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Introduction Melatonin is often prescribed to patients experiencing sleep disturbances, which has been linked to elevated risks of suicide. However, it remains to be assessed whether melatonin is associated with suicide and suicide attempts. Objectives We aimed to investigate whether individuals in treatment with melatonin had higher rates of suicide and suicide attempt when compared to individuals not in treatment. Methods Using longitudinal data on all persons aged 10+ years living in Denmark between 2007-2016 were obtained. Data from the National Prescription Register was used to identify periods of being in treatment with melatonin based on number of tablets and daily defined dose. Suicide and suicide attempt were identified in hospital and cause of death registries. Results Among 5,798,923 included individuals, 10,577 (0.18%) were in treatment with melatonin (mean treatment length 50 days). Out of 5,952 individuals who died by suicide, 22 (0.37%) were in melatonin treatment, while 134 (0.53%) out of 25,136 had a first suicide attempt. After adjustment for sex and age-group, people in treatment with melatonin were found to have a higher rate of suicide (IRR: 4.2; 95% CI, 2.7-6.4) and suicide attempt (IRR: 6.7-fold (95% CI, 5.7-7.9) when compared to those not in treatment. Conclusions Treatment with melatonin was associated with higher rates of suicide and suicide attempt. The association might be explained through mediators, such as psychiatric comorbidity and sleep disorders. Our findings indicate that attention towards these issues might be warranted. Disclosure No significant relationships.

Introduction Benzodiazepines and non-benzodiazepines have been linked to a variety of adverse effects including addiction. Long term use of these drugs has been associated with an increased risk of suicide. Objectives We assessed if individuals in treatment with non-benzodiazepine (n-BZD) and benzodiazepine (BZD) had higher rates of suicide when compared to individuals not in treatment with these drugs. Methods We utilized a cohort design and national longitudinal data on all individuals aged 10 or above who lived in Denmark between 1995 and 2018. Treatment with either n-BZD or BZD was identified via the Danish National Prescription Registry and suicide deaths were identified in the national cause of death registries. Results In a total of 6,494,206 individuals, 10,862 males and 4,214 females died by suicide. Of these, 1,220 (11.2%) males and 792 (18.8%) females had been in treatment with n-BZD, resulting in adjusted IRR for suicide of 4.2 (95% CI, 4.0 – 4.5) and 3.4 (95% CI, 3.1 – 3.7) for males and females, respectively, when compared to those not in treatment. In all, 529 (4.8%) males and 395 (9.3%) females who died by suicide had been in treatment with BZD. The IRRs for suicide were 2.4 (95% CI, 2.2 – 2.6) and 2.5 (95% CI, 2.3 – 2.8) for males and females, respectively, and compared to those not in treatment. Conclusions In this study we find that those in treatment experienced higher suicide rates than those not in treatment, this persisted when also adjusting for a large variety of covariates. Disclosure No significant relationships.

Introduction Sleep disorders and psychiatric disease are closely related, and psychiatric diseases are associated with elevated suicide risks. Yet, the association between sleep disorders and suicide remains to be assessed using a consistent measure of sleep disorders. Objectives The aim of this study was to examine whether people with a hospital-diagnosis of sleep disorders had higher suicide rates than people with no diagnosis. Methods In a cohort study, nationwide data on all persons aged 15+ years living in Denmark during 1980-2016 were analysed. Sleep disorders were identified through diagnoses recorded during contacts to somatic hospitals. Incidence Rate Ratios (IRR) were estimated using Poisson regression models and adjusted for relevant covariates. Results In all, 3,674,563 males and 3,688,164 females were included, of whom 82,223 (2.2%, mean age: 50.2, SD: 17.5) males and 40,003 (1.1%, mean age: 50.6, SD: 19.9) females had sleep disorder diagnoses. Compared to those with no sleep disorders, the adjusted IRRs for suicide were 1.6 (95% CI, 1.4-1.7) and 2.2 (95% CI, 1.8-2.6) for males and females with sleep disorders, respectively. Excess rates for narcolepsy were found for males (IRR:1.2, 95% CI, 1.0-1.5) and females (IRR:3.3, 95% CI, 3.0-4.1), and for sleep apnea in males (IRR:1.8, 95% CI, 1.5-2.2). Males and females had IRRs of 4.1 (95% CI, 3.1-5.5) and 7.0 (95% CI, 4.8-10.1), respectively, 6 months after being diagnosed with a sleep disorder. Conclusions Sleep disorders were associated with higher suicide rates even after adjusting for pre-existing mental disorders. Our findings suggest attention towards suicidal ideation in patients suffering from sleep disorders is warranted. Disclosure Disclosures and Acknowledgements: Adam Spira has received honoraria for serving as a consultant to Merck and from Springer Nature Switzerland AG for guest editing special issues of Current Sleep Medicine Reports. The other authors report no conflict of in

Background: Diesel engine exhaust (DEE) exposure causes lung cancer, but the molecular mechanisms by which this occurs are not well understood. Objectives: To assess transcriptomic alterations in nasal epithelium of DEE-exposed factory workers to better understand the cellular and molecular effects of DEE. Methods: Nasal epithelial brushings were obtained from 41 diesel engine factory workers exposed to relatively high levels of DEE (17.2–105.4 μg/m3), and 38 unexposed workers from factories without DEE exposure. mRNA was profiled for gene expression using Affymetrix microarrays. Linear modeling was used to identify differentially expressed genes associated with DEE exposure and interaction effects with current smoking status. Pathway enrichment among differentially expressed genes was assessed using EnrichR. Gene Set Enrichment Analysis (GSEA) was used to compare gene expression patterns between datasets. Results: 225 genes had expression associated with DEE exposure after adjusting for smoking status (FDR q

Abstract Although prior studies have examined associations of personality traits with sleep, most have investigated self-reported sleep, been cross-sectional, and focused on younger and middle-aged adults. We investigated associations of personality with actigraphic sleep parameters and changes in sleep in 398 cognitively normal adults aged 40–95 years (M ± SD = 70.1 ± 12.0) in the Baltimore Longitudinal Study of Aging. Participants completed the Revised NEO Personality Inventory (NEO-PI-R) and 6.61 days +/-1.01 nights of wrist actigraphy at the same study visit. Participants with wrist actigraphy at multiple study visits had actigraphy data at 3.11 ± 1.52 visits (follow-up = 2.35 ± 0.70 years). Adjusting for age, sex, race, education, depressive symptoms, comorbidities and interactions of these variables with time, greater extraversion was associated with higher sleep efficiency. After further adjustment for BMI, sleep medication use, and sleep apnea symptoms, greater extraversion was associated with shorter total sleep time, and greater openness was associated with shorter average wake bout length. We observed numerous interactions of personality with sex and age, with stronger personality-sleep associations generally present at younger ages (i.e., aged 50–60 vs. 70–80) and sex differences in associations. Middle-aged and older adults higher in extraversion and lower in openness may be more vulnerable to poor sleep and may benefit from screening for sleep disturbances.

To examine the interaction between educators' intercultural development and students' intercultural growth, we studied the impact of CIEE's Intercultural Communication and Leadership (ICL) course. Our results indicate that Educator, Country, Gender, and Field had impacts on students' intercultural gains (Gibson et al., 2023); the focus of this article is solely on educators' perceptions of the factors that shape their ability to foster student intercultural learning. Using the AAC&U's (2009) Intercultural Knowledge and Competence VALUE Rubric to frame the 22 educator interview responses, our study indicates the tangible results of formally and informally supported educators' intercultural professional development. As a result of educators' intentional intercultural development, they leverage skilled pedagogical techniques to effectively bridge with students to enhance their intercultural learning. Therefore, we argue for the investment, expansion, and mentorship of faculty development, particularly with regards to educator's own intercultural growth, in order to activate and expand students' learning while studying abroad.

In the realm of international education there are many calls to increase and improve faculty development to make study abroad experiences more intellectually and interculturally enriching, for both faculty and students (Anderson et al., 2016; Gillespie, 2019; Gillespie et al., 2020; Johnstone et al., 2020; Layne et al., 2020). In this study we analyze a particular faculty development structure as a model of effectiveness. Part of a larger study examining student learning on Council on International Educational Exchange (CIEE) programs, this article analyzes 22 educator interviews, specifically grouping and categorizing their stated pedagogical tactics, and found that this organization's intentional, highly mentored, relationship-rich faculty development program--centered on their own intercultural learning and growth--helped educators leverage pedagogies to effectively foster students' intercultural learning. We argue that faculty's intercultural learning is the key to empowering faculty's successful leveraging of dynamic pedagogies, not vice versa. Our study, thus, demonstrates the need for investment, expansion, and mentorship of integrated faculty development programming, particularly with regard to educators' own intercultural growth, in order to implement effective pedagogies that activate and expand students' deep learning, especially while studying abroad.

A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues using single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence (MIF). Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This was accompanied by a reduction in effector T cells and an increase of CD4+ regulatory T cells (Treg) in subsolid nodules. An independent set of resected pulmonary nodules consisting of both adenocarcinomas and associated premalignant lesions corroborated the early increment of Tregs in premalignant lesions compared with the associated normal lung tissues by MIF. Gene expression analysis indicated that cancer-associated alveolar type 2 cells and fibroblasts may contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid nodules through ligand-receptor interactions. These findings suggest that there is a suppression of immune surveillance across the spectrum of early-stage lung adenocarcinoma.SignificanceAnalysis of a spectrum of subsolid pulmonary nodules by single-cell RNA sequencing provides insights into the immune regulation and cell-cell interactions in the tumor microenvironment during early lung tumor development.

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 .

Background: Population-based evidence linking sleep characteristics with hearing is limited and how the associations change with age remains unknown. We aim to investigate cross-sectional associations between sleep characteristics and hearing by age in a nationally representative sample of U.S. adults. Methods: We included 3,100 participants aged 40 years and older from the National Health and Nutrition Examination Survey 2015–18. Audiometric hearing thresholds at 0.5, 1, 2 and 4 kilohertz were averaged to calculate better-ear pure-tone average (PTA). Sleep questions were self-reported, including sleep duration on weekdays or workdays, snoring, snorting or stopping breathing, trouble sleeping, and daytime sleepiness. Multivariable-adjusted linear regression with an interaction term between sleep characteristic (categorical) and age (continuous in years) was used. Primary models adjusted for demographic and lifestyle factors with additional adjustment for cardiovascular factors in secondary models. Results: There was no association of reported sleep duration with PTA at age 50; however, compared to those reporting 7–8 h of sleep, there was a borderline-significant association at age 60 (8 h: 1.25 dB, 95 % CI, -0.01, 2.51), and a significant association at age 70 (8 h: 2.67 dB, 95 % CI, 0.56, 4.79). No consistent associations for other sleep characteristics were found. Conclusions: Long sleep duration is associated with worse hearing among middle-aged and older adults and the association differs by age. Longitudinal evidence is needed to establish temporality and examine changes in hearing associated with sleep characteristics.

Adagrasib (MRTX849) is a KRASG12C inhibitor with favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system (CNS) penetration. As of September 1, 2022, a total of 853 patients with KRASG12C-mutated solid tumors, including patients with CNS metastases, had received adagrasib (monotherapy or in combination). Adagrasib-related treatment-related adverse events (TRAEs) are generally mild to moderate in severity, start early in treatment, resolve quickly with appropriate intervention, and result in a low rate of treatment discontinuation. Common TRAEs seen in clinical trials included gastrointestinal-related toxicities (diarrhea, nausea, and vomiting); hepatic toxicities (increased alanine aminotransferase/aspartate aminotransferase) and fatigue, which can be managed through dose modifications, dietary modifications, concomitant medications (such as anti-diarrheals and anti-emetics/anti-nauseants) and the monitoring of liver enzymes and electrolytes. To manage common TRAEs effectively, it is imperative that clinicians are informed, and patients are fully counseled on management recommendations at treatment initiation. In this review, we provide practical guidance on the management of adagrasib TRAEs and discuss some best practices for patient and caregiver counseling to facilitate optimal outcomes for patients. Safety and tolerability data from the phase II cohort of the KRYSTAL-1 study will be reviewed and presented with practical management recommendations based on our experience as clinical investigators.

Colorectal cancer (CRC) is a heterogeneous and complex disease with limited treatment options. Targeting transforming growth factor β (TGF-β) and programmed death ligand 1 pathways may enhance antitumor efficacy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. We report results from an expansion cohort of a phase I study (NCT02517398) in patients with heavily pretreated advanced CRC treated with bintrafusp alfa. As of May 15, 2020, 32 patients with advanced CRC had received bintrafusp alfa for a median duration of 7.1 weeks. The objective response rate was 3.1% and the disease control rate was 6.3% (1 partial response, 1 stable disease); 2 patients were not evaluable. The safety profile was consistent with previously reported data.

BackgroundThe incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC).Methods3,256 NSCLC tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified and assessed for HR expression. Hormone receptor (HR+) was defined as ≥ 1% nuclear staining of estrogen receptor-alpha (ER-a) or progesterone receptor (PR) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n=2753) and Illumina NextSeq 592 gene panel (n=503). An adjusted p-value (q-value)

ObjectivesDiscovering airway gene expression alterations associated with radiological bronchiectasis may improve the understanding of the pathobiology of early-stage bronchiectasis.MethodsPresence of radiological bronchiectasis in 173 individuals without a clinical diagnosis of bronchiectasis was evaluated. Bronchial brushings from these individuals were transcriptomically profiled and analysed. Single-cell deconvolution was performed to estimate changes in cellular landscape that may be associated with early disease progression.Results20 participants have widespread radiological bronchiectasis (three or more lobes). Transcriptomic analysis reflects biological processes associated with bronchiectasis including decreased expression of genes involved in cell adhesion and increased expression of genes involved in inflammatory pathways (655 genes, false discovery rate 0.25). Deconvolution analysis suggests that radiological bronchiectasis is associated with an increased proportion of ciliated and deuterosomal cells, and a decreased proportion of basal cells. Gene expression patterns separated participants into three clusters: normal, intermediate and bronchiectatic. The bronchiectatic cluster was enriched by participants with more lobes of radiological bronchiectasis (p

Young supernova remnants (SNRs) are believed to be the origin of energetic cosmic rays (CRs) below the “knee” of their spectrum at ∼3 PeV (10 ^15 eV). Nevertheless, the precise location, duration, and operation of CR acceleration in young SNRs are open questions. Here, we report on multiepoch X-ray observations of Cassiopeia A (Cas A), a 350 yr old SNR, in the 15–50 keV band that probes the most energetic CR electrons. The observed X-ray flux decrease (15% ± 1% over 10 yr), contrary to the expected >90% decrease based on previous radio, X-ray, and gamma-ray observations, provides unambiguous evidence for CR electron acceleration operating in Cas A. A temporal model for the radio and X-ray data accounting for electron cooling and continuous injection finds that the freshly injected electron spectrum is significantly harder (exponential cutoff power-law index q = 2.15), and its cutoff energy is much higher ( E _cut = 36 TeV), than the relic electron spectrum ( q = 2.44 ± 0.03, E _cut = 4 ± 1 TeV). Both electron spectra are naturally explained by the recently developed modified nonlinear diffusive shock acceleration (mNLDSA) mechanism. The CR protons producing the observed gamma rays are likely accelerated at the same location by the same mechanism as the injected electrons. The Cas A observations and spectral modeling represent the first time radio, X-ray, gamma-ray, and CR spectra have been self-consistently tied to a specific acceleration mechanism—mNLDSA—in a young SNR.

BACKGROUND: Selpercatinib is a first-in-class, highly selective RET kinase inhibitor with CNS activity that has shown efficacy in RET fusion-positive lung and thyroid cancers. RET fusions occur rarely in other tumour types. We aimed to investigate the efficacy and safety of selpercatinib in a diverse group of patients with RET fusion-positive non-lung or thyroid advanced solid tumours (ie, a tumour-agnostic population). METHODS: LIBRETTO-001 is an ongoing phase 1/2, single-group, open-label, basket trial of selpercatinib in patients aged 18 years and older (or ≥12 years, where permitted by regulatory authorities) with RET-altered cancers. The trial is being conducted at 89 sites in 16 countries; the tumour-agnostic population was enrolled at 30 sites (outpatient and inpatient medical facilities) across eight countries. A prespecified interim analysis of LIBRETTO-001 was planned to investigate the efficacy and safety of selpercatinib in a tumour-agnostic population of patients with RET fusion-positive advanced solid tumours; the data cutoff date was Sept 24, 2021. Eligible patients had disease progression on or after previous systemic therapies or no satisfactory therapeutic options and an Eastern Cooperative Oncology Group performance status of 0-2. Selpercatinib was orally administered in a continuous 28-day cycle. Patients enrolled in the phase 1 dose-escalation portion received between 20 mg once daily or 20-240 mg twice daily; the phase 2 recommended dose was 160 mg twice daily. The primary endpoint was the objective response rate as determined by the independent review committee. The efficacy-evaluable tumour-agnostic population was defined as patients with RET fusion-positive cancer, other than non-small-cell lung cancer and thyroid cancer, who had at least 6 months of follow-up from the first study dose at the time of data cutoff (all responders at the time of data cutoff were followed up for at least 6 months from the onset of response unless they progressed or died earlier). Safety was analysed in the tumour-agnostic population of patients who had been enrolled and received selpercatinib on or before the data cutoff date. This study is registered with ClinicalTrials.gov (NCT03157128) and is still recruiting participants. FINDINGS: Between Dec 4, 2017, and Aug 4, 2021, 45 patients with RET fusion-positive tumour-agnostic cancers were enrolled from the phase 1 dose-escalation and phase 2 dose-expansion cohorts of the trial. 43 (96%) of 45 patients received a starting dose of selpercatinib at the recommended dose of 160 mg twice daily. Of the two patients who did not, one received a dose of 160 mg twice daily via intra-patient dose escalation (as allowed per protocol for patients enrolled in the phase 1 portion of the study at lower doses) and the other patients starting dose of 120 mg twice daily was never escalated. Of the 41 efficacy-evaluable patients, the objective response rate as per the independent review committee was 43·9% (95% CI 28·5-60·3; 18 of 41 patients). The most common grade 3 or worse treatment-emergent adverse events were hypertension (ten [22%] of 45 patients), increased alanine aminotransferase (seven [16%]), and increased aspartate aminotransferase (six [13%]). Treatment-emergent serious adverse events occurred in 18 (40%) of 45 patients. No treatment-related deaths occurred. INTERPRETATION: Selpercatinib showed clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. Comprehensive genomic testing that includes RET fusions will be crucial for identifying patients who might benefit from selpercatinib. FUNDING: Loxo Oncology.

Study objectivesRecent initiatives to discourage overprescription of sleep medications have increased awareness of their potential adverse effects; however, it is unknown whether these efforts translated into a decline in use of these medications in the United States. We assessed recent national trends in the use of medications used for sleep disturbance.MethodsWe used data from n = 29,400 participants in the 2013-2018 National Health and Nutrition Examination Survey. At each of three waves of in-person assessments, participants presented prescription bottles for all medications used in the prior month. Interviewers recorded each medication and participants self-reported duration and reasons for use. We identified all medications used for sleep disturbance and categorized medications into two categories: Food and Drug Administration-approved sleep medications and those used off-label for sleep disturbance. We examined changes in the prevalence in use of these medications across the study period.ResultsThe odds of using medications for sleep disturbance decreased 31% between 2013 and 2018 (odds ratio = 0.69, 95% confidence interval = 0.51-0.93, P = .015). This trend was driven by declines in use of Food and Drug Administration-approved medications for sleep disturbance, especially for medium- and long-term duration of use. Notably, among those age 80+ years, we observed an 86% decline (odds ratio = 0.14, 95% confidence interval = 0.05-0.36, P < .001) in use of Food and Drug Administration-approved sleep medications over the study period.ConclusionsUse of prescription medications for sleep disturbance declined nationally, suggesting a possible effect of efforts to curb overprescription and encourage judicious use of these agents. Future research needs to examine whether these changes have coincided with improved population sleep health.CitationKaufmann CN, Spira AP, Wickwire EM, et al. Declining trend in use of medications for sleep disturbance in the United States from 2013 to 2018. J Clin Sleep Med. 2022;18(10):2459-2465.