide evidence for the distinct neural substrate of music processing, differentiating music-related functions from language, providing a testable target for noninvasive brain stimulation to treat amusia.

Are pharmacotherapeutics effective for treating aphasia?

INTRODUCTION: Aphasia is a communication disorder resulting from stroke and/or neurodegenerative conditions which involve the left cerebral hemisphere. It is a debilitating disorder affecting a person's ability to speak, understand, read, and write. Its impact on daily life necessitates therapeutic strategies to aid patients with aphasia. AREAS COVERED: In this special report, the authors speculate whether current pharmacotherapeutic strategies are effective in treating aphasia. The authors look at aphasia caused by different conditions and how this could impact therapy before providing the reader with their expert perspectives. The aim of this paper is for the reader to gain a clearer understanding of the efficacy of the current pharmacotherapeutic treatment paradigms as well as potential future developments. EXPERT OPINION: The exploration of pharmacotherapy for aphasia in vascular brain disorders and neurodegenerative diseases has received much attention in recent years with various therapeutic strategies having been put forward. In terms of whether pharmacotherapy is effective for the treatment of aphasia, there is still no clear-cut answer. Further research is needed with more studies requiring a greater emphasis on language and communication deficits. Biomarkers may also help clinicians provide their patients with a more personalized treatment plan.

Progressive lesion necrosis is related to increasing aphasia severity in chronic stroke.

BACKGROUND: Volumetric investigations of cortical damage resulting from stroke indicate that lesion size and shape continue to change even in the chronic stage of recovery. However, the potential clinical relevance of continued lesion growth has yet to be examined. In the present study, we investigated the prevalence of lesion expansion and the relationship between expansion and changes in aphasia severity in a large sample of individuals in the chronic stage of aphasia recovery. METHODS: Retrospective structural MRI scans from 104 S survivors with at least 2 observations (k = 301 observations; mean time between scans = 31 months) were included. Lesion demarcation was performed using an automated lesion segmentation software and lesion volumes at each timepoint were subsequently calculated. A linear mixed effects model was conducted to investigate the effect of days between scan on lesion expansion. Finally, we investigated the association between lesion expansion and changes on the Western Aphasia Battery (WAB) in a group of participants assessed and scanned at 2 timepoints (N = 54) using a GLM. RESULTS: Most participants (81 %) showed evidence of lesion expansion. The mixed effects model revealed lesion volumes significantly increase, on average, by 0.02 cc each day (7.3 cc per year) following a scan (p < 0.0001). Change on language performance was significantly associated with change in lesion volume (p = 0.025) and age at stroke (p = 0.031). The results suggest that with every 10 cc increase in lesion size, language performance decreases by 0.9 points, and for every 10-year increase in age at stroke, language performance decreases by 1.9 points. CONCLUSIONS: The present study confirms and extends prior reports that lesion expansion occurs well into the chronic stage of stroke. For the first time, we present evidence that expansion is predictive of longitudinal changes in language performance in individuals with aphasia. Future research should focus on the potential mechanisms that may lead to necrosis in areas surrounding the chronic stroke lesion.

[Transcranial direct current stimulation to enhance training effectiveness in chronic poststroke aphasia-A challenge for recruiting participants]. / Transkranielle Gleichstromstimulation zur Verbesserung der Trainingseffektivität bei chronischer Aphasie nach Schlaganfall ­ wie gelingt die Studienrekrutierung Betroffener?

INTRODUCTION/BACKGROUND: DC_TRAIN_APHASIA is an ongoing multicenter, randomized controlled trial, conducted since November 2019 under the lead of the University Medicine Greifswald (ClinicalTrials.gov Identifier: NCT03930121). The study seeks to determine whether adjuvant transcranial direct current stimulation (tDCS) can increase the effectiveness of a 3­week treatment with intensive speech-language therapy in chronic post-stroke aphasia. MATERIAL AND METHOD: Until the end of 2024, a total of 130 patients are to be included in Germany. Recruitment has been a challenge throughout the study and substantial efforts went into devising innovative recruiting approaches. Standard recruitment strategies were used, such as directly approaching people with aphasia in clinical settings, inpatient and outpatient language rehabilitation facilities, and patient support and advocacy groups, alongside more innovative techniques including radio commercials, dissemination of study information via national television and social media platforms. PROVISIONAL RESULTS: Up until now, 110 patients have been included into the study. The largest short-term response was achieved via television and radio. The largest long-term response was obtained through recruitment via logopaedic and neurological facilities, patient support groups, and social media. Participants served as "testimonials", expressing that they were satisfied with the therapy and the tDCS application. DISCUSSION: The multicenter study DC_TRAIN_APHASIA aims to provide evidence on tDCS as an adjuvant application to increase the effect size of intensive speech-language therapy in chronic post-stroke aphasia. The present review may guide future studies in recruiting samples that involve people with impaired communicative abilities.

The effectiveness and safety of noninvasive brain stimulation technology combined with speech training on aphasia after stroke: A systematic review and meta-analysis.

BACKGROUND: Although the effectiveness of noninvasive brain stimulation (NIBS) technology in assisting rehabilitation is widely recognized, its therapeutic efficacy in patients with poststroke aphasia (PSA) requires further validation. Here, we aimed to explore the efficacy and safety of the NIBS technique combined with speech training in PSA by traditional Meta-analysis and to compare the intervention effects of the 2 NIBS techniques by Network meta-analysis. METHODS: Randomized controlled trials of the NIBS technique combined with speech training for treating PSA in 9 databases, including Web of Science, PubMed, and CNKI, and 2 clinical trial registries were searched by computer. Literature screening was performed using EndNote X9 software, and data analysis and presentation of results were performed using RevMan 5.4.1 and Stata 17.0 software. RESULTS: Screening yielded 17 studies with 1013 patients with PSA. Meta-analysis showed that aphasia quotient scores were higher in the intervention group than in the control group [standardized mean difference (SMD) = 1.06, 95% confidence interval (CI) (0.63, 1.49), Z = 4.80, P < .00001]; Western aphasia battery scores on all 4 subscales were higher than those of the control group, the spontaneous language score is [SMD = 0.62, 95% CI (0.46, 0.78), Z = 7.52, P < .00001], the listening comprehension score is [SMD = 0.46, 95% CI (0.30, 0.62), Z = 5.62, P < .00001], the repetition score is [SMD = 1.14, 95% CI (0.59, 1.70), Z = 4.04, P < .0001], the naming score is [SMD = 1.06, 95% CI (0.79, 1.32), Z = 7.85, P < .00001]; The effective rate of the intervention group was higher than that of the control group [odd ratio = 4.19, 95% CI (2.39, 7.37), Z = 4.99, P < .00001]. The results of the Network meta-analysis showed that the best probability ranking of the 2 NIBS techniques combined with speech training in improving aphasia quotient scores was repetitive transcranial magnetic stimulation group (92.2%) > transcranial direct current stimulation group (55.7%). Regarding safety, it was not found that the NIBS technique combined with speech training to treat PSA increases the risk of adverse reactions. CONCLUSION: The NIBS technique combined with speech training can effectively improve the recovery of language function in PSA patients with minimal adverse effects, and the clinic can give priority to r TMS combined with speech training in treating PSA.

The Intersectionality of Climate Change and Post-Stroke Aphasia.

Persons with communication disabilities including persons with post-stroke aphasia (PWAs) possess a vulnerability to climate change as a result of their communication impairments. The disproportionate effects of climate change are likely to exacerbate preexisting inequities in social determinants of health. Communication disability intersecting with other characteristics subject to discrimination (e.g., race, age, sex, income) may lead to inequities in climate-related adaptive capacity. This article echoes earlier concerns related to climate change and further educates healthcare professionals about the impact of climate change on the global human population, with particular consideration of PWAs. The aims of this article are the following: (1) to broaden the understanding of aphasiologists and clinicians caring for PWAs about climate change and the contributions of human activity (anthropogenic) to this crisis; (2) to describe climate change and its impact on health; (3) to detail the intersectionality of climate and health; (4) to explore climate change and its potential effects on PWAs; and (5) to offer hope through emissions reduction, adaptation, resilience, and immediate change.

The volume and the distribution of premorbid white matter hyperintensities: Impact on post-stroke aphasia.

White matter hyperintensities (WMH) are a radiological manifestation of progressive white matter integrity loss. The total volume and distribution of WMH within the corpus callosum have been associated with pathological cognitive ageing processes but have not been considered in relation to post-stroke aphasia outcomes. We investigated the contribution of both the total volume of WMH, and the extent of WMH lesion load in the corpus callosum to the recovery of language after first-ever stroke. Behavioural and neuroimaging data from individuals (N = 37) with a left-hemisphere stroke were included at the early subacute stage of recovery. Spoken language comprehension and production abilities were assessed using word and sentence-level tasks. Neuroimaging data was used to derive stroke lesion variables (volume and lesion load to language critical regions) and WMH variables (WMH volume and lesion load to three callosal segments). WMH volume did not predict variance in language measures, when considered together with stroke lesion and demographic variables. However, WMH lesion load in the forceps minor segment of the corpus callosum explained variance in early subacute comprehension abilities (t = -2.59, p = .01) together with corrected stroke lesion volume and socio-demographic variables. Premorbid WMH lesions in the forceps minor were negatively associated with early subacute language comprehension after aphasic stroke. This negative impact of callosal WMH on language is consistent with converging evidence from pathological ageing suggesting that callosal WMH disrupt the neural networks supporting a range of cognitive functions.

A literature review and meta-analysis of the optimal factors study of repetitive transcranial magnetic stimulation in post-infarction aphasia.

BACKGROUND: The existing literature indicates that repetitive transcranial magnetic stimulation (rTMS) can potentially enhance the prognosis of poststroke aphasia (PSA). Nevertheless, these investigations did not identify the most effective parameters or settings for achieving optimal treatment outcomes. This study involved a meta-analysis aimed to identify the optimal variables for rTMS in treating post-infarction aphasia to guide the use of rTMS in rehabilitating PSA. METHODS: PubMed, Embase, and Cochrane Library databases were searched from inception to May 2023, and articles were reviewed manually using subject words and free words and supplemented with references from the included literature to obtain additional relevant literature. The search terms included "poststroke aphasia" and "repetitive transcranial magnetic stimulation (rTMS)" repetitive transcranial magnetic stimulation. Additionally, a review of the reference lists of previously published systematic reviews identified through the Cochrane Database of Systematic Reviews (search terms: poststroke aphasia, rTMS; restrictions: none) and PubMed (search terms: poststroke aphasia, rTMSs; restrictions: systematic review or meta-analysis) was performed. Information from studies involving different doses of rTMS in PSA was independently screened and extracted by 2 researchers. RESULTS: This meta-analysis included 387 participants with PSA across 18 randomized controlled trials. The results showed that the total pulse had a trend toward a significant correlation with the treatment effect (P = 0.088), while all other variables did not correlate significantly. When rTMS was not grouped by stimulus parameter and location, our nonlinear results showed that when the total pulses were 40,000 (standardized mean difference (SMD):1.86, 95% credible interval (CrI) 0.50 to 3.33), the pulse/session was 1000 (SMD:1.05, 95% CrI 0.55-1.57), and an RMT of 80% (SMD:1.08, 95% CrI 0.60-1.57) had the best treatment effect. When rTMS was grouped by stimulus parameters and location, our nonlinear results showed that when the total low-frequency (LF)-rTMS-right inferior frontal gyrus (RIFG) pulse was 40,000 (SMD:1.76, 95% CrI:0.36-3.29), the pulse/session was 1000 (SMD:1.06, 95% CrI:0.54-1.59). Optimal results were obtained with an RMT of 80% (SMD:1.14, 95% CrI 0.54 - 1.76). CONCLUSIONS: The optimal treatment effects of rTMS for PSA may be obtained with a total pulse of 40,000, a pulse/session of 1000, and an RMT of 80%. Further rigorous randomized controlled studies are required to substantiate the validity of these results.