Sex differences in the distribution and density of regulatory interneurons in the striatum.

Introduction: Dysfunction of the cortico-basal circuitry - including its primary input nucleus, the striatum - contributes to neuropsychiatric disorders, such as autism and Tourette Syndrome (TS). These conditions show marked sex differences, occurring more often in males than in females. Regulatory interneurons, such as cholinergic interneurons (CINs) and parvalbumin-expressing GABAergic fast spiking interneurons (FSIs), are implicated in human neuropsychiatric disorders such as TS, and ablation of these interneurons produces relevant behavioral pathology in male mice, but not in females. Here we investigate sex differences in the density and distribution of striatal interneurons. Methods: We use stereological quantification of CINs, FSIs, and somatostatin-expressing (SOM) GABAergic interneurons in the dorsal striatum (caudate-putamen) and the ventral striatum (nucleus accumbens) in male and female mice. Results: Males have a higher density of CINs than females, especially in the dorsal striatum; females have equal distribution between dorsal and ventral striatum. FSIs showed similar distributions, with a greater dorsal-ventral density gradient in males than in females. SOM interneurons were denser in the ventral than in the dorsal striatum, with no sex differences. Discussion: These sex differences in the density and distribution of FSIs and CINs may contribute to sex differences in basal ganglia function, particularly in the context of psychopathology.

Sex differences in sensitivity to fentanyl effects in mice: Behavioral and molecular findings during late adolescence.

PURPOSE: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. MATERIALS AND METHODS: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the µ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. RESULTS: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. CONCLUSIONS: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.

Prevalence of depressive disorders among the very old in the 21st century.

BACKGROUND: The aim of this study is to explore the prevalence of depressive disorders in very old adults over time, in rural/urban environments, between men/women, as well as to explore other factors associated with depressive disorders. METHODS: This study was conducted utilizing the GERDA-database data, which consists of four cohorts of 85, 90 and 95+ year olds living in Northern Sweden. Participants could reside independently or in residential care. Data collections took place between 2000 and 2017. Descriptive data and logistic regression models were utilized to explore data. RESULTS: The prevalence of depressive disorders increased between 2000/02 and 2015/17 in all age groups, with the highest percentages observed in the 95+ age group, reaching 53.6 % in 2015/17. The prevalence varied from 20.3 % in those without dementia to 65.1 % in those with dementia. Sex or living in an urban/rural environment was not associated with an increased risk of depression in the fully adjusted models. Dementia and reduced capacity in activities of daily living were associated with depressive disorders among 85 and 90-year-olds, while living alone was associated with depressive disorders in the 95+ age group. LIMITATIONS: Potentially limited generalizability, as this study took place in northern Sweden. CONCLUSIONS: The prevalence of depressive disorders among very old adults increases with age and the prevalence also increases throughout cohorts and time. These alarming rates of depressive disorders among the very old require immediate measures and further investigation. Future studies are needed to explore and monitor trends and to plan and design tailored interventions.

Open Label Pilot of Lorcaserin (a serotonin 2C-receptor agonist) for Cannabis Use Disorder.

Background And Objective: Cannabis Use Disorder (CUD) has no FDA approved treatment. Serotonin-2c (5HT2c) agonists have preclinical and human laboratory evidence for potential efficacy for CUD. We assessed the tolerability and effects of lorcaserin (5HT2c agonist) on CUD. Methods: In a 10-week, open label, uncontrolled trial, the tolerability of lorcaserin was tested in outpatients with CUD. Adverse events (AE) were assessed weekly. Cannabis use was assessed twice weekly by the Timeline follow-back and quantitative urine metabolites. Results: 17 participants enrolled, and 14 received medication. Participants' average age was 35 years; majority were male (N=12). The medication was well tolerated in males. There were no serious adverse events (SAE). The most common AE's were headache/migraine (N=4, all females), anorexia (N=3), and irritability (N=2). Participants decreased their frequency of cannabis use significantly (p < 0.001), adjusted for baseline use. By the end of the trial, participants decreased by 1.76 (SE=0.47) cannabis using days/week. Average daily amount of cannabis and urine THC metabolite levels did not change significantly. Conclusions: Lorcaserin was well tolerated in males but not females suggesting possible sex differences. Future trials of other 5HT2c agonists (lorcaserin was withdrawn at the request of the FDA) should consider longer dose titration phases. Trial Registration: NCT02932215.

Gender Inequalities of Health and Quality of Life in Informal Caregivers in Spain: Protocol for the Longitudinal and Multicenter CUIDAR-SE Study.

BACKGROUND: The aging population and increased disability prevalence in Spain have heightened the demand for long-term care. Informal caregiving, primarily performed by women, plays a crucial role in this scenario. This protocol outlines the CUIDAR-SE study, focusing on the gender-specific impact of informal caregiving on health and quality of life among caregivers in Andalusia and the Basque Country from 2013 to 2024. OBJECTIVE: This study aims to analyze the gender differences in health and quality of life indicators of informal caregivers residing in 2 Spanish autonomous communities (Granada, Andalusia, and Gipuzkoa; Basque Country) and their evolution over time, in relation to the characteristics of caregivers, the caregiving situation, and support received. METHODS: The CUIDAR-SE study uses a longitudinal, multicenter design across 3 phases, tracking health and quality of life indicators among informal caregivers. Using a questionnaire adapted to the Spanish context that uses validated scales and multilevel analysis, the research captures changes in caregivers' experiences amid societal crises, notably the 2008 economic crisis and the COVID-19 pandemic. A multistage randomized cluster sampling technique is used to minimize study design effects. RESULTS: Funding for the CUIDAR-SE study was in 3 phases starting in January 2013, 2017, and 2021, spanning a 10-year period. Data collection commenced in 2013 and continued annually, except for 2016 and 2020 due to financial and pandemic-related challenges. As of March 2024, a total of 1294 participants have been enrolled, with data collection ongoing for 2023. Initial data analysis focused on gender disparities in caregiver health, quality of life, burden, perceived needs, and received support, with results from phase I published. Currently, analysis is ongoing for phases II and III, as well as longitudinal analysis across all phases. CONCLUSIONS: This protocol aims to provide comprehensive insights into caregiving dynamics and caregivers' experiences over time, as well as understand the role of caregiving on gender inequality in health, considering regional variations. Despite limitations in participant recruitment, focusing on registered caregivers, the study offers a detailed exploration of the health impacts of caregiving in Spain. The incorporation of a gender perspective and the examination of diverse contextual factors enrich the study's depth, contributing significantly to the discourse on caregiving health complexities in Spain. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/58440.

Musicians have an advantage on a spatial-hearing task only when they are highly trained, start training early, and continue to play.

Musicians perform better than non-musicians on a variety of non-musical sound-perception tasks. Whether that musicians' advantage extends to spatial hearing is a topic of increasing interest. Here we investigated one facet of that topic by assessing musicians' and non-musicians' sensitivity to the two primary cues to sound-source location on the horizontal plane: interaural-level-differences (ILDs) and interaural-time-differences (ITDs). Specifically, we measured discrimination thresholds for ILDs at 4 kHz (n =246) and ITDs at 0.5 kHz (n = 137) in participants whose musical-training histories covered a wide range of lengths, onsets, and offsets. For ILD discrimination, when only musical-training length was considered in the analysis, no musicians' advantage was apparent. However, when thresholds were compared between subgroups of non-musicians (<2 years of training) and extreme musicians (≥10 years of training, started ≤ age 7, still playing) a musicians' advantage emerged. Threshold comparisons between the extreme musicians and other subgroups of highly trained musicians (≥10 years of training) further indicated that the advantage required both starting young and continuing to play. In addition, the advantage was larger in males than in females, by some measures, and was not evident in an assessment of learning. For ITD discrimination, in contrast to ILD discrimination, parallel analyses revealed no apparent musicians' advantage. The results suggest that musicianship is associated with greater sensitivity to ILDs, a fundamental sound-localization cue, even though that sensitivity is not central to music, that this musicians' advantage arises, at least in part, from nurture, and that it is governed by a neural substrate where ILDs are processed separately from, and more malleably than, ITDs.

Sex differences in binge drinking-related higher morning cortisol levels and in prospective association with future alcohol intake.

AIMS: Peripheral cortisol represents one biological measure of the hypothalamic-pituitary-adrenal (HPA) axis, a significant component of the stress system, which is altered by chronic alcohol consumption. However, whether heavy alcohol use affects the HPA axis differentially between the sexes and whether basal cortisol levels are a biomarker of prospective alcohol intake is unknown. METHODS: We recruited light moderate (LM) and binge-heavy (BH) drinkers of alcohol (n = 118). Repeated fasting morning cortisol levels were studied over a 2-hour period to assess basal levels while participants underwent a neuroimaging scan. RESULTS: Significantly higher average cortisol levels in BH compared to LM groups across four timepoints were observed (P < .018). Overall sex differences were observed with women showing higher initial cortisol levels at the first timepoint with a blunted decrease over the morning relative to men (P < .003). Average morning cortisol differentially predicted prospective future 30-day daily reports of alcohol consumption by sex and group, such that LM males had a positive significant relationship and BH males had a negative non-significant relationship between cortisol and drinking. CONCLUSIONS: Findings indicate that morning plasma cortisol is upregulated in the BH vs. LM group. Although females had higher initial morning cortisol levels, BH males showed a dysregulated negative relationship between stress and binge drinking in contrast to the LM group. Future work should further investigate the role of cortisol and other stress hormones as biomarkers of problematic drinking behaviors in men and women.

Sex Differences in Mouse Models of Voluntary Alcohol Drinking and Abstinence-Induced Negative Emotion.

Alcohol Use Disorder (AUD) is a growing problem worldwide, causing an incredible burden on health and the economy. Though AUD impacts people of all backgrounds and demographics, increasing evidence has suggested robust sex differences in alcohol drinking patterns and AUD-induced negative emotionality or hyperkatifeia. Rates of problematic drinking have significantly risen among women, and women face more severe negative emotional consequences in abstinence such as increased risk of comorbidity with an anxiety or mood disorder and more severe symptoms of depression. As such, a bevy of preclinical literature using contingent methods of alcohol (ethanol) consumption has amassed in recent years to better understand sex as a biological variable in alcohol drinking and abstinence-induced negative emotionality. Mice are widely used to model alcohol drinking, as they are conducive to genetic manipulation strategies, and many strains will voluntarily consume alcohol. Sex-specific results from these mouse studies, however, have been inconsistent. Therefore, this review aims to summarize the current knowledge on sex differences in AUD-related contingent ethanol drinking and abstinence-induced negative emotionality in mice. Various contingent mouse drinking models and negative emotional-based behavioral paradigms are introduced and subsequently discussed in the context of sex differences to show increasing indications of sex specificity in mouse preclinical studies of AUD. With this review, we hope to inform future research on potential sex differences in preclinical mouse models of AUD and provide mounting evidence supporting the need for more widespread inclusion of preclinical female subjects in future studies.

Sex differences in patient-reported outcomes and the association with clinical factors in axial spondyloarthritis patients treated with tumour necrosis factor inhibitors.

OBJECTIVES: To investigate sex differences in patient-reported outcome measures (PROMs) among axSpA patients initiating their first TNFi and identify factors contributing to these disparities over the follow-up. METHODS: Data were included from 15 EuroSpA registries and consisted of axSpA patients initiating their first TNFi, with ≥2 measurements for each analysed PROM (BASDAI and BASFI, scale 0-100) taken at any time point. Linear mixed models were employed to analyse sex differences in PROMs over 24 months and to evaluate how baseline characteristics were related to the observed sex differences. RESULTS: We analysed 13 102 (38% women) in the BASDAI analyses and 10 623 (38% women) in the BASFI analyses. At follow-up, mean sex differences in BASDAI increased from 4.3 units at baseline (95% CI, 3.5-5.1)-8.0 (7.2-8.8) at 6 months, and in BASFI from 2.2 (1.4-3.1)-4.6 (3.6-5.5), with consistently worse scores in women. Baseline characteristics could not substantially account for the observed sex differences over time; however, the magnitude of the sex differences was reduced by HLA-B27 positivity, longer disease duration, and increased CRP levels, but increased by TNFi initiation in later years and peripheral arthritis. CONCLUSION: In axSpA patients initiating their first TNFi, baseline sex differences in BASDAI and BASFI increased two-fold after 6 months of treatment and persisted thereafter, with worse scores in women. Several baseline characteristics moderated the sex differences, though none could fully account for them. These findings improve our understanding of sex differences and underscore their importance in axSpA.

Alanine aminotransferase predicts incident steatotic liver disease of metabolic etiology: Long life to the old biomarker!

Alanine aminotransferase (ALT) serum levels increase because of hepatocellular damage. Metabolic dysfunction-associated fatty liver disease (MAFLD), which identifies steatotic liver disease (SLD) associated with ≥ 2 metabolic abnormalities, has prominent sexual differences. The Metabolic Syndrome defines a cluster comprising abdominal obesity, altered glucose metabolism, dyslipidemia, and hypertension. Male sex, body mass index, glucose, lipids, ferritin, hypertension, and age independently predict ALT levels among blood donors. Over the last few decades, the reference range of ALT levels has been animatedly debated owing to attempts to update sex-specific reference ranges. With this backset, Chen et al have recently published a study which has two main findings. First, > 80% of individuals with MAFLD had normal ALT levels. Second, there was a linear increasing trend in the association between cumulative excess high-normal ALT levels and the rate of incident MAFLD. This study has biologically credible findings. However, it inaccurately considered sex differences in the MAFLD arena. Therefore, future studies on SLD owing to metabolic dysfunction should adopt locally determined and prospectively validated reference ranges of ALT and carefully consider sex differences in liver enzymes and MAFLD pathobiology.

Systematic review and meta-analysis of Chinese coach leadership and athlete satisfaction and cohesion.

Introduction: This meta-analysis investigates the relationship between coach leadership behaviors and athlete satisfaction and group cohesion within the realm of Chinese sports. The study also explores player sex and player classification as potential moderating variables. The primary focus is on evaluating the impact of coaching behaviors, as measured by the Leadership Scale for Sports, on athlete satisfaction and group cohesion. Methods: Standard literature searches from China National Knowledge Infrastructure and Wanfang academic databases produced 26 studies encompassing a total of 319 effect sizes and a participant pool of 7,121 athletes across various sports. Results: Using the Comprehensive Meta-Analysis (CMA) to examine relevant data, results reveal a moderate and positive association between coach leadership and athlete satisfaction (ES = 0.412). Specifically, training and instruction (ES = 0.531), positive feedback (ES = 0.526), social support, and democratic decision-making exhibit positive effects, while autocratic behavior demonstrates a marginal positive effect. Similarly, a moderate positive relationship is identified between coach leadership and overall group cohesion (ES = 0.275), with training and instruction (ES = 0.396), social support (ES = 0.356), positive feedback, and democratic behavior positively influencing cohesion. Conversely, autocratic behavior has a small negative impact on cohesion. Furthermore, female athletes (ES = 0.603) and professional players (ES = 0.544) display stronger positive associations between coach leadership and satisfaction. Conclusion: These findings highlight the significance of diverse coaching behaviors aligned with player characteristics for fostering positive athlete satisfaction and group cohesion within the Chinese sports context, offering valuable guidance to Chinese coaches aiming to enhance their coaching strategies.

Effects of Sex Differences and Combined Use of Clozapine on Initial Dosage Optimization of Valproic Acid in Patients with Bipolar Disorder.

BACKGROUND: Due to the narrow therapeutic window and large pharmacokinetic variation of valproic acid (VPA), it is difficult to make an optimal dosage regimen. The present study aims to optimize the initial dosage of VPA in patients with bipolar disorder. METHODS: A total of 126 patients with bipolar disorder treated by VPA were included to construct the VPA population pharmacokinetic model retrospectively. Sex differences and combined use of clozapine were found to significantly affect VPA clearance in patients with bipolar disorder. The initial dosage of VPA was further optimized in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. RESULTS: The CL/F and V/F of VPA in patients with bipolar disorder were 11.3 L/h and 36.4 L, respectively. It was found that sex differences and combined use of clozapine significantly affected VPA clearance in patients with bipolar disorder. At the same weight, the VPA clearance rates were 1.134, 1, 1.276884, and 1.126 in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. This study further optimized the initial dosage of VPA in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. CONCLUSION: This study is the first to investigate the initial dosage optimization of VPA in patients with bipolar disorder based on sex differences and the combined use of clozapine. Male patients had higher clearance, and the recommended initial dose decreased with increasing weight, providing a reference for the precision drug use of VPA in clinical patients with bipolar disorder.

Sex- and Age-Associated Differences in Genomic Alterations among Patients with Advanced Non-Small Cell Lung Cancer (NSCLC).

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher's exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18-102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.

Sex Differences in the Survival of Patients with Neuroendocrine Neoplasms: A Comparative Study of Two National Databases.

BACKGROUND: Neuroendocrine neoplasms (NENs) are increasing in incidence globally. Previous analysis of the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed a notable female survival advantage in most tumour sites. This study aims to compare NCRAS to the Surveillance, Epidemiology, and End Results Program (SEER) to validate these results using the same statistical methods. METHODS: A total of 14,834 and 108,399 patients with NENs were extracted from NCRAS and SEER, respectively. Sixty-months survival for both males and females for each anatomical site of NENs were calculated using restricted mean survival time (RMST) and Kaplan-Meier Survival estimates. The sixty-month RMST female survival advantage (FSA) was calculated. RESULTS: FSA was similar in NCRAS and SEER. The highest FSA occurred in lung and stomach NENs. CONCLUSIONS: The data from SEER confirm the findings published by NCRAS. Female survival advantage remains unexplained.

Steroidogenic Factor-1 Regulation of Dorsomedial Ventromedial Hypothalamic Nucleus Ghrh Neuron Transmitter Marker and Estrogen Receptor Gene Expression in Male Rat.

Ventromedial hypothalamic nucleus (VMN) growth hormone-releasing hormone (Ghrh) neurotransmission shapes counterregulatory hormone secretion. Dorsomedial VMN Ghrh neurons express the metabolic-sensitive transcription factor steroidogenic factor-1/NR5A1 (SF-1). In vivo SF-1 gene knockdown tools were used here to address the premise that in male rats, SF-1 may regulate basal and/or hypoglycemic patterns of Ghrh, co-transmitter biosynthetic enzyme, and estrogen receptor (ER) gene expression in these neurons. Single-cell multiplex qPCR analyses showed that SF-1 regulates basal profiles of mRNAs that encode Ghrh and protein markers for neurochemicals that suppress (γ-aminobutyric acid) or enhance (nitric oxide; glutamate) counterregulation. SF-1 siRNA pretreatment respectively exacerbated or blunted hypoglycemia-associated inhibition of glutamate decarboxylase67 (GAD67/GAD1) and -65 (GAD65/GAD2) transcripts. Hypoglycemia augmented or reduced nitric oxide synthase and glutaminase mRNAs, responses that were attenuated by SF-1 gene silencing. Ghrh and Ghrh receptor transcripts were correspondingly refractory to or increased by hypoglycemia, yet SF-1 knockdown decreased both gene profiles. Hypoglycemic inhibition of ER-alpha and G protein-coupled-ER gene expression was amplified by SF-1 siRNA pretreatment, whereas as ER-beta mRNA was amplified. SF-1 knockdown decreased (corticosterone) or elevated [glucagon, growth hormone (GH)] basal counterregulatory hormone profiles, but amplified hypoglycemic hypercorticosteronemia and -glucagonemia or prevented elevated GH release. Outcomes document SF-1 control of VMN Ghrh neuron counterregulatory neurotransmitter and ER gene transcription. SF-1 likely regulates Ghrh nerve cell receptivity to estradiol and release of distinctive neurochemicals during glucose homeostasis and systemic imbalance. VMN Ghrh neurons emerge as a likely substrate for SF-1 control of glucose counterregulation in the male rat.

Changes in levels of the zinc transporter SLC39A12 in Brodmann's area 44: Effects of sex, suicide, CNS pH and schizophrenia.

Disturbed CNS zinc homeostasis is suggested as part of the pathophysiology of schizophrenia. Our data, from multiple studies, suggests levels of cortical RNA for the solute carrier family 39 member 12 (SLC39A12), a putative zinc transporter, is higher in people with schizophrenia and is more perturbed in a sub-group of people with the disorder that can be separated because they have very low levels of muscarinic M1 receptors (MRDS). In this study qPCR was used to measure levels of two RNA splice variants of SLC39A12 (a and b) in Brodmann's area (BA) 44 from new cohorts of controls and people with schizophrenia. For the first time, in our study cohort as a whole, we report levels of both splice variants of SLC39A12 are lower in females compared to males and there are correlations between levels of SLC39A12 a and b and CNS pH. Levels of both splice variants were also lower in people with schizophrenia who were suicide completers compared to those who were not. Accounting for these factors, we showed levels of SLC39A12 a and b were higher in BA 44 in schizophrenia compared to controls. In further analyses, with and without our previous data on SLC39A12 a and b, we confirmed changes in levels of SLC39A12 RNAs were more profound in MRDS. In conclusion, our study argues there are higher levels of SLC39A12 a and b in BA 44 in schizophrenia which could be contributing to the breakdown in CNS zinc homeostasis suggested as part of the pathophysiology of schizophrenia, particularly in those with MRDS.

A preliminary investigation of sex differences in cognitive and fMRI changes following 28 days of cannabis abstinence.

BACKGROUND: Previous studies have investigated the influence of cannabis on cognition among people with MS (pwMS), yet the influence of sex in the context of cannabis use remains unexplored. We aim to fill this gap by investigating cannabis-sex related differences in verbal learning, memory and processing speed in association with fMRI (resting state, and task-based) metrics. METHOD: Our sample consisted of 19 long-term, frequent cannabis users (8 males, 11 females). Assessments were conducted at baseline and after 28 days of cannabis abstinence. The tests included measures of verbal memory (Selective Reminding Test (SRT)), working memory (n-back), information processing speed (Symbol Digit Modalities Test (SDMT)) and the resting state DMN. To evaluate the effects of cannabis abstinence, we performed a group x time interaction analysis using repeated measures ANCOVA. This analysis controlled for several covariates, including the level of disability (EDSS), baseline cannabis THC metabolite levels, and cannabis withdrawal symptoms. By controlling for these variables, we aimed to isolate the impact of cannabis abstinence on cognitive performance over time. Statistical significance was set at p < 0.05. RESULTS: There were no baseline cognitive differences between the sexes. After 28 days of cannabis abstinence, females performed better on the Selective Reminding Test (SRT) (p = 0.04), with a large effect size (η² = 0.286). The mean correct response improved over time for females, but there was no statistically significant group x time interaction on the Symbol Digit Modalities Test (SDMT) and the n-back task. Resting state default mode network data showed overall increased activation in females relative to males at day 28, which meshed with lower brain activation during task-based fMRI paradigms. CONCLUSION: Cannabis negated sex-based cognitive differences. Functional MRI task-based paradigms revealed less cerebral activation in females compared to males, which was associated with comparable or better cognitive performance in females, particularly after cannabis abstinence.

Grading of Aortic Valve Calcification Severity and Risk Stratification in Aortic Stenosis.

BACKGROUND: Thresholds of aortic valve calcification (AVC) to define hemodynamically moderate aortic stenosis (AS) from mild are lacking. We aimed to establish a novel grading classification of AVC as quantified by computed tomography and determine its prognostic value. METHODS AND RESULTS: This study included 915 patients with at least mild AS (mean age 70±12 years, 30% women) from a multicenter prospective registry. All patients underwent Doppler-echocardiography and noncontrast computed tomography within 3 months. Primary end point was the occurrence of all-cause death. Receiver operating characteristic curves analyses were used to determine the sensitivity and specificity of sex-specific thresholds of AVC to identify hemodynamically moderate AS. Optimal thresholds (ie, with best sensitivity/specificity) of AVC to distinguish moderate (aortic valve area 1.0-1.5 cm2 and mean gradient 20-39 mm Hg) from mild AS (aortic valve area >1.5 cm2 and mean gradient <20 mm Hg) were AVC ≥360 arbitrary units in women and ≥1037 arbitrary units in men. Based on the guidelines' thresholds for severe AS and the new thresholds in our study for moderate AS, 312 (34%) patients had mild, 253 (28%) moderate, and 350 (38%) severe AVC. During a mean follow-up of 5.6±3.9 years, 183 (27%) deaths occurred. In Cox multivariable models, AVC remained associated with an increased risk of death (adjusted hazard ratio per grade increase, 1.94 [95% CI, 1.53-2.56]; P<0.001). CONCLUSIONS: A novel grading classification of anatomic AS severity based on sex-specific thresholds of AVC provides significant prognostic value for predicting mortality. These findings support the complementarity of computed tomography-calcium scoring to Doppler-echocardiography to corroborate AS severity and enhance risk stratification in patients with AS.

The influence of temperament and perinatal factors on language development: a longitudinal study.

Early language development is characterized by large individual variation. Several factors were proposed to contribute to individual pathways of language acquisition in infancy and childhood. One of the biologically based explaining factors is temperament, however, the exact contributions and the timing of the effects merits further research. Pre-term status, infant sex, and environmental factors such as maternal education and maternal language are also involved. Our study aimed to investigate the longitudinal relationship between infant temperament and early language development, also considering infant gender, gestational age, and birthweight. Early temperament was assessed at 6, 9, 18, 24, and 30 months with the Very Short Form of Infant Behavior Questionnaire (IBQ-R) and the Very Short Form of Early Childhood Behavior Questionnaire (ECBQ). Early nonverbal communication skills, receptive and expressive vocabulary were evaluated with the Hungarian version of The MacArthur Communicative Development Inventory (HCDI). Our study adds further evidence to the contribution of infant temperament to early language development. Temperament, infant gender, and gestational age were associated with language development in infancy. Infants and toddlers with higher Surgency might enter communicative situations more readily and show more engagement with adult social partners, which is favorable for communication development. Gestational age was previously identified as a predictor for language in preterm infants. Our results extend this association to the later and narrower gestational age time window of term deliveries. Infants born after longer gestation develop better expressive vocabulary in toddlerhood. Gestational age may mark prenatal developmental processes that may exert influence on the development of verbal communication at later ages.

Sex differences in discrimination behavior and orbitofrontal engagement during context-gated reward prediction.

Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, post-traumatic stress disorder, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here, we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two auditory reward-predictive cues was informed by the presence, or absence, of a visual contextual feature (LIGHT: X+/DARK: X-/LIGHT: Y-/DARK: Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex (OFC) compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between the speed of acquisition and the robustness of performance in the contextual modulation of cued reward seeking. The different distribution of sexes along the fast learning ↔ steady performance continuum might reflect different levels of engagement of the OFC, and might have implications for our understanding of sex differences in psychiatric disorders.