Sex differences in postconcussive symptom reporting in those with history of concussion: Findings from the federal interagency traumatic brain injury research (FITBIR) database.

Objective: This study investigated influence of biological sex on postconcussive symptoms (PCS) following concussion using the Federal Interagency Traumatic Brain Injury Research (FITBIR) database. Method: All studies with publicly released data as of 4/7/21 that included both males and females, enough information to determine severity of injury consistent with concussion, a measure of PCS, and objective measures of neurocognitive functioning were used. This resulted in 6 studies with a total of 9890 participants (3206 females, 6684 males); 815 participants completed the Neurobehavioral Symptom Inventory (NSI), 471 completed the Rivermead Post-Concussion Symptoms Questionnaire (RPSQ), and 8604 completed the Sport Concussion Assessment Tool-3rd Edition (SCAT 3). Questionnaires were harmonized and the following symptom composite scores were computed: total score, somatic, cognitive, and affective. Data were analyzed using linear mixed-effects models. Results: Females endorsed higher total symptoms relative to males and that military personnel endorsed higher symptoms relative to civilians. Additionally, there was a small but significant interaction effect, such that female military personnel endorsed even higher symptoms than would be predicted by the main effects. Similar patterns were observed for somatic, cognitive, and affective symptom domains. Conclusions: Further understanding sex differences in PCS reporting is key to informing the most appropriate treatment options. Future work will need to examine whether sex differences in symptom reporting is due to sex differences in endorsement styles or genuine differences in symptom presentation, as well as the relationship between study population (e.g., military, civilian, sport) and sex on objective cognitive functioning and other functional outcomes.

Deep Learning Resolves Myovascular Dynamics in the Failing Human Heart.

The adult mammalian heart harbors minute levels of cycling cardiomyocytes (CMs). Large numbers of images are needed to accurately quantify cycling events using microscopy-based methods. CardioCount is a new deep learning-based pipeline to rigorously score nuclei in microscopic images. When applied to a repository of 368,434 human microscopic images, we found evidence of coupled growth between CMs and cardiac endothelial cells in the adult human heart. Additionally, we found that vascular rarefaction and CM hypertrophy are interrelated in end-stage heart failure. CardioCount is available for use via GitHub and via Google Colab for users with minimal machine learning experience.

KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma.

BACKGROUND: Predictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information. METHODS: The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations. Additionally, two previously published immunotherapy and two surgical patient cohorts were analyzed. Therapy benefit was stratified by KRAS and TP53 mutations. Molecular characteristics underlying KRASmut/TP53mut tumours were revealed by the analysis of TCGA data. RESULTS: An interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses of overall survival (Hazard ratio [HR] = 0.56, p = 0.0044 and HR = 0.53, p = 0.0021) resulting in a stronger benefit for KRASmut/TP53mut tumours (HR = 0.71, CI 0.55-0.92). This observation was confirmed in immunotherapy cohorts but not observed in surgical cohorts. Tumour mutational burden, proliferation, and PD-L1 mRNA were significantly higher in TP53-mutated tumours, regardless of KRAS status. Genome-wide expression analysis revealed 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristic of KRASmut/TP53mut tumours. CONCLUSIONS: KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumour features. Mutation testing of the two genes can be easily implemented using small NGS panels.

Pathological and clinical outcomes following neoadjuvant dual HER2 therapy for early-stage breast cancer: An Australian institutional real-world experience.

AIM: There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non-metastatic HER2-positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long-lasting toxicity. Hence, de-escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real-world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. METHODS: This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non-metastatic HER2-positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post-surgical prescribing patterns and also undertook survival analyses for invasive disease-free survival (iDFS) as well as exploratory analyses for correlations between pre-specified clinicopathologic factors and pathological response at surgery. RESULTS: Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease-free at 3 years of follow-up. Only 3 events of recurrence or death were recorded at a median follow-up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. CONCLUSION: This study demonstrates that de-escalated adjuvant treatment for HER2-positive early breast cancer achieved favourable pathological and long-term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

The Xenorhabdus nematophila LrhA transcriptional regulator modulates production of γ-keto-N-acyl amides with inhibitory activity against mutualistic host nematode egg hatching.

Xenorhabdus nematophila is a symbiotic Gammaproteobacterium that produces diverse natural products that facilitate mutualistic and pathogenic interactions in their nematode and insect hosts, respectively. The interplay between X. nematophila secondary metabolism and symbiosis stage is tuned by various global regulators. An example of such a regulator is the LysR-type protein transcription factor LrhA, which regulates amino acid metabolism and is necessary for virulence in insects and normal nematode progeny production. Here, we utilized comparative metabolomics and molecular networking to identify small molecule factors regulated by LrhA and characterized a rare γ-ketoacid (GKA) and two new N-acyl amides, GKA-Arg (1) and GKA-Pro (2) which harbor a γ-keto acyl appendage. A lrhA null mutant produced elevated levels of compound 1 and reduced levels of compound 2 relative to wild type. N-acyl amides 1 and 2 were shown to be selective agonists for the human G-protein-coupled receptors (GPCRs) C3AR1 and CHRM2, respectively. The CHRM2 agonist 2 deleteriously affected the hatch rate and length of Steinernema nematodes. This work further highlights the utility of exploiting regulators of host-bacteria interactions for the identification of the bioactive small molecule signals that they control. IMPORTANCE: Xenorhabdus bacteria are of interest due to their symbiotic relationship with Steinernema nematodes and their ability to produce a variety of natural bioactive compounds. Despite their importance, the regulatory hierarchy connecting specific natural products and their regulators is poorly understood. In this study, comparative metabolomic profiling was utilized to identify the secondary metabolites modulated by the X. nematophila global regulator LrhA. This analysis led to the discovery of three metabolites, including an N-acyl amide that inhibited the egg hatching rate and length of Steinernema carpocapsae nematodes. These findings support the notion that X. nematophila LrhA influences the symbiosis between X. nematophila and S. carpocapsae through N-acyl amide signaling. A deeper understanding of the regulatory hierarchy of these natural products could contribute to a better comprehension of the symbiotic relationship between X. nematophila and S. carpocapsae.

First experiences with machine learning predictions of accelerated declining eGFR slope of living kidney donors 3 years after donation.

BACKGROUND: Living kidney donors are screened pre-donation to estimate the risk of end-stage kidney disease (ESKD). We evaluate Machine Learning (ML) to predict the progression of kidney function deterioration over time using the estimated GFR (eGFR) slope as the target variable. METHODS: We included 238 living kidney donors who underwent donor nephrectomy. We divided the dataset based on the eGFR slope in the third follow-up year, resulting in 185 donors with an average eGFR slope and 53 donors with an accelerated declining eGFR-slope. We trained three Machine Learning-models (Random Forest [RF], Extreme Gradient Boosting [XG], Support Vector Machine [SVM]) and Logistic Regression (LR) for predictions. Predefined data subsets served for training to explore whether parameters of an ESKD risk score alone suffice or additional clinical and time-zero biopsy parameters enhance predictions. Machine learning-driven feature selection identified the best predictive parameters. RESULTS: None of the four models classified the eGFR slope with an AUC greater than 0.6 or an F1 score surpassing 0.41 despite training on different data subsets. Following machine learning-driven feature selection and subsequent retraining on these selected features, random forest and extreme gradient boosting outperformed other models, achieving an AUC of 0.66 and an F1 score of 0.44. After feature selection, two predictive donor attributes consistently appeared in all models: smoking-related features and glomerulitis of the Banff Lesion Score. CONCLUSIONS: Training machine learning-models with distinct predefined data subsets yielded unsatisfactory results. However, the efficacy of random forest and extreme gradient boosting improved when trained exclusively with machine learning-driven selected features, suggesting that the quality, rather than the quantity, of features is crucial for machine learning-model performance. This study offers insights into the application of emerging machine learning-techniques for the screening of living kidney donors.

Socioeconomic factors, sleep timing and duration, and amygdala resting-state functional connectivity in children.

Introduction: Reduced sleep health has been consistently linked with increased negative emotion in children. While sleep characteristics have been associated with neural function in adults and adolescents, much less is known about these associations in children while considering socioeconomic context. In this study, we examined the associations among socioeconomic factors, sleep duration and timing, and resting-state functional connectivity (rsFC) of the amygdala in children. Methods: Participants were typically-developing 5- to 9-year-olds from socioeconomically diverse families (61% female; N = 94). Parents reported on children's weekday and weekend bedtimes and wake-up times, which were used to compute sleep duration and midpoint. Analyses focused on amygdala-anterior cingulate cortex (ACC) connectivity followed by amygdala-whole brain connectivity. Results: Lower family income-to-needs ratio and parental education were significantly associated with later weekday and weekend sleep timing and shorter weekday sleep duration. Shorter weekday sleep duration was associated with decreased amygdala-ACC and amygdala-insula connectivity. Later weekend sleep midpoint was associated with decreased amygdala-paracingulate cortex and amygdala-postcentral gyrus connectivity. Socioeconomic factors were indirectly associated with connectivity in these circuits via sleep duration and timing. Discussion: These results suggest that socioeconomic disadvantage may interfere with both sleep duration and timing, in turn possibly altering amygdala connectivity in emotion processing and regulation circuits in children. Effective strategies supporting family economic conditions may have benefits for sleep health and brain development in children.

Enhancing patient-clinician collaboration during treatment decision-making: study protocol for a community-engaged, mixed method hybrid type 1 trial of collaborative decision skills training (CDST) for veterans with psychosis.

BACKGROUND: Patient participation in treatment decision making is a pillar of recovery-oriented care and is associated with improvements in empowerment and well-being. Although demand for increased involvement in treatment decision-making is high among veterans with serious mental illness, rates of involvement are low. Collaborative decision skills training (CDST) is a recovery-oriented, skills-based intervention designed to support meaningful patient participation in treatment decision making. An open trial among veterans with psychosis supported CDST's feasibility and demonstrated preliminary indications of effectiveness. A randomized control trial (RCT) is needed to test CDST's effectiveness in comparison with an active control and further evaluate implementation feasibility. METHODS: The planned RCT is a hybrid type 1 trial, which will use mixed methods to systematically evaluate the effectiveness and implementation feasibility of CDST among veterans participating in a VA Psychosocial Rehabilitation and Recovery Center (PRRC) in Southern California. The first aim is to assess the effectiveness of CDST in comparison with the active control via the primary outcome, collaborative decision-making behavior during usual care appointments between veterans and their VA mental health clinicians, and secondary outcomes (i.e., treatment engagement, satisfaction, and outcome). The second aim is to characterize the implementation feasibility of CDST within the VA PRRC using the Practical Robust Implementation and Sustainability Model framework, including barriers and facilitators within the PRRC context to support future implementation. DISCUSSION: If CDST is found to be effective and feasible, implementation determinants gathered throughout the study can be used to ensure sustained and successful implementation at this PRRC and other PRRCs and similar settings nationally. TRIAL REGISTRATION: ClinicalTrials.gov NCT04324944. Registered on March 27, 2020. Trial registration data can be found in Appendix 1.

Meta-analysis of Cognitive Function Following Non-severe SARS-CoV-2 Infection.

To effectively diagnose and treat subjective cognitive symptoms in post-acute sequalae of COVID-19 (PASC), it is important to understand objective cognitive impairment across the range of acute COVID-19 severity. Despite the importance of this area of research, to our knowledge, there are no current meta-analyses of objective cognitive functioning following non-severe initial SARS-CoV-2 infection. The aim of this meta-analysis is to describe objective cognitive impairment in individuals with non-severe (mild or moderate) SARS-CoV-2 cases in the post-acute stage of infection. This meta-analysis was pre-registered with Prospero (CRD42021293124) and utilized the PRISMA checklist for reporting guidelines, with screening conducted by at least two independent reviewers for all aspects of the screening and data extraction process. Fifty-nine articles (total participants = 22,060) with three types of study designs met our full criteria. Individuals with non-severe (mild/moderate) initial SARS-CoV-2 infection demonstrated worse objective cognitive performance compared to healthy comparison participants. However, those with mild (nonhospitalized) initial SARS-CoV-2 infections had better objective cognitive performance than those with moderate (hospitalized but not requiring ICU care) or severe (hospitalized with ICU care) initial SARS-CoV-2 infections. For studies that used normative data comparisons instead of healthy comparison participants, there was a small and nearly significant effect when compared to normative data. There were high levels of heterogeneity (88.6 to 97.3%), likely reflecting small sample sizes and variations in primary study methodology. Individuals who have recovered from non-severe cases of SARS-CoV-2 infections may be at risk for cognitive decline or impairment and may benefit from cognitive health interventions.

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

BACKGROUND: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

Diagnostic leukapheresis reveals distinct phenotypes of NSCLC circulating tumor cells.

BACKGROUND: Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA's full potential, this study introduces a novel approach for CTC enrichment from DLAs. METHODS: DLA was applied to six advanced stage NSCLC patients. For an unbiased CTC enrichment, a two-step approach based on negative depletion of hematopoietic cells was used. Single-cell (sc) whole-transcriptome sequencing was performed, and CTCs were identified based on gene signatures and inferred copy number variations. RESULTS: Remarkably, this innovative approach led to the identification of unprecedented 3,363 CTC transcriptomes. The extensive heterogeneity among CTCs was unveiled, highlighting distinct phenotypes related to the epithelial-mesenchymal transition (EMT) axis, stemness, immune responsiveness, and metabolism. Comparison with sc transcriptomes from primary NSCLC cells revealed that CTCs encapsulate the heterogeneity of their primary counterparts while maintaining unique CTC-specific phenotypes. CONCLUSIONS: In conclusion, this study pioneers a transformative method for enriching CTCs from DLA, resulting in a substantial increase in CTC numbers. This allowed the creation of the first-ever single-cell whole transcriptome in-depth characterization of the heterogeneity of over 3,300 NSCLC-CTCs. The findings not only confirm the diagnostic value of CTCs in monitoring tumor heterogeneity but also propose a CTC-specific signature that can be exploited for targeted CTC-directed therapies in the future. This comprehensive approach signifies a major leap forward, positioning CTCs as a key player in advancing our understanding of cancer dynamics and paving the way for tailored therapeutic interventions.

Testing the structural disconnection hypothesis: Myelin content correlates with memory in healthy aging.

INTRODUCTION: The "structural disconnection" hypothesis of cognitive aging suggests that deterioration of white matter (WM), especially myelin, results in cognitive decline, yet in vivo evidence is inconclusive. METHODS: We examined age differences in WM microstructure using Myelin Water Imaging and Diffusion Tensor Imaging in 141 healthy participants (age 20-79). We used the Virginia Cognitive Aging Project and the NIH Toolbox® to generate composites for memory, processing speed, and executive function. RESULTS: Voxel-wise analyses showed that lower myelin water fraction (MWF), predominantly in prefrontal WM, genu of the corpus callosum, and posterior limb of the internal capsule was associated with reduced memory performance after controlling for age, sex, and education. In structural equation modeling, MWF in the prefrontal white matter and genu of the corpus callosum significantly mediated the effect of age on memory, whereas fractional anisotropy (FA) did not. DISCUSSION: Our findings support the disconnection hypothesis, showing that myelin decline contributes to age-related memory loss and opens avenues for interventions targeting myelin health.

Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics.

Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer's disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater ß-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for ß-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased ß-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.

Cellular metabolism of substance P produces neurokinin-1 receptor peptide agonists with diminished cyclic AMP signaling.

Substance P (SP) is released from sensory nerves in the arteries and heart. It activates neurokinin-1 receptors (NK1Rs) causing vasodilation, immune modulation, and adverse cardiac remodeling. The hypothesis was tested: SP and SP metabolites activate different second messenger signaling pathways. Macrophages, endothelial cells, and fibroblasts metabolized SP to N- and C-terminal metabolites to varying extents. SP 5-11 was the most abundant metabolite followed by SP 1-4, SP 7-11, SP 6-11, SP 3-11, and SP 8-11. In NK1R-expressing human embryonic kidney 293 (HEK293) cells, SP and some C-terminal SP metabolites stimulate the NK1R, promoting the dissociation of several Gα proteins, including Gαs and Gαq from their ßγ subunits. SP increases intracellular calcium concentrations ([Ca]i) and cyclic 3',5'-adenosine monophosphate (cAMP) accumulation with similar -log EC50 values of 8.5 ± 0.3 and 7.8 ± 0.1 M, respectively. N-terminal metabolism of SP by up to five amino acids and C-terminal deamidation of SP produce peptides that retain activity to increase [Ca]i but not to increase cAMP. C-terminal metabolism results in the loss of both activities. Thus, [Ca]i and cAMP signaling are differentially affected by SP metabolism. To assess the role of N-terminal metabolism, SP and SP 6-11 were compared with cAMP-mediated activities in NK1R-expressing 3T3 fibroblasts. SP inhibits nuclear factor κB (NF-κB) activity, cell proliferation, and wound healing and stimulates collagen production. SP 6-11 had little or no activity. Cyclooxygenase-2 (COX-2) expression is increased by SP but not by SP 6-11. Thus, metabolism may select the cellular response to SP by inhibiting or redirecting the second messenger signaling pathway activated by the NK1R.NEW & NOTEWORTHY Endothelial cells, macrophages, and fibroblasts metabolize substance P (SP) to N- and C-terminal metabolites with SP 5-11 as the most abundant metabolite. SP activates neurokinin-1 receptors to increase intracellular calcium and cyclic AMP. In contrast, SP metabolites of N-terminal metabolism and C-terminal deamidation retain the ability to increase calcium but lose the ability to increase cyclic AMP. These new insights indicate that the metabolism of SP directs cellular functions by regulating specific signaling pathways.

Change in Resting-State Functional Connectivity Following Working Memory Training in Individuals With Repetitive Negative Thinking.

BACKGROUND: Repetitive negative thinking (RNT) symptoms, which are characterized by pervasive, uncontrollable negative thoughts, are common in individuals with mood, anxiety, and traumatic stress disorders. Inability to regulate the contents of working memory is a hypothesized etiological factor in RNT, which suggests that training to improve working memory may be beneficial. This study examined the effects of working memory training on resting-state functional connectivity (rsFC) in individuals with elevated RNT and whether such changes would be associated with clinical improvement. METHODS: We conducted a secondary analysis of pre-post resting-state data collected as part of a randomized controlled trial (NCT04912089) of working memory training interventions (n = 42) compared with a waitlist control group (n = 23). We hypothesized that individuals who completed training would show increased rsFC between the 2 key intrinsic connectivity networks-the default mode network (posterior cingulate cortex) and the frontoparietal network (dorsolateral prefrontal cortex). We explored whether the magnitude of rsFC change was associated with change in RNT symptom severity. RESULTS: rsFC increased between the posterior cingulate cortex and regions including the frontal and parietal cortex in the training group compared with the waitlist group. Increased connectivity between the posterior cingulate cortex and superior frontal cortex was associated with RNT symptom reduction. CONCLUSIONS: These data provide evidence that working memory training can modulate neural circuitry at rest in individuals with RNT. Results are consistent with accounts of working memory training effects on large-scale neurocircuitry changes and suggest that these changes may contribute to clinical promise of this type of intervention on transdiagnostic RNT symptoms.

Greater social jetlag predicts poorer NIH Toolbox crystallized cognitive and academic performance in the Adolescent Brain Cognitive Development (ABCD) study.

Academic performance plays a crucial role in long-term educational attainment and occupational function. Chronotype refers to an individual's daily tendencies for times for waking, activity, and sleep. Social jetlag reflects the mismatch between an individual's chronotype and their social schedule. Because school typically starts early in the morning, later chronotype is often associated with daytime sleepiness, insufficient sleep, and poor academic performance. However, the relationship between academic performance, chronotype, and social jetlag has not been extensively examined in large samples like the Adolescent Brain Cognitive Development (ABCD) study. We hypothesized that greater social jetlag would predict poorer cognitive and academic performance. Year 2 (ages 11-14) cross-sectional data from the ABCD cohort (n = 6,890 adolescents) were used to evaluate academic performance (i.e. self-reported past year grades), NIH Toolbox cognitive performance measures, chronotype, and social jetlag from the Munich Chronotype Questionnaire. We found that later chronotype and greater social jetlag predicted poorer cognitive and academic performance with small effect sizes. Our findings emphasize the importance of individual differences in chronotype and social jetlag when designing class schedules, as aligning school activities with student optimal sleep-wake times may contribute to improved academic performance.

Molecular Imaging and Therapy of Differentiated Thyroid Carcinoma in Adults.

ABSTRACT: Differentiated thyroid carcinoma (DTC) has been increasing in incidence in the United States over the last several decades, although mortality rates have remained low. Radioactive iodine therapy (RAI-T) has been a mainstay of treatment for DTC since the 1940s. Imaging of DTC before and after RAI-T primarily focuses on molecular imaging of the sodium iodide symporter. The expanding understanding of the molecular profile of DTC has increased available treatment options. Incorporation of risk stratification to treatment approaches has led to deintensification of both surgical and nonsurgical treatments, leading to decreased morbidity without compromising disease control.

Emergency contraception for individuals weighing 80 kg or greater: A randomized trial of 30 mg ulipristal acetate and 1.5 mg or 3.0 mg levonorgestrel.

OBJECTIVES: To compare the efficacy of emergency contraception (EC) regimens used within 72 hours of unprotected intercourse in individuals weighing ≥80 kg. STUDY DESIGN: We enrolled reproductive-aged healthy women in a multicenter, single-blind, randomized study of levonorgestrel 1.5 mg (LNG1X) and 3.0 mg (LNG2X) and ulipristal acetate 30 mg (UPA) (enrollment goal 1200). Key eligibility requirements included regular cycles, weight >/= 80kg, unprotected intercourse within 72 hours, no recent use of hormonal contraception, a negative urine pregnancy test (UPT), and willingness to abstain from intercourse until next menses. To assess our primary outcome of incidence of pregnancy, participants completed home UPTs; if no menses by 2-weeks post-treatment, or a positive UPT, they returned for an in-person visit with quantitative serum human chorionic gonadotropin and ultrasound. RESULTS: We enrolled and randomized 532; 44 were not dosed or not evaluable for primary end point, leaving an analyzable sample of 488 (173 LNG1X, 158 LNG2X, 157 UPA) with similar demographics between groups (mean age 29.6 years [5.74], body mass index 37.09 kg/m2 [6.95]). Five pregnancies occurred (LNG1X n = 1, LNG2X n = 1, UPA n = 3); none occurred during the highest at-risk window (day of ovulation and the 3 days prior). We closed the study before achieving our enrollment goal because the low pregnancy rate in all groups established futility based on an interim blinded analysis. CONCLUSIONS: Although slow enrollment limited our study power, we found no differences in pregnancy rates between EC regimens among women weighing 80 kg or more. Our results are not able to refute or support differences between the treatment arms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clincialtrials.gov Clinical trials#: NCT03537768. IMPLICATIONS: Women weighing 80 kg or more experienced no differences in pregnancy rates between oral EC regimens but due to several significant study limitations including sample size and the lack of a study population at high risk of pregnancy, our results are not able to determine if differences in treatment effectiveness exist.

Early auditory processing abnormalities alter individual learning trajectories and sensitivity to computerized cognitive training in schizophrenia.

BACKGROUND: Auditory system plasticity is a promising target for neuromodulation, cognitive rehabilitation and therapeutic development in schizophrenia (SZ). Auditory-based targeted cognitive training (TCT) is a 'bottom up' intervention designed to enhance the speed and accuracy of auditory information processing, which has been shown to improve neurocognition in certain SZ patients. However, the dynamics of TCT learning as a function of training exercises and their impact on neurocognitive functioning and therapeutic outcomes are unknown. METHODS: Forty subjects (SZ, n = 21; healthy subjects (HS), n = 19) underwent comprehensive clinical, cognitive, and auditory assessments, including measurements of auditory processing speed (APS) at baseline and after 1-h of TCT. SZ patients additionally completed 30-hours of TCT and repeated assessments ~10-12 weeks later. RESULTS: SZ patients were deficient in APS at baseline (d = 0.96, p < 0.005) relative to HS. After 1-h of TCT, analyses revealed significant main effects of diagnosis (d = 1.75, p = 0.002) and time (d = 1.04, p < 0.001), and a diagnosis × time interaction (d = 0.85, p = 0.02) on APS. APS learning effects were robust after 1-h in SZ patients (d = 1.47, p < 0.001) and persisted throughout the 30-h of training. Baseline APS was associated with verbal learning gains after 30-h of TCT (r = 0.51, p = 0.02) in SZ. CONCLUSIONS: TCT learning metrics may have prognostic utility and aid in the prospective identification of individuals likely to benefit from TCT. Future experimental medicine studies may advance predictive algorithms that enhance TCT-related clinical, cognitive and functional outcomes.