The language network as a natural kind within the broader landscape of the human brain.

Language behaviour is complex, but neuroscientific evidence disentangles it into distinct components supported by dedicated brain areas or networks. In this Review, we describe the 'core' language network, which includes left-hemisphere frontal and temporal areas, and show that it is strongly interconnected, independent of input and output modalities, causally important for language and language-selective. We discuss evidence that this language network plausibly stores language knowledge and supports core linguistic computations related to accessing words and constructions from memory and combining them to interpret (decode) or generate (encode) linguistic messages. We emphasize that the language network works closely with, but is distinct from, both lower-level - perceptual and motor - mechanisms and higher-level systems of knowledge and reasoning. The perceptual and motor mechanisms process linguistic signals, but, in contrast to the language network, are sensitive only to these signals' surface properties, not their meanings; the systems of knowledge and reasoning (such as the system that supports social reasoning) are sometimes engaged during language use but are not language-selective. This Review lays a foundation both for in-depth investigations of these different components of the language processing pipeline and for probing inter-component interactions.

Inaccurately Reported Statin Use Affects the Assessing of Lipid Profile Measures and Their Association with Coronary Artery Disease Risk.

BACKGROUND: Lipid profiling is central for coronary artery disease (CAD) risk assessment. Nonadherence or unreported use of lipid-lowering drugs, particularly statins, can significantly complicate the association between lipid profile measures and CAD clinical outcomes. By combining medication history evaluation with statin analysis in plasma, we determined the effects of inaccurately reported statin use on lipid profile measures and their association with CAD risk. METHODS: We compared medication history of statin use with statin concentration measurements, by liquid chromatography-tandem mass spectrometry, in 690 participants undergoing coronary angiography (63 ± 11 years of age). Nominal logistic regression was employed to model CAD diagnosis with statin measurements, phenotypic, and lipid profile characteristics. RESULTS: Medication history of statin use was confirmed by statin assay for 81% of the patients. Surprisingly, statins were detected in 46% of patients without statin use records. Nonreported statin use was disproportionately higher among older participants. Stratifying samples by statin history resulted in underestimated LDL-lipid measures. Apolipoprotein B concentrations had a significant inverse CAD association, which became nonsignificant upon re-stratification using the statin assay data. CONCLUSIONS: Our study uncovered prominent discrepancies between medication records and actual statin use measured by mass spectrometry. We showed that inaccurate statin use assessments may lead to overestimation and underestimation of LDL levels in statin user and nonuser categories, exaggerating the reverse epidemiology association between LDL levels and CAD diagnosis. Combining medication history and quantitative statin assay data can significantly improve the design, analysis, and interpretation of clinical and epidemiological studies.

Cannabis Use Among Adults in Cigarette Smoking Cessation Treatment in Ontario, Canada: Prevalence and Association With Tobacco Cessation Outcome, 2015-2021.

Objectives. To examine cannabis use prevalence and its association with tobacco cessation among adults enrolled in cigarette smoking cessation treatment before and after Canada legalized recreational cannabis in October 2018. Methods. The sample comprised 83 206 adults enrolled in primary care-based cigarette smoking cessation treatment between 2015 and 2021 in Ontario, Canada. Past-30-day cannabis use was self-reported at enrollment and cigarette smoking abstinence at 6-month follow-up. Results. Past-30-day prevalence of cannabis use increased from 20.2% in 2015 to 37.7% in 2021. The prevalence increased linearly both before and after legalization. Cannabis and tobacco co-use was associated with lower odds of self-reported cigarette smoking abstinence at 6-month follow-up than tobacco use only (24.4% vs 29.3%; odds ratio [OR] = 0.78; 95% confidence interval [CI] = 0.75, 0.81). This association was attenuated after adjustment for covariates (OR = 0.93; 95% CI = 0.89, 0.97) and weakened slightly over time. Conclusions. Cannabis use prevalence almost doubled from 2015 to 2021 among primary care patients in Ontario seeking treatment to quit cigarettes and was associated with poorer quit outcomes. Further research into the impact of cannabis policy on cannabis and tobacco co-use is warranted to mitigate harm. (Am J Public Health. 2024;114(1):98-107. https://doi.org/10.2105/AJPH.2023.307445).

Sequence of Structural and Magnetic Phase Transitions in (NO)Mn6(NO3)13.

New nitrosonium manganese(II) nitrate, (NO)Mn6(NO3)13, has been synthesized and structurally characterized. In the temperature range of 45-298 K, the crystal is hexagonal (centrosymmetric sp. gr. P63/m). Mn2+ ions are assembled into tubes along axis c with both NO3- filling and coating. The nitrosonium cation is located in the framework cavity and is disordered by a 3-fold axis. At the temperature TS1 = 190 K, a structural phase transition related to the libration of the intertube NO3 group and a small variation of Mn polyhedron is observed. Moreover, the anomalies in physical properties of (NO)Mn6(NO3)13 allow suggesting that ordering of NO+ units occurs at low temperatures. The antiferromagnetic ordering in this compound is preceded by the formation of a short-range correlation regime at about 25 K and takes place in two steps at TN1 = 12.0 K and TN2 = 8.4 K.

Evaluation of a flexible piecewise linear mixed-effects model in the analysis of randomized cross-over trials.

Cross-over designs are commonly used in randomized clinical trials to estimate efficacy of a new treatment. They have received a lot of attention, particularly in connection with regulatory requirements for new drugs. The main advantage of using cross-over designs over conventional parallel designs is increased precision, thanks to within-subject comparisons. In the statistical literature, more recent developments are discussed in the analysis of cross-over trials, in particular regarding repeated measures. A piecewise linear model within the framework of mixed effects has been proposed in the analysis of cross-over trials. In this article, we report on a simulation study comparing performance of a piecewise linear mixed-effects (PLME) model against two commonly cited models-Grizzle's mixed-effects (GME) and Jones & Kenward's mixed-effects (JKME) models-used in the analysis of cross-over trials. Our simulation study tried to mirror real-life situation by deriving true underlying parameters from empirical data. The findings from real-life data confirmed the original hypothesis that high-dose iodine salt have significantly lowering effect on diastolic blood pressure (DBP). We further sought to evaluate the performance of PLME model against GME and JKME models, within univariate modeling framework through a simulation study mimicking a 2 × 2 cross-over design. The fixed-effects, random-effects and residual error parameters used in the simulation process were estimated from DBP data, using a PLME model. The initial results with full specification of random intercept and slope(s), showed that the univariate PLME model performed better than the GME and JKME models in estimation of variance-covariance matrix (G) governing the random effects, allowing satisfactory model convergence during estimation. When a hierarchical view-point is adopted, in the sense that outcomes are specified conditionally upon random effects, the variance-covariance matrix of the random effects must be positive-definite. The PLME model is preferred especially in modeling an increased number of random effects, compared to the GME and JKME models that work equally well with random intercepts only. In some cases, additional random effects could explain much variability in the data, thus improving precision in estimation of the estimands (effect size) parameters.

A Novel Anti-CD47 Nanobody Tetramer for Cancer Therapy.

CD47 acts as a defense mechanism for tumor cells by sending a "don't eat me" signal via its bond with SIRPα. With CD47's overexpression linked to poor cancer outcomes, its pathway has become a target in cancer immunotherapy. Though monoclonal antibodies offer specificity, they have limitations like the large size and production costs. Nanobodies, due to their small size and unique properties, present a promising therapeutic alternative. In our study, a high-affinity anti-CD47 nanobody was engineered from an immunized alpaca. We isolated a specific VHH from the phage library, which has nanomolar affinity to SIRPα, and constructed a streptavidin-based tetramer. The efficacy of the nanobody and its derivative was evaluated using various assays. The new nanobody demonstrated higher affinity than the monoclonal anti-CD47 antibody, B6H12.2. The nanobody and its derivatives also stimulated substantial phagocytosis of tumor cell lines and induced apoptosis in U937 cells, a response confirmed in both in vitro and in vivo settings. Our results underscore the potential of the engineered anti-CD47 nanobody as a promising candidate for cancer immunotherapy. The derived nanobody could offer a more effective, cost-efficient alternative to conventional antibodies in disrupting the CD47-SIRPα axis, opening doors for its standalone or combinatorial therapeutic applications in oncology.

Dissociating language and thought in large language models.

Large language models (LLMs) have come closest among all models to date to mastering human language, yet opinions about their linguistic and cognitive capabilities remain split. Here, we evaluate LLMs using a distinction between formal linguistic competence (knowledge of linguistic rules and patterns) and functional linguistic competence (understanding and using language in the world). We ground this distinction in human neuroscience, which has shown that formal and functional competence rely on different neural mechanisms. Although LLMs are surprisingly good at formal competence, their performance on functional competence tasks remains spotty and often requires specialized fine-tuning and/or coupling with external modules. We posit that models that use language in human-like ways would need to master both of these competence types, which, in turn, could require the emergence of separate mechanisms specialized for formal versus functional linguistic competence.

Menstrual attitudes in adult women: A cross-sectional study on the association with menstruation factors, contraceptive use, genital self-image, and sexual openness.

BACKGROUND: Menstruation is a central part of the everyday life of most women, and menstrual attitudes may impact health and well-being. OBJECTIVES: This article aimed to map menstrual attitudes among adult women and examine factors associated with these attitudes, such as aspects of menarche and current menstruation, and rarely studied factors, such as genital self-image and sexual openness. STUDY DESIGN: A cross-sectional online survey. METHOD: A sample of 1470 women, aged 18-50 years, were recruited through social media sites. The Menstrual Self-Evaluation Scale was used to measure three different attitudes: menstruation as natural, shameful, and bothersome. Multiple linear regression analysis was used to investigate the relationship between each attitude and factors related to menarche and current menstruation, contraceptive use, genital self-image (assessed by Female Genital Self-Image Scale), and sexual openness (Personal Comfort with Sexuality Scale). Sociodemographic variables were included into the models as covariates. RESULTS: Agreeing with the attitude of menstruation as something natural was predicted primarily by positive emotions at menarche, experiencing less menstrual pain, using no or nonhormonal contraception, and having a positive genital self-image. Perceiving menstruation as bothersome was predicted by a lower educational level, experiencing stronger menstrual pain, having more perimenstrual psychological symptoms, and using hormonal contraceptives. Menstruation as something shameful was chiefly predicted by lower sexual openness and a negative genital self-image. CONCLUSION: Many women held attitudes about menstruation as both something natural and bothersome. Menarche and current menstruation experiences, and contraceptive method, played central roles in shaping attitudes toward menstruation as natural and bothersome. Viewing menstruation as shameful stood out from other attitudes by indicating a triad of self-objectified shame that includes menstruation, sexuality, and genital self-image. Further research into the relationships between menstruation, contraceptive use, sexuality, and body image is needed to enhance our understanding of women's menstrual health.

The Language Network Reliably "Tracks" Naturalistic Meaningful Nonverbal Stimuli.

The language network, comprised of brain regions in the left frontal and temporal cortex, responds robustly and reliably during language comprehension but shows little or no response during many nonlinguistic cognitive tasks (e.g., Fedorenko & Blank, 2020). However, one domain whose relationship with language remains debated is semantics-our conceptual knowledge of the world. Given that the language network responds strongly to meaningful linguistic stimuli, could some of this response be driven by the presence of rich conceptual representations encoded in linguistic inputs? In this study, we used a naturalistic cognition paradigm to test whether the cognitive and neural resources that are responsible for language processing are also recruited for processing semantically rich nonverbal stimuli. To do so, we measured BOLD responses to a set of ∼5-minute-long video and audio clips that consisted of meaningful event sequences but did not contain any linguistic content. We then used the intersubject correlation (ISC) approach (Hasson et al., 2004) to examine the extent to which the language network "tracks" these stimuli, that is, exhibits stimulus-related variation. Across all the regions of the language network, meaningful nonverbal stimuli elicited reliable ISCs. These ISCs were higher than the ISCs elicited by semantically impoverished nonverbal stimuli (e.g., a music clip), but substantially lower than the ISCs elicited by linguistic stimuli. Our results complement earlier findings from controlled experiments (e.g., Ivanova et al., 2021) in providing further evidence that the language network shows some sensitivity to semantic content in nonverbal stimuli.

Integrative brain omics approach reveals key role for sn-1 lysophosphatidylethanolamine in Alzheimer's dementia.

The biology of individual lipid species and their relevance in Alzheimer's disease (AD) remains incompletely understood. We utilized non-targeted mass spectrometry to examine brain lipids variations across 316 post-mortem brains from participants in the Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP) cohorts classified as either control, asymptomatic AD (AAD), or symptomatic AD (SAD) and integrated the lipidomics data with untargeted proteomic characterization on the same individuals. Lipid enrichment analysis and analysis of variance identified significantly lower abundance of lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) species in SAD than controls or AAD. Lipid-protein co-expression network analyses revealed that lipid modules consisting of LPE and LPC exhibited a significant association to protein modules associated with MAPK/metabolism, post-synaptic density, and Cell-ECM interaction pathways and were associated with better antemortem cognition and with neuropathological changes seen in AD. Particularly, LPE 22:6 [sn-1] levels are significantly decreased across AD cases (SAD) and show the most influence on protein changes compared to other lysophospholipid species. LPE 22:6 may be a lipid signature for AD and could be leveraged as potential therapeutic or dietary targets for AD.

Cost of outpatient hypertension pharmacotherapy: comparative study between Bulgaria and Serbia / Coste de la farmacoterapia antihipertensiva ambulatoria: estudio comparativo entre Bulgaria y Serbia

Objective: To compare the prescribing practice and pharmacotherapy outpatient cost of hypertension and its common complications between two neighboring countries, Bulgaria and Serbia. The study questions focus on consistency of the prescribing practice with the treatment guidelines; comparability of the treatment patterns among both countries, and burden of hypertension cost to the population and third party payer in the countries under consideration. Methods: Retrospective study, one year time horizon is for outpatient therapy. Results: Patients with arterial hypertension in Bulgaria are most often on monotherapy (61% vs 6% in Serbia), as well as those with complications (66% vs 0% Serbia). In both countries the first choice of therapy are the ACE inhibitors (37.01% in Serbia and 41% in Bulgaria) and then follows the calcium antagonists, beta-blockers, and diuretics. The weighed monthly cost of hypertension and complicated hypertension is almost doubled in Serbia (12.56 vs 8.23 EUR for hypertension, and 13.39 vs 8.23 EUR) and prevailing part is reimbursed (88% vs 44% in Bulgaria). Conclusion: Our study confirms that hypertension and its complications therapy consumes a huge amount of financial resources. In both countries under consideration the therapy is corresponding with the European treatment guidelines. The international cost comparisons are possible but they depend on many external factors as the regulatory measures, prescribing habits and reimbursement policy and should be analysed within this framework (AU)

Objetivo: Comparar las prácticas de prescripción y el coste del tratamiento ambulatorio de la hipertensión y sus complicaciones comunes en dos países vecinos, Bulgaria y Serbia. Las preguntas de investigación se centran en la consistencia de las prácticas de prescripción con las guías de tratamiento; la comparabilidad de los patrones de prescripción entre los dos países, y el peso del coste de la hipertensión para la población y las aseguradoras en los países en estudio. Métodos: Estudio retrospectivo con un horizonte temporal de un año para el tratamiento ambulatorio. Resultados: Los pacientes con hipertensión arterial en Bulgaria están más frecuentemente en monoterapia (61% vs 6% en Serbia). En ambos países la primera elección de tratamiento son los IECA (37,01% en Serbia y 41% en Bulgaria) seguidos de los calcio-antagonistas, betabloqueantes y diuréticos. El coste mensual ponderado de la hipertensión complicada es casi el doble en Serbia (12,56 vs 8,23 EUR para hipertensión y 13,39 vs 8,23 EUR) y la parte principal es reembolsada (88% vs 44% en Bulgaria). Conclusión: Nuestro estudio confirma que la hipertensión y sus complicaciones consumen una enorme cantidad de recursos financieros. En ambos países estudiados el tratamiento se corresponde con las guías europeas de tratamiento. Las comparaciones internacionales de costes son factibles pero dependen de muchos factores externos como las medidas regulatorias, los hábitos de prescripción y las políticas de reembolso, y deberían analizarse en estos marcos (AU)