Children's shyness and physiological arousal to a peer's social stress.

Previous work has shown that children's shyness is related to personal anxiety during social stress, but we know little about how shyness is related to anxiety during a peer's social stress. Children (Mage  = 10.22 years, SD = 0.81, N = 62) were paired with an unfamiliar peer and engaged in a speech task while electrocardiography was recorded. We modeled changes in children's heart rate, a physiological correlate of anxiety, while they observed their peer prepare and deliver a speech. Results revealed that the observing child's shyness related to increases in their heart rate during their peer's preparation period, but modulation of this arousal was sensitive to the presenting peer's anxious behavior while delivering their speech. Specifically, if the presenting child displayed high levels of anxious behavior, the observing child's shyness was related to further increases in heart rate, but if the presenting child displayed low levels of anxious behavior, the observing child's shyness was related to decreases in heart rate from the preparation period. Shy children may experience physiological arousal to a peer's social stress but can regulate this arousal based on social cues from the peer, which may be due to heightened social threat detection and/or empathic anxiety.

Poor air passenger knowledge of COVID-19 symptoms and behaviour undermines strategies aimed at preventing the import of SARS-CoV-2 into the UK.

Air travel mediates transboundary movement of SARS-CoV-2. To prepare for future pandemics, we sought to understand air passenger behaviour and perceived risk during the COVID-19 pandemic. This study of UK adults (n = 2103) quantified knowledge of COVID-19 symptoms, perceived health risk of contracting COVID-19, likelihood of returning to the UK with COVID-19 symptoms, likelihood to obey self-quarantining guidelines, how safe air travellers felt when flying during the pandemic (n = 305), and perceptions towards face covering effectiveness.Overall knowledge of COVID-19 symptoms was poor. Men and younger age groups (18-44) were less informed than women and older age groups (44 +). A significant proportion (21%) of the population would likely travel back to the UK whilst displaying COVID-19 symptoms with many expressing that they would not fully comply with self-isolation guidelines. Overall, males and younger age groups had a reduced perceived personal risk from contracting COVID-19, posing a higher risk of transporting SARS-CoV-2 back to the UK. Poor passenger knowledge and behaviour undermines government guidelines and policies aimed at preventing SARS-CoV-2 entry into the UK. This supports the need for stricter, clearer and more targeted guidelines with point-of-departure viral testing and stricter quarantining upon arrival.

Impact of COVID-19 policies on perceptions of loneliness in people aged 75 years and over in the cognitive function and aging study (CFAS II).

BACKGROUND: The COVID-19 pandemic and associated social distancing measures have profoundly impacted society and social contact patterns, with older people disproportionately affected. Concerns have been raised about a resulting pandemic of loneliness in older people, although the current evidence is mixed. This study provides a unique perspective on the prevalence of loneliness in a population cohort of older people before the pandemic, followed up after the introduction of social restrictions. METHODS: Data analysis was conducted using Wave 3 of the longitudinal Cognitive Function and Aging Study II (2018-2019) and a sub-study focusing on experiences during the COVID-19 pandemic (2020). The sample comprised 379 adults aged over 75 living in Cambridge, Newcastle, and Nottingham. Multivariable binary logistic regression was conducted to identify correlates of prevalent loneliness, adjusted for confounding covariates, during the pandemic. The prevalence of loneliness during the pandemic was compared to loneliness in 2018-2019. RESULTS: Prevalence of loneliness in this sample during the pandemic was 25.1% (95% CI 20.9%-29.7%) compared to 17.2% (95% CI 13.7%-21.3%) in 2018-2019 (χ2  = 14.1, p < 0.01). Variables associated with increased odds of prevalent loneliness included: prior loneliness, living alone, female gender, living in an area of higher deprivation, frequent pre-pandemic social contact at community groups, and separation from family during the pandemic, adjusted for age and sex. Weekly technology-mediated contact using telephone or video calls was associated with lower odds of loneliness. CONCLUSIONS: COVID-19 recovery plans should address loneliness in older people. Target groups should include those who have previously been lonely, people who live alone, those living in deprived areas, and those who had previously been socially active through community groups.

A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling.

Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.

The Prominence of Self-referential Processing across ERP and Memory Consolidation in Children.

We examined behavioral and electrophysiological indices of self-referential and valence processing during a Self-Referential Encoding Task in 9- to 12-year-old children, followed by surprise memory tasks for self- and other-referential trait adjectives. Participants endorsed more positive than negative self-referential information but equally endorsed positive and negative information about the other character. Children demonstrated enhanced parietal LPP amplitudes in response to self- compared to other-referential trait adjectives. Positive and negative information was differentially remembered depending on the order of the referent cues presented, suggesting that social information undergoes differential consolidation processes depending on the referent and the order of presentation.

Chemoresistance is mediated by ovarian cancer leader cells in vitro.

BACKGROUND: Leader cells are a subset of cancer cells that coordinate the complex cell-cell and cell-matrix interactions required for ovarian cancer migration, invasion, tumour deposition and are negatively associated with progression-free survival and response to therapy. Emerging evidence suggests leader cells may be enriched in response to chemotherapy, underlying disease recurrence following treatment. METHODS: CRISPR was used to insert a bicistronic T2A-GFP cassette under the native KRT14 (leader cell) promoter. 2D and 3D drug screens were completed in the presence of chemotherapies used in ovarian cancer management. Leader cell; proliferative (Ki67); and apoptotic status (Cleaved Caspase 3) were defined by live cell imaging and flow cytometry. Quantitative real-time PCR defined "stemness" profiles. Proliferation was assessed on the xCELLigence real time cell analyser. Statistical Analysis was performed using unpaired non-parametric t-tests or one-way ANOVA and Tukey's multiple comparison post hoc. RESULTS: Leader cells represent a transcriptionally plastic subpopulation of ovarian cancer cells that arise independently of cell division or DNA replication, and exhibit a "stemness" profile that does not correlate with epithelial-to-mesenchymal transition. Chemotherapeutics increased apoptosis-resistant leader cells in vitro, who retained motility and expressed known chemo-resistance markers including ALDH1, Twist and CD44v6. Functional impairment of leader cells restored chemosensitivity, with leader cell-deficient lines failing to recover following chemotherapeutic intervention. CONCLUSIONS: Our data demonstrate that ovarian cancer leader cells are resistant to a diverse array of chemotherapeutic agents, and are likely to play a critical role in the recurrence of chemo-resistant disease as drivers of poor treatment outcomes.

The cibarial pump of the xylem-feeding froghopper Philaenus spumarius produces negative pressures exceeding 1 MPa.

The xylem sap of vascular plants is an unlikely source of nutrition, being both nutrient poor and held under tensions (negative pressures) that can exceed 1 MPa. But some insects feed on xylem sap exclusively, extracting copious quantities using a muscular cibarial pump. However, neither the strength of the insect's suction, nor the direct energetic cost of xylem ingestion, have ever been quantified. Philaenus spumarius froghoppers were used to address these gaps in our knowledge. Micro-CT scans of its cibarium and measurements of cibarial muscle sarcomere length revealed that P. spumarius can generate a maximum tension of 1.3 ± 0.2 MPa within its cibarium. The energetic cost of xylem extraction was quantified using respirometry to measure the metabolic rate (MR) of P. spumarius while they fed on hydroponically grown legumes, while xylem sap excretion rate and cibarial pumping frequency were simultaneously recorded. Increasing the plants' xylem tensions up to 1.1 MPa by exposing their roots to polyethylene glycol did not reduce the insects' rate of xylem excretion, but significantly increased both MR and pumping frequency. We conclude that P. spumarius can gain energy feeding on xylem sap containing previously reported energy densities and at xylem tensions up to their maximum suction capacity.

Comparison of two targeted ultra-deep sequencing technologies for analysis of plasma circulating tumour DNA in endocrine-therapy-resistant breast cancer patients.

PURPOSE: There is growing interest in the application of circulating tumour DNA (ctDNA) as a sensitive tool for monitoring tumour evolution and guiding targeted therapy in patients with cancer. However, robust comparisons of different platform technologies are still required. Here we compared the InVisionSeq™ ctDNA Assay with the Oncomine™ Breast cfDNA Assay to assess their concordance and feasibility for the detection of mutations in plasma at low (< 0.5%) variant allele fraction (VAF). METHODS: Ninety-six plasma samples from 50 patients with estrogen receptor (ER)-positive metastatic breast cancer (mBC) were profiled using the InVision Assay. Results were compared to the Oncomine assay in 30 samples from 26 patients, where there was sufficient material and variants were covered by both assays. Longitudinal samples were analysed for 8 patients with endocrine resistance. RESULTS: We detected alterations in 59/96 samples from 34/50 patients analysed with the InVision assay, most frequently affecting ESR1, PIK3CA and TP53. Complete or partial concordance was found in 28/30 samples analysed by both assays, and VAF values were highly correlated. Excellent concordance was found for most genes, and most discordant calls occurred at VAF < 1%. In longitudinal samples from progressing patients with endocrine resistance, we detected consistent alterations in sequential samples, most commonly in ESR1 and PIK3CA. CONCLUSION: This study shows that both ultra-deep next-generation sequencing (NGS) technologies can detect genomic alternations even at low VAFs in plasma samples of mBC patients. The strong agreement of the technologies indicates sufficient reproducibility for clinical use as prognosic and predictive biomarker.

Investigating awareness, fear and control associated with norovirus and other pathogens and pollutants using best-worst scaling.

Pollutants found in the water and air environment represent an ever-growing threat to human health. Contact with some air-, water- and foodborne pathogens (e.g. norovirus) results in gastrointestinal diseases and outbreaks. For future risk mitigation, we aimed to measure people's awareness of waterborne and foodborne norovirus relative to other environment-associated pollutants (e.g. pesticides, bioaerosols, antibiotic resistant bacteria) and well-known risks (e.g. diabetes, dementia, terrorist attack). We used an online survey, which included a best-worst scaling component to elicit personal levels of control and fear prompted by norovirus relative to 15 other risks. There was a negative correlation between levels of fear vs. control for all 16 measured risks. Perceived infection control levels were higher amongst women compared to men and correlated with age and the level of qualification in both groups. Participants who had sought advice regarding the symptoms caused by norovirus appeared to have more control over the risks. Norovirus is associated with high levels of fear, however, the levels of control over it is low compared to other foodborne illnesses, e.g. Salmonella. Addressing this deficit in the public's understanding of how to control exposure to the pathogen in an important health need.

Relationships between resource availability and elevation vary between metrics creating gradients of nutritional complexity.

Plant and animal community composition changes at higher elevations on mountains. Plant and animal species richness generally declines with elevation, but the shape of the relationship differs between taxa. There are several proposed mechanisms, including the productivity hypotheses; that declines in available plant biomass confers fewer resources to consumers, thus supporting fewer species. We investigated resource availability as we ascended three aspects of Helvellyn mountain, UK, measuring several plant nutritive metrics, plant species richness and biomass. We observed a linear decline in plant species richness as we ascended the mountain but there was a unimodal relationship between plant biomass and elevation. Generally, the highest biomass values at mid-elevations were associated with the lowest nutritive values, except mineral contents which declined with elevation. Intra-specific and inter-specific increases in nutritive values nearer the top and bottom of the mountain indicated that physiological, phenological and compositional mechanisms may have played a role. The shape of the relationship between resource availability and elevation was different depending on the metric. Many consumers actively select or avoid plants based on their nutritive values and the abundances of consumer taxa vary in their relationships with elevation. Consideration of multiple nutritive metrics and of the nutritional requirements of the consumer may provide a greater understanding of changes to plant and animal communities at higher elevations. We propose a novel hypothesis for explaining elevational diversity gradients, which warrants further study; the 'nutritional complexity hypothesis', where consumer species coexist due to greater variation in the nutritional chemistry of plants.

Clinical Relevance of an Amplicon-Based Liquid Biopsy for Detecting ALK and ROS1 Fusion and Resistance Mutations in Patients With Non-Small-Cell Lung Cancer.

PURPOSE: Liquid biopsy specimen genomic profiling is integrated in non-small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for ALK /ROS1 alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with ALK/ROS1-positive NSCLC and its impact on outcomes. PATIENTS AND METHODS: Patients with advanced ALK/ROS1-positive NSCLC were prospectively enrolled in the study by researchers at eight French institutions. Plasma samples were analyzed using InVisionFirst-Lung and correlated with clinical outcomes. RESULTS: Of the 128 patients included in the study, 101 were positive for ALK and 27 for ROS1 alterations. Blood samples (N = 405) were collected from 29 patients naïve for treatment with tyrosine kinase inhibitors (TKI) or from 375 patients under treatment, including 105 samples collected at disease progression (PD). Sensitivity was 67% (n = 18 of 27) for ALK/ROS1 fusion detection. Higher detection was observed for ALK fusions at TKI failure (n = 33 of 74; 46%) versus in patients with therapeutic response (n = 12 of 109; 11%). ALK-resistance mutations were detected in 22% patients (n = 16 of 74) overall; 43% of the total ALK-resistance mutations identified occurred after next-generation TKI therapy. ALK G1202R was the most common mutation detected (n = 7 of 16). Heterogeneity of resistance was observed. ROS1 G2032R resistance was detected in 30% (n = 3 of 10). The absence of circulating tumor DNA mutations at TKI failure was associated with prolonged median overall survival (105.7 months). Complex ALK-resistance mutations correlated with poor overall survival (median, 26.9 months v NR for single mutation; P = .003) and progression-free survival to subsequent therapy (median 1.7 v 6.3 months; P = .003). CONCLUSION: Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of ALK/ROS1 fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy.

Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non-Small Cell Lung Cancer.

PURPOSE: The limited knowledge on the molecular profile of patients with BRAF-mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAF-mutant NSCLC. EXPERIMENTAL DESIGN: This was a prospective study of 78 patients with advanced BRAF-mutant NSCLC, enrolled in 27 centers across France. Blood samples (n = 208) were collected from BRAF-TT-naïve patients (n = 47), patients nonprogressive under treatment (n = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA. RESULTS: BRAFV600E ctDNA was detected in 74% of BRAF-TT-naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as BRAF-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1, and CTNNB1. CONCLUSIONS: ctDNA sequencing is clinically relevant for the detection of BRAF-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAF-mutant NSCLC.

Outcomes in oncogenic-addicted advanced NSCLC patients with actionable mutations identified by liquid biopsy genomic profiling using a tagged amplicon-based NGS assay.

Circulating tumor DNA (ctDNA)-based molecular profiling is rapidly gaining traction in clinical practice of advanced cancer patients with multi-gene next-generation sequencing (NGS) panels. However, clinical outcomes remain poorly described and deserve further validation with personalized treatment of patients with genomic alterations detected in plasma ctDNA. Here, we describe the outcomes, disease control rate (DCR) at 3 months and progression-free survival (PFS) in oncogenic-addicted advanced NSCLC patients with actionable alterations identified in plasma by ctDNA liquid biopsy assay, InVisionFirst®-Lung. A pooled retrospective analysis was completed of 81 advanced NSCLC patients with all classes of alterations predicting response to current FDA approved drugs: sensitizing common EGFR mutations (78%, n = 63) with T790M (73%, 46/63), ALK / ROS1 gene fusions (17%, n = 14) and BRAF V600E mutations (5%, n = 4). Actionable driver alterations detected in liquid biopsy were confirmed by prior tissue genomic profiling in all patients, and all patients received personalized treatment. Of 82 patients treated with matched targeted therapies, 10% were at first-line, 41% at second-line, and 49% beyond second-line. Acquired T790M at TKI relapse was detected in 73% (46/63) of patients, and all prospective patients (34/46) initiated osimertinib treatment based on ctDNA results. The 3-month DCR was 86% in 81 evaluable patients. The median PFS was of 14.8 months (12.1-22.9m). Baseline ctDNA allelic fraction of genomic driver did not correlate with the response rate of personalized treatment (p = 0.29). ctDNA molecular profiling is an accurate and reliable tool for the detection of clinically relevant molecular alterations in advanced NSCLC patients. Clinical outcomes with targeted therapies endorse the use of liquid biopsy by amplicon-based NGS ctDNA analysis in first line and relapse testing for advanced NSCLC patients.

Are you as important as me? Self-other discrimination within trait-adjective processing.

Healthy adults typically display enhanced processing for self- (relative to other-) relevant and positive (relative to negative) information. However, it is unclear whether these two biases interact to form a self-positivity bias, whereby self-positive information receives prioritized processing. It is also unclear how a blocked versus mixed referent design impacts reference and valence processing. We addressed these questions using behavioral and electrophysiological indices across two studies using a Self-Referential Encoding Task, followed by surprise recall and recognition tasks. Early (P1) and late (LPP) event-related potentials were time-locked to a series of trait adjectives, encoded relative to oneself or a fictional character, with referent presented in a blocked (Exp. 1) or mixed (Exp. 2) trial design. Regardless of study design, participants recalled and recognized more self- than other-relevant adjectives, and recognized more positive than negative adjectives. Additionally, participants demonstrated larger LPP amplitudes for self-relevant and positive adjectives. The LPP self-relevance effect emerged earlier and persisted longer in the blocked (400-800 ms) versus mixed design (600-800 ms). The LPP valence effect was not apparent in the blocked design, but appeared late in the mixed design (600-1200 ms). Critically, the interaction between self-relevance and valence appeared only behaviorally in the mixed design, suggesting that overall self-relevance and valence independently impact neural socio-cognitive processing.

High Prevalence of Somatic Oncogenic Driver Alterations in Patients With NSCLC and Li-Fraumeni Syndrome.

INTRODUCTION: Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown. METHODS: Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants. RESULTS: Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation. CONCLUSIONS: Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.

Similarities and Differences Across Bipolar Disorder Subtypes Among Adolescents.

Objectives: To compare demographic, clinical, and familial characteristics across bipolar disorder (BD) subtypes in adolescents. Methods: A total of 168 participants, 13 to 19 years of age, with BD-I (n = 41), BD-II (n = 68), or operationalized BD-not otherwise specified (NOS) (n = 59) were recruited from a tertiary subspecialty clinic at an academic health sciences center. Diagnoses were determined using the semistructured K-SADS-PL (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) interview. Omnibus analyses were followed up with post hoc pairwise comparisons. Results: After controlling for age, race, and living with both natural parents, BD-I was associated with greater functional impairment, increased rates of psychiatric hospitalization, psychosis, and lifetime exposure to second-generation antipsychotics and lithium, less self-injurious behavior, less anxiety disorders, and less severe worst lifetime depression and lower levels of emotional dysregulation and lability compared with both BD-II and BD-NOS. Lifetime most severe manic symptoms were highest in BD-I, lowest in BD-NOS, with BD-II intermediate. Lifetime exposure to psychosocial treatment followed the opposite pattern: lowest in BD-I, highest in BD-NOS, with BD-II intermediate. Variables for which there were no significant between-group differences included suicidal ideation, suicide attempts, comorbidities other than anxiety, or family history of BD. Conclusion: Among observed differences, most distinguish BD-I from other subtypes, whereas few variables differed between BD-II and BD-NOS. Different BD subtypes share important similarities in multiple clinical and familial characteristics, including family history of BD. Present findings support and extend knowledge regarding the course and outcome of bipolar youth study operationalized definition of BD-NOS. Further research is warranted to evaluate intermediate phenotypes and treatment strategies that address these subtype-related differences.

Circulating Tumor DNA Analysis for Patients with Oncogene-Addicted NSCLC With Isolated Central Nervous System Progression.

INTRODUCTION: In patients with oncogene-addicted NSCLC and isolated central nervous system progression (iCNS), tissue biopsy is challenging, and the clinical utility of plasma liquid biopsy (i.e., circulating tumor DNA [ctDNA]) is unknown. METHODS: Patients with advanced NSCLC with known baseline genomic alteration (GA) (EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, PIK3CA, STK11, TP53) on tissue were divided into three groups on the basis of their disease progression pattern: iCNS, extra-CNS only (noCNS), or both (cCNS). All patients with available plasma ctDNA were included and were analyzed by next-generation sequencing InVisionFirst-Lung. ctDNA was considered positive if at least one GA was detected. Cell-free tumor DNA was analyzed in cerebrospinal fluid when available. RESULTS: Out of 517 patients screened, 247 were included: 54 had iCNS, 99 had noCNS, and 94 had cCNS progressive disease (64, 128, and 110 ctDNA samples, respectively). CtDNA was positive in 52% iCNS versus 84% in noCNS and 92% in cCNS (p < 0.00001), with lower detection of driver (37% versus 77% and 73%, respectively) and resistance alterations (6% versus 45% and 44%). Patients with iCNS and positive ctDNA were more at risk of extra-CNS progression (32% versus 7%, p = 0.026). In 12 patients with iCNS, ctDNA was positive in six (50%) plasma and in 10 (83%) paired cerebrospinal fluid (p = 0.193). CONCLUSIONS: Although tagged amplicon-based next-generation sequencing has high detection rates of GA in plasma ctDNA in patients with NSCLC with extra-CNS disease, detection rate of GAs (52%) is lower in the subset of patients with iCNS disease. Complementary tests such as cerebrospinal fluid cell-free DNA may be useful. Further evidence would be beneficial to understand the genomic landscape in patients with NSCLC and iCNS.

Keratin-14 (KRT14) Positive Leader Cells Mediate Mesothelial Clearance and Invasion by Ovarian Cancer Cells.

Epithelial ovarian cancer metastasis is driven by spheroids, which are heterogeneous cancer cell aggregates released from the primary tumour mass that passively disseminate throughout the peritoneal cavity to promote tumour spread, disease recurrence, and acquired chemoresistance. Despite their clinical importance, the molecular events that control spheroid attachment and invasion into underlying healthy tissues remain poorly understood. We examined a novel in vitro invasion model using imaging mass spectrometry to establish a "snapshot" of the spheroid/mesothelial interface. Amongst numerous adhesion-related proteins, we identified a sub-population of highly motile, invasive cells that expressed the basal epithelial marker KRT14 as an absolute determinant of invasive potential. The loss of KRT14 completely abrogated the invasive capacity, but had no impact on cell viability or proliferation, suggesting an invasion-specific role. Our data demonstrate KRT14 cells as an ovarian cancer "leader cell" phenotype underlying tumor invasion, and suggest their importance as a clinically relevant target in directed anti-tumour therapies.

Prevalence and epidemiological associates of novel psychedelic use in the United States adult population.

BACKGROUND: Novel psychedelics approximate classic psychedelics, but unlike classic psychedelics, novel psychedelics have been used by humans for a shorter period of time, with fewer data available on these substances. AIMS: The purpose of this study was to determine the prevalence of novel psychedelic use and the associations of novel psychedelic use with mental health outcomes. METHODS: We estimated the prevalence of self-reported, write-in lifetime novel psychedelic use and evaluated the associations of novel psychedelic use with psychosocial characteristics, past month psychological distress, and past year suicidality among adult respondents pooled from years 2008-2016 of the National Survey on Drug Use and Health (weighted n=234,914,788). RESULTS: A fraction (weighted n=273,720; 0.12%) reported lifetime novel psychedelic use. This cohort tended to be younger, male, and White, have greater educational attainment but less income, be more likely to have never been married, engage in self-reported risky behavior, and report lifetime illicit use of other drugs, particularly classic psychedelics (96.9%). (2-(4-Bromo-2,5-dimethoxyphenyl)ethanamine) (2C-B) (30.01%), (2,5-dimethoxy-4-iodophenethylamine) (2C-I) (23.9%), and (1-(2,5-dimethoxy-4-ethylphenyl)-2-aminoethane) (2C-E) (14.8%) accounted for the majority of lifetime novel psychedelic use. Although lifetime novel psychedelic use was not associated with psychological distress or suicidality compared to no lifetime novel psychedelic use or classic psychedelic use, relative to lifetime use of classic psychedelics but not novel psychedelics, lifetime novel psychedelic use was associated with a greater likelihood of past year suicidal thinking (adjusted Odds Ratio (aOR)=1.4 (1.1-1.9)) and past year suicidal planning (aOR=1.6 (1.1-2.4)). CONCLUSION: Novel psychedelics may differ from classic psychedelics in meaningful ways, though additional, directed research is needed.

Real-World Utility of an Amplicon-Based Next-Generation Sequencing Liquid Biopsy for Broad Molecular Profiling in Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSE: To assess the feasibility and utility of circulating tumor DNA (ctDNA) by amplicon-based next-generation sequencing (NGS) analysis in the daily clinical setting in a cohort of patients with advanced non-small-cell lung cancer (NSCLC), as an alternative approach to tissue molecular profiling. PATIENTS AND METHODS: In this single-center prospective study, treatment-naïve and previously treated patients with advanced NSCLC were enrolled. Clinical validation of ctDNA using amplicon-based NGS analysis (with a 36-gene panel) was performed against standard-of-care tissue molecular analysis in treatment-naïve patients. The feasibility, utility, and prognostic value of ctDNA as a dynamic marker of treatment efficacy was evaluated. Results of tissue molecular profile were blinded during ctDNA analysis. RESULTS: Of 214 patients with advanced NSCLC who were recruited, 156 were treatment-naïve patients and 58 were pretreated patients with unknown tissue molecular profile. ctDNA screening was successfully performed for 91% (n = 194) of all patients, and mutations were detected in 77% of these patients. Tissue molecular analysis was available for 111 patients (52%), and tissue somatic mutations were found for 78% (n = 87) of patients. For clinically relevant variants, concordance agreement between ctDNA and tumor tissue analysis was 95% among 94 treatment-naïve patients who had concurrent liquid and tumor biopsy molecular profiles. Sensitivity and specificity were 81% and 97%, respectively. Of the 103 patients with no tissue available, ctDNA detected potential actionable mutations in 17% of patients; of these, 10% received personalized treatment. ctDNA kinetics correlated with response rate and progression-free survival in 31 patients treated with first-line platinum-based chemotherapy. CONCLUSION: These real-world data from a prospective study endorse ctDNA molecular profile by amplicon-based NGS as an accurate and reliable tool to detect and monitor clinically relevant molecular alterations in patients with advanced NSCLC.