Global and localized network characteristics of the resting brain predict and adapt to foreign language learning in older adults

Resting brain (rs) activity has been shown to be a reliable predictor of the level of foreign language (L2) proficiency younger adults can achieve in a given time-period. Since rs properties change over the lifespan, we investigated whether L2 attainment in older adults (aged 64–74 years) is also predicted by individual differences in rs activity, and to what extent rs activity itself changes as a function of L2 proficiency. To assess how neuronal assemblies communicate at specific frequencies to facilitate L2 development, we examined localized and global measures (Minimum Spanning Trees) of connectivity. Results showed that central organization within the beta band (~ 13–29.5 Hz) predicted measures of L2 complexity, fluency and accuracy, with the latter additionally predicted by a left-lateralized centro-parietal beta network. In contrast, reduced connectivity in a right-lateralized alpha (~ 7.5–12.5 Hz) network predicted development of L2 complexity. As accuracy improved, so did central organization in beta, whereas fluency improvements were reflected in localized changes within an interhemispheric beta network. Our findings highlight the importance of global and localized network efficiency and the role of beta oscillations for L2 learning and suggest plasticity even in the ageing brain. We interpret the findings against the background of networks identified in socio-cognitive processes

FSHB Genotype Identified as a Relevant Diagnostic Parameter Revealed by Cluster Analysis of Men With Idiopathic Infertility

Introduction and ObjectivesAbout 30-75% of infertile men are diagnosed with idiopathic infertility, thereby lacking major causative factors to explain their impaired fertility status. In this study, we used a large cohort of idiopathic infertile men to determine whether subgroups could be identified by an unbiased clustering approach and whether underlying etiologic factors could be delineated. Patients and MethodsFrom our in-house database Androbase(R), we retrospectively selected patients (from 2008 to 2018) with idiopathic male infertility (azoo- to normozoospermia) who fit the following selection criteria: FSH >= 1 IU/l, testosterone >= 8 nmol/l, ejaculate volume >= 1.5 ml. Patients with genetic abnormalities or partners with female factors were excluded.For the identified study population (n=2742), we used common andrologic features (somatic, semen and hormonal parameters, including the FSHB c.-211G>T (rs10835638) single nucleotide polymorphism) for subsequent analyses. Cluster analyses were performed for the entire study population and for two sub-cohorts, which were separated by total sperm count (TSC) thresholds: Cohort A (TSC >= 1 mill/ejac; n=2422) and Cohort B (TSC < 1 mill/ejac; n=320). For clustering, the partitioning around medoids method was employed, and the quality was evaluated by average silhouette width. ResultsThe applied cluster approach for the whole study population yielded two separate clusters, which showed significantly different distributions in bi-testicular volume, FSH and FSHB genotype. Cluster 1 contained all men homozygous for G (wildtype) in FSHB c.-211G>T (100%), while Cluster 2 contained most patients carrying a T allele (>96.6%). In the analyses of sub-cohorts A/B, two clusters each were formed too. Again, the strongest segregation markers between the respective clusters were bi-testicular volume, FSH and FSHB c.-211G>T. ConclusionWith this first unbiased approach for revealing putative subgroups within a heterogenous group of idiopathic infertile men, we did indeed identify distinct patient clusters. Surprisingly, across all diverse phenotypes of infertility, the strongest segregation markers were FSHB c.-211G>T, FSH, and bi-testicular volume. Further, Cohorts A and B were significantly separated by FSHB genotype (wildtype vs. T-allele carriers), which supports the notion of a contributing genetic factor. Consequently, FSHB genotyping should be implemented as diagnostic routine in patients with idiopathic infertility

Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility

We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DR beta 1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition. A GWAS in a large case-control cohort of European ancestry identifies two genomic regions, the MHC class II gene HLA-DRB1 and an upstream locus of VRK1, that are associated with the most severe phenotype of spermatogenic failure

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry

Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p <.001. Over 24 months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10 ml/min/1.73 m2 decrease), that was most notable in patients with eGFR <30 ml/min/1.73 m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

EEG Resting-State and Event-Related Potentials as Markers of Learning Success in Older Adults Following Second Language Training: A Pilot Study

Objectives: In this pilot study, we evaluated the use of electrophysiological measures at rest as paradigm-independent predictors of second language (L2) development for the first time in older adult learners. We then assessed EEG correlates of the learning outcome in a language-switching paradigm after the training, which to date has only been done in younger adults and at intermediate to advanced L2 proficiency. Methods: Ten (Swiss) German-speaking adults between 65–74 years of age participated in an intensive 3-week English training for beginners. A resting-state EEG was recorded before the training to predict the ensuing L2 development (Experiment 1). A language-switching ERP experiment was conducted after the training to assess the learning outcome (Experiment 2). Results: All participants improved their L2 skills but differed noticeably in their individual development. Experiment 1 showed that beta1 oscillations at rest (13–14.5 Hz) predicted these individual differences. We interpret resting-state beta1 oscillations as correlates of attentional capacities and semantic working memory that facilitate the extraction and processing of novel forms and meanings from the L2 input. In Experiment 2, we found that language switching from the L2 into the native language (L1) elicited an N400 component, which was reduced in the more advanced learners. Thus, for learners beginning the acquisition of an L2 in third age, language switching appears to become less effortful with increasing proficiency, suggesting that the lexicons of the L1 and L2 become more closely linked. Conclusions: In sum, our findings extend the available evidence of neurological processes in L2 learning from younger to older adults, suggesting that electrophysiological mechanisms are similar across the lifespan

Global and localized network characteristics of the resting brain predict and adapt to foreign language learning in older adults

Resting brain (rs) activity has been shown to be a reliable predictor of the level of foreign language (L2) proficiency younger adults can achieve in a given time-period. Since rs properties change over the lifespan, we investigated whether L2 attainment in older adults (aged 64-74 years) is also predicted by individual differences in rs activity, and to what extent rs activity itself changes as a function of L2 proficiency. To assess how neuronal assemblies communicate at specific frequencies to facilitate L2 development, we examined localized and global measures (Minimum Spanning Trees) of connectivity. Results showed that central organization within the beta band (~ 13-29.5 Hz) predicted measures of L2 complexity, fluency and accuracy, with the latter additionally predicted by a left-lateralized centro-parietal beta network. In contrast, reduced connectivity in a right-lateralized alpha (~ 7.5-12.5 Hz) network predicted development of L2 complexity. As accuracy improved, so did central organization in beta, whereas fluency improvements were reflected in localized changes within an interhemispheric beta network. Our findings highlight the importance of global and localized network efficiency and the role of beta oscillations for L2 learning and suggest plasticity even in the ageing brain. We interpret the findings against the background of networks identified in socio-cognitive processes.ISSN:2045-232

Word stress processing integrates phonological abstraction with lexical access – An ERP study

It is unclear whether word stress in a language is stored as part of the word or whether it is generated by a rule. We test the generativist hypothesis of lexical storage stating that only unpredictable stress is stored in long-term memory against the contrasting usage-based approach assuming that all phonetic information regardless of its (un)predictability is stored in the mental lexicon together with the word. In a correctness judgment task involving correctly and incorrectly stressed penults and antepenults, we found that incorrectly stressed penults do not evoke an N400 effect, whereas incorrectly stressed antepenults do: there is increased negativity with a peak latency around 350–600 ms from word onset. Only changes to words with exceptional stress cause lexical inhibition, hence exceptional but not default stress markers are stored in the lexicon. Additionally, differences in processing patterns between the N400 and the late positivity component window point to an integration of two stages of word processing: pre-lexical stress recognition and stress-to-meaning matching. The results of the study support the view that stress should be understood as abstract phonological information