Polypill Strategy in Secondary Cardiovascular Prevention.

BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

Neural dynamics differentially encode phrases and sentences during spoken language comprehension.

Human language stands out in the natural world as a biological signal that uses a structured system to combine the meanings of small linguistic units (e.g., words) into larger constituents (e.g., phrases and sentences). However, the physical dynamics of speech (or sign) do not stand in a one-to-one relationship with the meanings listeners perceive. Instead, listeners infer meaning based on their knowledge of the language. The neural readouts of the perceptual and cognitive processes underlying these inferences are still poorly understood. In the present study, we used scalp electroencephalography (EEG) to compare the neural response to phrases (e.g., the red vase) and sentences (e.g., the vase is red), which were close in semantic meaning and had been synthesized to be physically indistinguishable. Differences in structure were well captured in the reorganization of neural phase responses in delta (approximately <2 Hz) and theta bands (approximately 2 to 7 Hz),and in power and power connectivity changes in the alpha band (approximately 7.5 to 13.5 Hz). Consistent with predictions from a computational model, sentences showed more power, more power connectivity, and more phase synchronization than phrases did. Theta-gamma phase-amplitude coupling occurred, but did not differ between the syntactic structures. Spectral-temporal response function (STRF) modeling revealed different encoding states for phrases and sentences, over and above the acoustically driven neural response. Our findings provide a comprehensive description of how the brain encodes and separates linguistic structures in the dynamics of neural responses. They imply that phase synchronization and strength of connectivity are readouts for the constituent structure of language. The results provide a novel basis for future neurophysiological research on linguistic structure representation in the brain, and, together with our simulations, support time-based binding as a mechanism of structure encoding in neural dynamics.

Delta-Band Neural Responses to Individual Words Are Modulated by Sentence Processing.

To understand language, we need to recognize words and combine them into phrases and sentences. During this process, responses to the words themselves are changed. In a step toward understanding how the brain builds sentence structure, the present study concerns the neural readout of this adaptation. We ask whether low-frequency neural readouts associated with words change as a function of being in a sentence. To this end, we analyzed an MEG dataset by Schoffelen et al. (2019) of 102 human participants (51 women) listening to sentences and word lists, the latter lacking any syntactic structure and combinatorial meaning. Using temporal response functions and a cumulative model-fitting approach, we disentangled delta- and theta-band responses to lexical information (word frequency), from responses to sensory and distributional variables. The results suggest that delta-band responses to words are affected by sentence context in time and space, over and above entropy and surprisal. In both conditions, the word frequency response spanned left temporal and posterior frontal areas; however, the response appeared later in word lists than in sentences. In addition, sentence context determined whether inferior frontal areas were responsive to lexical information. In the theta band, the amplitude was larger in the word list condition ∼100 milliseconds in right frontal areas. We conclude that low-frequency responses to words are changed by sentential context. The results of this study show how the neural representation of words is affected by structural context and as such provide insight into how the brain instantiates compositionality in language.SIGNIFICANCE STATEMENT Human language is unprecedented in its combinatorial capacity: we are capable of producing and understanding sentences we have never heard before. Although the mechanisms underlying this capacity have been described in formal linguistics and cognitive science, how they are implemented in the brain remains to a large extent unknown. A large body of earlier work from the cognitive neuroscientific literature implies a role for delta-band neural activity in the representation of linguistic structure and meaning. In this work, we combine these insights and techniques with findings from psycholinguistics to show that meaning is more than the sum of its parts; the delta-band MEG signal differentially reflects lexical information inside and outside sentence structures.

IDLaS-NL - A platform for running customized studies on individual differences in Dutch language skills via the Internet.

We introduce the Individual Differences in Language Skills (IDLaS-NL) web platform, which enables users to run studies on individual differences in Dutch language skills via the Internet. IDLaS-NL consists of 35 behavioral tests, previously validated in participants aged between 18 and 30 years. The platform provides an intuitive graphical interface for users to select the tests they wish to include in their research, to divide these tests into different sessions and to determine their order. Moreover, for standardized administration the platform provides an application (an emulated browser) wherein the tests are run. Results can be retrieved by mouse click in the graphical interface and are provided as CSV file output via e-mail. Similarly, the graphical interface enables researchers to modify and delete their study configurations. IDLaS-NL is intended for researchers, clinicians, educators and in general anyone conducting fundamental research into language and general cognitive skills; it is not intended for diagnostic purposes. All platform services are free of charge. Here, we provide a description of its workings as well as instructions for using the platform. The IDLaS-NL platform can be accessed at www.mpi.nl/idlas-nl .

Linguistic Structure and Meaning Organize Neural Oscillations into a Content-Specific Hierarchy.

Neural oscillations track linguistic information during speech comprehension (Ding et al., 2016; Keitel et al., 2018), and are known to be modulated by acoustic landmarks and speech intelligibility (Doelling et al., 2014; Zoefel and VanRullen, 2015). However, studies investigating linguistic tracking have either relied on non-naturalistic isochronous stimuli or failed to fully control for prosody. Therefore, it is still unclear whether low-frequency activity tracks linguistic structure during natural speech, where linguistic structure does not follow such a palpable temporal pattern. Here, we measured electroencephalography (EEG) and manipulated the presence of semantic and syntactic information apart from the timescale of their occurrence, while carefully controlling for the acoustic-prosodic and lexical-semantic information in the signal. EEG was recorded while 29 adult native speakers (22 women, 7 men) listened to naturally spoken Dutch sentences, jabberwocky controls with morphemes and sentential prosody, word lists with lexical content but no phrase structure, and backward acoustically matched controls. Mutual information (MI) analysis revealed sensitivity to linguistic content: MI was highest for sentences at the phrasal (0.8-1.1 Hz) and lexical (1.9-2.8 Hz) timescales, suggesting that the delta-band is modulated by lexically driven combinatorial processing beyond prosody, and that linguistic content (i.e., structure and meaning) organizes neural oscillations beyond the timescale and rhythmicity of the stimulus. This pattern is consistent with neurophysiologically inspired models of language comprehension (Martin, 2016, 2020; Martin and Doumas, 2017) where oscillations encode endogenously generated linguistic content over and above exogenous or stimulus-driven timing and rhythm information.SIGNIFICANCE STATEMENT Biological systems like the brain encode their environment not only by reacting in a series of stimulus-driven responses, but by combining stimulus-driven information with endogenous, internally generated, inferential knowledge and meaning. Understanding language from speech is the human benchmark for this. Much research focuses on the purely stimulus-driven response, but here, we focus on the goal of language behavior: conveying structure and meaning. To that end, we use naturalistic stimuli that contrast acoustic-prosodic and lexical-semantic information to show that, during spoken language comprehension, oscillatory modulations reflect computations related to inferring structure and meaning from the acoustic signal. Our experiment provides the first evidence to date that compositional structure and meaning organize the oscillatory response, above and beyond prosodic and lexical controls.

Speaking in the Brain: The Interaction between Words and Syntax in Sentence Production.

This neuroimaging study investigated the neural infrastructure of sentence-level language production. We compared brain activation patterns, as measured with BOLD-fMRI, during production of sentences that differed in verb argument structures (intransitives, transitives, ditransitives) and the lexical status of the verb (known verbs or pseudoverbs). The experiment consisted of 30 mini-blocks of six sentences each. Each mini-block started with an example for the type of sentence to be produced in that block. On each trial in the mini-blocks, participants were first given the (pseudo-)verb followed by three geometric shapes to serve as verb arguments in the sentences. Production of sentences with known verbs yielded greater activation compared to sentences with pseudoverbs in the core language network of the left inferior frontal gyrus, the left posterior middle temporal gyrus, and a more posterior middle temporal region extending into the angular gyrus, analogous to effects observed in language comprehension. Increasing the number of verb arguments led to greater activation in an overlapping left posterior middle temporal gyrus/angular gyrus area, particularly for known verbs, as well as in the bilateral precuneus. Thus, producing sentences with more complex structures using existing verbs leads to increased activation in the language network, suggesting some reliance on memory retrieval of stored lexical-syntactic information during sentence production. This study thus provides evidence from sentence-level language production in line with functional models of the language network that have so far been mainly based on single-word production, comprehension, and language processing in aphasia.

[Ethics University on Regenerative Medicine - As an Instrument for the Development of Valid Public Opinions?] / Ethik-Universität zur Regenerativen Medizin ­ ein Instrument der fundierten Meinungsbildung für Laien?

OBJECTIVES: In 2016, we invited interested citizens to participate in the "ethics university on regenerative medicine" at Hannover Medical School. The present study analyses if and how this discursive and informative event inspired participants to form their own opinion on the issues at hand and to develop their general ethics literacy. METHODS: The "ethics university" was performed twice in 2016; each run consisted of four single consecutive events. Lectures were combined with interactive learning stations, and group discussions. Opinions and information level of all participants were surveyed by means of a postal questionnaire before and after the course to detect any changes of opinions and information levels; additionally, we surveyed participants' self-assessment. Participants of the second run were asked to form a waiting list control group to compare results from first run-participants. Furthermore, we conducted a content analysis of group discussions during the ethics university. RESULTS: Of 168 participants of both runs, 101 took part in the pre/post-survey. In addition, 30 questionnaires of the waiting list control group were analysed. Participants showed a higher level of information after the ethics university (changes between 0.75 and 1.93 points on a five-point scale). Between 50.5 and 66.0% of participants indicated that their opinion on different issues had become either more affirmative or more disapprobative as a result of attending the ethics university. On average, opinions were more positive after participation (between 0.44 and 1.0 points on a 5-point scale). Respondents in the waiting list control group showed no changes in opinion or information level. Participants themselves felt that they formed their opinions mainly on the basis of information they received in lectures, conversations with experts, interactive learning sessions, and written information. However, for many participants, interacting with other participants in the group discussions, as well as reflecting their own views was an important to forming informed opinions. CONCLUSION: Results of the evaluation show that participants were inspired to form their own opinions by the ethics university and to develop their ethics literacy (e. g. ability to reflect on normative questions). For future ethics universities, the group of participants should be as diverse as possible. In addition, interactive and discursive elements should be given a higher priority.

Larger communities create more systematic languages.

Understanding worldwide patterns of language diversity has long been a goal for evolutionary scientists, linguists and philosophers. Research over the past decade has suggested that linguistic diversity may result from differences in the social environments in which languages evolve. Specifically, recent work found that languages spoken in larger communities typically have more systematic grammatical structures. However, in the real world, community size is confounded with other social factors such as network structure and the number of second languages learners in the community, and it is often assumed that linguistic simplification is driven by these factors instead. Here, we show that in contrast to previous assumptions, community size has a unique and important influence on linguistic structure. We experimentally examine the live formation of new languages created in the laboratory by small and larger groups, and find that larger groups of interacting participants develop more systematic languages over time, and do so faster and more consistently than small groups. Small groups also vary more in their linguistic behaviours, suggesting that small communities are more vulnerable to drift. These results show that community size predicts patterns of language diversity, and suggest that an increase in community size might have contributed to language evolution.

The production effect and the generation effect improve memory in picture naming.

The production effect (better memory for words read aloud than words read silently) and the picture superiority effect (better memory for pictures than words) both improve item memory in a picture naming task (Fawcett, J. M., Quinlan, C. K., & Taylor, T. L. (2012). Interplay of the production and picture superiority effects: A signal detection analysis. Memory (Hove, England), 20(7), 655-666. doi: 10.1080/09658211.2012.693510 ). Because picture naming requires coming up with an appropriate label, the generation effect (better memory for generated than read words) may contribute to the latter effect. In two forced-choice memory experiments, we tested the role of generation in a picture naming task on later recognition memory. In Experiment 1, participants named pictures silently or aloud with the correct name or an unreadable label superimposed. We observed a generation effect, a production effect, and an interaction between the two. In Experiment 2, unreliable labels were included to ensure full picture processing in all conditions. In this experiment, we observed a production and a generation effect but no interaction, implying the effects are dissociable. This research demonstrates the separable roles of generation and production in picture naming and their impact on memory. As such, it informs the link between memory and language production and has implications for memory asymmetries between language production and comprehension.

Listeners normalize speech for contextual speech rate even without an explicit recognition task.

Speech can be produced at different rates. Listeners take this rate variation into account by normalizing vowel duration for contextual speech rate: An ambiguous Dutch word /m?t/ is perceived as short /mɑt/ when embedded in a slow context, but long /ma:t/ in a fast context. While some have argued that this rate normalization involves low-level automatic perceptual processing, there is also evidence that it arises at higher-level cognitive processing stages, such as decision making. Prior research on rate-dependent speech perception has only used explicit recognition tasks to investigate the phenomenon, involving both perceptual processing and decision making. This study tested whether speech rate normalization can be observed without explicit decision making, using a cross-modal repetition priming paradigm. Results show that a fast precursor sentence makes an embedded ambiguous prime (/m?t/) sound (implicitly) more /a:/-like, facilitating lexical access to the long target word "maat" in a (explicit) lexical decision task. This result suggests that rate normalization is automatic, taking place even in the absence of an explicit recognition task. Thus, rate normalization is placed within the realm of everyday spoken conversation, where explicit categorization of ambiguous sounds is rare.

Planning to speak in L1 and L2.

The leading theories of sentence planning - Hierarchical Incrementality and Linear Incrementality - differ in their assumptions about the coordination of processes that map preverbal information onto language. Previous studies showed that, in native (L1) speakers, this coordination can vary with the ease of executing the message-level and sentence-level processes necessary to plan and produce an utterance. We report the first series of experiments to systematically examine how linguistic experience influences sentence planning in native (L1) speakers (i.e., speakers with life-long experience using the target language) and non-native (L2) speakers (i.e., speakers with less experience using the target language). In all experiments, speakers spontaneously generated one-sentence descriptions of simple events in Dutch (L1) and English (L2). Analyses of eye-movements across early and late time windows (pre- and post-400 ms) compared the extent of early message-level encoding and the onset of linguistic encoding. In Experiment 1, speakers were more likely to engage in extensive message-level encoding and to delay sentence-level encoding when using their L2. Experiments 2-4 selectively facilitated encoding of the preverbal message, encoding of the agent character (i.e., the first content word in active sentences), and encoding of the sentence verb (i.e., the second content word in active sentences) respectively. Experiment 2 showed that there is no delay in the onset of L2 linguistic encoding when speakers are familiar with the events. Experiments 3 and 4 showed that the delay in the onset of L2 linguistic encoding is not due to speakers delaying encoding of the agent, but due to a preference to encode information needed to select a suitable verb early in the formulation process. Overall, speakers prefer to temporally separate message-level from sentence-level encoding and to prioritize encoding of relational information when planning L2 sentences, consistent with Hierarchical Incrementality.

The combined use of virtual reality and EEG to study language processing in naturalistic environments.

When we comprehend language, we often do this in rich settings where we can use many cues to understand what someone is saying. However, it has traditionally been difficult to design experiments with rich three-dimensional contexts that resemble our everyday environments, while maintaining control over the linguistic and nonlinguistic information that is available. Here we test the validity of combining electroencephalography (EEG) and virtual reality (VR) to overcome this problem. We recorded electrophysiological brain activity during language processing in a well-controlled three-dimensional virtual audiovisual environment. Participants were immersed in a virtual restaurant while wearing EEG equipment. In the restaurant, participants encountered virtual restaurant guests. Each guest was seated at a separate table with an object on it (e.g., a plate with salmon). The restaurant guest would then produce a sentence (e.g., "I just ordered this salmon."). The noun in the spoken sentence could either match ("salmon") or mismatch ("pasta") the object on the table, creating a situation in which the auditory information was either appropriate or inappropriate in the visual context. We observed a reliable N400 effect as a consequence of the mismatch. This finding validates the combined use of VR and EEG as a tool to study the neurophysiological mechanisms of everyday language comprehension in rich, ecologically valid settings.

AlignTool: The automatic temporal alignment of spoken utterances in German, Dutch, and British English for psycholinguistic purposes.

In language production research, the latency with which speakers produce a spoken response to a stimulus and the onset and offset times of words in longer utterances are key dependent variables. Measuring these variables automatically often yields partially incorrect results. However, exact measurements through the visual inspection of the recordings are extremely time-consuming. We present AlignTool, an open-source alignment tool that establishes preliminarily the onset and offset times of words and phonemes in spoken utterances using Praat, and subsequently performs a forced alignment of the spoken utterances and their orthographic transcriptions in the automatic speech recognition system MAUS. AlignTool creates a Praat TextGrid file for inspection and manual correction by the user, if necessary. We evaluated AlignTool's performance with recordings of single-word and four-word utterances as well as semi-spontaneous speech. AlignTool performs well with audio signals with an excellent signal-to-noise ratio, requiring virtually no corrections. For audio signals of lesser quality, AlignTool still is highly functional but its results may require more frequent manual corrections. We also found that audio recordings including long silent intervals tended to pose greater difficulties for AlignTool than recordings filled with speech, which AlignTool analyzed well overall. We expect that by semi-automatizing the temporal analysis of complex utterances, AlignTool will open new avenues in language production research.

Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer's Disease-Studies on Relation to Effective Target Occupancy.

Numerous studies suggest that the majority of amyloid-ß (Aß) peptides deposited in Alzheimer's disease (AD) are truncated and post-translationally modified at the N terminus. Among these modified species, pyroglutamyl-Aß (pE-Aß, including N3pE-Aß40/42 and N11pE-Aß40/42) has been identified as particularly neurotoxic. The N-terminal modification renders the peptide hydrophobic, accelerates formation of oligomers, and reduces degradation by peptidases, leading ultimately to the accumulation of the peptide and progression of AD. It has been shown that the formation of pyroglutamyl residues is catalyzed by glutaminyl cyclase (QC). Here, we present data about the pharmacological in vitro and in vivo efficacy of the QC inhibitor (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one (PQ912), the first-in-class compound that is in clinical development. PQ912 inhibits human, rat, and mouse QC activity, with Ki values ranging between 20 and 65 nM. Chronic oral treatment of hAPPSLxhQC double-transgenic mice with approximately 200 mg/kg/day via chow shows a significant reduction of pE-Aß levels and concomitant improvement of spatial learning in a Morris water maze test paradigm. This dose results in a brain and cerebrospinal fluid concentration of PQ912 which relates to a QC target occupancy of about 60%. Thus, we conclude that >50% inhibition of QC activity in the brain leads to robust treatment effects. Secondary pharmacology experiments in mice indicate a fairly large potency difference for Aß cyclization compared with cyclization of physiologic substrates, suggesting a robust therapeutic window in humans. This information constitutes an important translational guidance for predicting the therapeutic dose range in clinical studies with PQ912.

Picture naming in typically developing and language-impaired children: the role of sustained attention.

BACKGROUND: Children with specific language impairment (SLI) have problems not only with language performance but also with sustained attention, which is the ability to maintain alertness over an extended period of time. Although there is consensus that this ability is impaired with respect to processing stimuli in the auditory perceptual modality, conflicting evidence exists concerning the visual modality. AIMS: To address the outstanding issue whether the impairment in sustained attention is limited to the auditory domain, or if it is domain-general. Furthermore, to test whether children's sustained attention ability relates to their word-production skills. METHODS & PROCEDURES: Groups of 7-9 year olds with SLI (N = 28) and typically developing (TD) children (N = 22) performed a picture-naming task and two sustained attention tasks, namely auditory and visual continuous performance tasks (CPTs). OUTCOMES & RESULTS: Children with SLI performed worse than TD children on picture naming and on both the auditory and visual CPTs. Moreover, performance on both the CPTs correlated with picture-naming latencies across developmental groups. CONCLUSIONS & IMPLICATIONS: These results provide evidence for a deficit in both auditory and visual sustained attention in children with SLI. Moreover, the study indicates there is a relationship between domain-general sustained attention and picture-naming performance in both TD and language-impaired children. Future studies should establish whether this relationship is causal. If attention influences language, training of sustained attention may improve language production in children from both developmental groups.

Structural priming is not a Royal Road to representations.

Branigan & Pickering (B&P) propose that the structural priming paradigm is a Royal Road to linguistic representations of any kind, unobstructed by influences of psychological processes. In my view, however, they are too optimistic about the versatility of the paradigm and, more importantly, its ability to provide direct evidence about the nature of stored linguistic representations.

Effects of Word Frequency and Transitional Probability on Word Reading Durations of Younger and Older Speakers.

High-frequency units are usually processed faster than low-frequency units in language comprehension and language production. Frequency effects have been shown for words as well as word combinations. Word co-occurrence effects can be operationalized in terms of transitional probability (TP). TPs reflect how probable a word is, conditioned by its right or left neighbouring word. This corpus study investigates whether three different age groups-younger children (8-12 years), adolescents (12-18 years) and older (62-95 years) Dutch speakers-show frequency and TP context effects on spoken word durations in reading aloud, and whether age groups differ in the size of these effects. Results show consistent effects of TP on word durations for all age groups. Thus, TP seems to influence the processing of words in context, beyond the well-established effect of word frequency, across the entire age range. However, the study also indicates that age groups differ in the size of TP effects, with older adults having smaller TP effects than adolescent readers. Our results show that probabilistic reduction effects in reading aloud may at least partly stem from contextual facilitation that leads to faster reading times in skilled readers, as well as in young language learners.

Relative Leukocyte Telomere Length, Hematological Parameters and Anemia - Data from the Berlin Aging Study II (BASE-II).

BACKGROUND: The length of the chromosome ends, telomeres, is widely accepted as a biomarker of aging. However, the dynamic of the relationship between telomere length and hematopoietic parameters in the normal aging process, which is of particular interest with respect to age-related anemia, is not well understood. OBJECTIVE: We have analyzed the relationship between relative leukocyte telomere length (rLTL) and several hematological parameters in the older group of the Berlin Aging Study II (BASE-II) participants. This paper also compares rLTL between both BASE-II age groups (22-37 and 60-83 years). METHODS: Genomic DNA was extracted from peripheral blood leukocytes of BASE-II participants and used to determine rLTL by a quantitative PCR protocol. Standard methods were used to determine blood parameters, and the WHO criteria were used to identify anemic participants. RESULTS: Telomere length data were available for 444 younger participants (28.4 ± 3.1 years old; 52% women) and 1,460 older participants (68.2 ± 3.7 years old; 49.4% women). rLTL was significantly shorter in BASE-II participants of the older group (p = 3.7 × 10-12) and in women (p = 4.2 × 10-31). rLTL of older men exhibited a statistically significant, positive partial correlation with mean corpuscular hemoglobin (MCH; p = 0.012) and MCH concentration (p = 0.002). While these correlations were only observed in men, the rLTL of older women was negatively correlated with the number of thrombocytes (p = 0.015) in the same type of analysis. Among all older participants, 6% met the criteria to be categorized as 'anemic'; however, there was no association between anemia and rLTL. CONCLUSION: In the present study, we have detected isolated correlations between rLTL and hematological parameters; however, in all cases, rLTL explained only a small part of the variation of the analyzed parameters. In disagreement with some other studies showing similar data, we interpret the association between rLTL and some of the hematological parameters studied here to be at most marginal. This applies also to the role of rLTL in anemia, at least in the age group investigated here. Since BASE-II is yet another large cohort in which women have on average shorter telomeres than men, this finding will be addressed in the discussion with respect to the ongoing debate on gender differences in telomere length.

Genetic Burden Analyses of Phenotypes Relevant to Aging in the Berlin Aging Study II (BASE-II).

BACKGROUND: Body mass index (BMI), bone mineral density (BMD), and telomere length are phenotypes that modulate the course of aging. Over 40% of their phenotypic variance is determined by genetics. Genome-wide association studies (GWAS) have recently uncovered >100 independent single-nucleotide polymorphisms (SNPs) showing genome-wide significant (p < 5 × 10-8) association with these traits. OBJECTIVE: To test the individual and combined impact of previously reported GWAS SNPs on BMI, BMD, and relative leukocyte telomere length (rLTL) in ∼1,750 participants of the Berlin Aging Study II (BASE-II), a cohort consisting predominantly of individuals >60 years of age. METHODS: Linear regression analyses were performed on a total of 101 SNPs and BMI, BMD measurements of the femoral neck (FN) and lumbar spine (LS), and rLTL. The combined effect of all trait-specific SNPs was evaluated by generating a weighted genomic profile score (wGPS) used in the association analyses. The predictive capability of the wGPS was estimated by determining the area under the receiver operating curve (AUC) for osteoporosis status (determined by BMD) with and without the wGPS. RESULTS: Five loci showed experiment-wide significant association with BMI (FTO rs1558902, p = 1.80 × 10-5) or BMD (MEPE rs6532023, pFN = 5.40 × 10-4, pLS = 1.09 × 10-4; TNFRSF11B rs2062377, pLS = 8.70 × 10-4; AKAP11 rs9533090, pLS = 1.05 × 10-3; SMG6 rs4790881, pFN = 3.41 × 10-4) after correction for multiple testing. Several additional loci showed nominally significant (p < 0.05) association with BMI and BMD. The trait-specific wGPS was highly significantly associated with BMD (p < 2 × 10-16) and BMI (p = 1.10 × 10-6). No significant association was detected for rLTL in either single-SNP or wGPS-based analyses. The AUC for osteoporosis improved modestly from 0.762 (95% CI 0.733-0.800) to 0.786 (95% CI 0.756-0.823) and 0.785 (95% CI 0.757-0.824) upon inclusion of the FN- and LS-BMD wGPS, respectively. CONCLUSION: Our study provides an independent validation of previously reported genetic association signals for BMI and BMD in the BASE-II cohort. Additional studies are needed to pinpoint the factors underlying the proportion of phenotypic variance that remains unexplained by the current models.

Priming sentence planning.

Sentence production requires mapping preverbal messages onto linguistic structures. Because sentences are normally built incrementally, the information encoded in a sentence-initial increment is critical for explaining how the mapping process starts and for predicting its timecourse. Two experiments tested whether and when speakers prioritize encoding of different types of information at the outset of formulation by comparing production of descriptions of transitive events (e.g., A dog is chasing the mailman) that differed on two dimensions: the ease of naming individual characters and the ease of apprehending the event gist (i.e., encoding the relational structure of the event). To additionally manipulate ease of encoding, speakers described the target events after receiving lexical primes (facilitating naming; Experiment 1) or structural primes (facilitating generation of a linguistic structure; Experiment 2). Both properties of the pictured events and both types of primes influenced the form of target descriptions and the timecourse of formulation: character-specific variables increased the probability of speakers encoding one character with priority at the outset of formulation, while the ease of encoding event gist and of generating a syntactic structure increased the likelihood of early encoding of information about both characters. The results show that formulation is flexible and highlight some of the conditions under which speakers might employ different planning strategies.