Neuroticism/Negative Emotionality Is Associated with Increased Reactivity to Uncertain Threat in the Bed Nucleus of the Stria Terminalis, Not the Amygdala.

Neuroticism/negative emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and well-being. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment to psychiatric illness. Animal research suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to humans has remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to test this hypothesis in an ethnoracially diverse, sex-balanced sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is preferentially associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat (aversive multimodal stimulation), whereas N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to threat-related faces. It is often assumed that different threat paradigms are interchangeable assays of individual differences in brain function, yet this has rarely been tested. Our results revealed negligible associations between BST/Ce reactivity to the anticipation of threat and the presentation of threat-related faces, indicating that the two tasks are nonfungible. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for refining mechanistic research.

A shared threat-anticipation circuit is dynamically engaged at different moments by certain and uncertain threat.

Temporal dynamics play a central role in models of emotion: "fear" is widely conceptualized as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Yet the underlying human neurobiology remains contentious. Leveraging an ethnoracially diverse sample, translationally relevant paradigm, and theory-driven modeling approach, we demonstrate that certain and uncertain threat recruit a shared threat-anticipation circuit. This cortico-subcortical circuit exhibits persistently elevated activation when anticipating uncertain-threat encounters and a transient burst of activation in the moments before certain encounters. For many scientists and clinicians, feelings are the defining feature of human fear and anxiety. Here we used an independently validated brain signature to covertly decode the momentary dynamics of anticipatory distress for the first time. Results mirrored the dynamics of neural activation. These observations provide fresh insights into the neurobiology of threat-elicited emotions and set the stage for more ambitious clinical and mechanistic research. SIGNIFICANCE STATEMENT: "Fear" is often viewed as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Prior work begun to reveal the neural systems recruited by different threats, but has yet to plumb the moment-by-moment dynamics anticipated by theory and behavioral research. Here we used a novel combination of neuroimaging techniques to demonstrate that certain and uncertain threat recruit a shared threat-anticipation circuit. Activity in this circuit and covert measures of distress showed similar patterns of context-dependent dynamics, exhibiting persistent increases when anticipating uncertain-threat encounters and transient surges in the seconds before certain encounters. These observations provide fresh insights into the neurobiology of fear and anxiety, laying the groundwork for more ambitious clinical and mechanistic research.

Adolescent social anxiety is associated with diminished discrimination of anticipated threat and safety in the bed nucleus of the stria terminalis.

Social anxiety-which typically emerges in adolescence-lies on a continuum and, when extreme, can be devastating. Socially anxious individuals are prone to heightened fear, anxiety, and the avoidance of contexts associated with potential social scrutiny. Yet most neuroimaging research has focused on acute social threat. Much less attention has been devoted to understanding the neural systems recruited during the uncertain anticipation of potential encounters with social threat. Here we used a novel fMRI paradigm to probe the neural circuitry engaged during the anticipation and acute presentation of threatening faces and voices in a racially diverse sample of 66 adolescents selectively recruited to encompass a range of social anxiety and enriched for clinically significant levels of distress and impairment. Results demonstrated that adolescents with more severe social anxiety symptoms experience heightened distress when anticipating encounters with social threat, and reduced discrimination of uncertain social threat and safety in the bed nucleus of the stria terminalis (BST), a key division of the central extended amygdala (EAc). Although the EAc-including the BST and central nucleus of the amygdala-was robustly engaged by the acute presentation of threatening faces and voices, the degree of EAc engagement was unrelated to the severity of social anxiety. Together, these observations provide a neurobiologically grounded framework for conceptualizing adolescent social anxiety and set the stage for the kinds of prospective-longitudinal and mechanistic research that will be necessary to determine causation and, ultimately, to develop improved interventions for this often-debilitating illness.

Patients With Atypical Chest Pain: Epidemiology and Reported Consequences.

BACKGROUND: Approximately a quarter of the global population experiences chest pain during their lifetime worldwide. Although largely non-life-threatening, many patients experience mental, physical, social, and financial consequences. AIM: This study aimed to describe and determine the epidemiology and consequences of patients presenting with atypical chest pain (ACP).  Method: Data were obtained from 102 participants, from a desired sample size of 166. The target population was patients who presented with ACP at the Accident and Emergency Department of a Teaching Hospital in Trinidad during a two-year period, from January 2021 to December 2022. The data collection instrument used was a 34-item online questionnaire. Data were analyzed using both descriptive and inferential statistical methods. RESULTS: Participants were predominantly women (63.7%; n = 65), between 31 and 50 years of age (74.5%; n = 76), in full-time employment (n = 58; 56.9%), who lived with at least one person (90.2%; n = 92) at the time of the episode. Overall, 61.8% (n = 63) reported having a stressful life. Hypertension (30.4%; n = 31) and diabetes (18.6%; n = 19) were the leading comorbidities. Participants experienced mild to severe anxiety (53.9%; n = 55), moderate to severe depression (25.5%; n = 26), moderate stress (65.7%; n = 67), and loneliness (25.5%; n = 26). A stressful life was associated with, and was a predictor of, both anxiety and loneliness. No sociodemographic variables were associated with depression or stress. The most common self-reported consequences were "fear as a result of the pain" (68.6%; n = 69), "interruptions to daily life" (60.8%; n = 61), "reduction in time spent on hobbies" (62.7%; n = 63), and costly diagnostic/investigative tests (62.7%; n = 64). The majority of patients (52.9%; n = 53) reported reduced quality of life. The most common treatment prescribed was paracetamol (53.9%; n = 55) and exercise (23.5%; n = 24). CONCLUSION: The study participants were mainly women, 31-50 years old, who had experienced anxiety, stress, or depression. They mainly experienced fear and self-reported a reduced quality of life.

Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala.

Neuroticism/Negative Emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and wellbeing. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment and divorce to mental illness and premature death. Work in animals suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to the human brain and temperament have remained unclear. Here we used a combination of psychometric, psychophysiological, and neuroimaging approaches to rigorously test this hypothesis in an ethnoracially diverse sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is selectively associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat. In contrast, N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to 'threat-related' faces. Implicit in much of the neuroimaging literature is the assumption that different threat paradigms are statistically interchangeable probes of individual differences in neural function, yet our results revealed negligible evidence of convergence between popular threat-anticipation and emotional-face tasks. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for informing the next generation of mechanistic research.

Social mobility and mental health: A systematic review and meta-analysis.

Socioeconomic status (SES) is a robust correlate of mental health, and emerging research indicates that life course trajectories of SES (i.e., social mobility) may be more predictive for health outcomes than point-in-time SES assessments. This paper presents five primary meta-analyses to determine how mental health differs between social mobility groups. We conducted a systematic review of PsycINFO, Web of Science, and PubMed for studies of social mobility and mental health. We used random-effects multilevel meta-analyses to compare mental health problems between individuals who experienced upward mobility, downward mobility, stable high SES, and stable low SES. We included data from 21 studies and 157,763 unique participants yielding 105 effect sizes. Upwardly mobile participants experienced more mental health problems than stable high SES participants (d = 0.11), fewer mental health problems than stable low SES participants (d = -0.24), and fewer mental health problems than downwardly mobile participants (d = -0.17). Downwardly mobile individuals experienced more mental health problems than stable high SES participants (d = 0.26) and fewer mental health problems than stable low SES participants (d = -0.10). Subgroup analyses revealed that the magnitude of effects did not differ by continent of study, type of generational mobility (intergenerational vs. intragenerational), or SES indicator. Meta-regressions with continuous moderators (age, gender, race, study quality) were also non-significant. Taken together, these results indicate that both upwardly and downwardly mobile individuals experience more mental health problems than those who are persistently advantaged, and they both experience fewer mental health problems than those who are persistently disadvantaged. Our findings suggest that while current SES has a stronger association with adult mental health than childhood SES, it is important to also consider the impact of early life and prior generation SES to account for lingering effects of early disadvantage.

Acute nicotine abstinence amplifies subjective withdrawal symptoms and threat-evoked fear and anxiety, but not extended amygdala reactivity.

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

To Proceed Via Telehealth or Not? Considerations for Pediatric Anxiety and Related Disorders Beyond COVID-19.

The COVID-19 pandemic accelerated a widespread shift to telehealth among mental health professionals to prioritize both providers' and clients' safety. Telehealth is likely here to stay; however, there is limited practical guidance for clinicians about how to make decisions regarding who should proceed with care via telehealth versus in-person. There also is virtually no data on the effectiveness of hybrid approaches to care; yet this can be an attractive option with potential clinical benefit. This paper provides practice-informed guidance to support shared clinical decision-making between clinicians and families to decide whether to engage in therapy services in-person or via telehealth. We specifically focus on decision-making guidance relevant for youth with anxiety or related disorders, given the unique implications of telehealth for these youth. Guided by the three-legged stool of evidence-based practice, we discuss how clinicians can use principles of shared decision-making to inform clinical recommendations about treatment modality.

Factors associated with abuse in the workplace in Bangladesh: An empirical investigation.

Workplace abuse is a much-discussed global phenomenon in the world of work. Bangladesh, being a developing country that relies heavily on its labor resource, should have definite methods to protect the workers' rights and safety. Unfortunately, weak frameworks are in place to prevent it, and the lack of awareness among the workers is helping the problem to establish its roots more firmly. Despite the gravity of workplace abuse and its consequences, comprehensive studies for addressing or understanding the problem at a national level is difficult to find in the context of Bangladesh. Using the latest nationally representative survey namely the Quarterly Labour Force Survey (QLFS) 2016-17, this study attempts to bridge the existing gaps through an empirical investigation of the factors associated with workplace abuse in Bangladesh. A total of 16,646 participants with males of 75.9% and females of 24.1% are used for the analysis. A probit model analysis has been applied in this paper to explore how the workers' demographic and socioeconomic characteristics, as well as workplace features, may be associated with experiencing abuse in the workplace. The study finds that younger, less educated, females, elementary job-holders, non-governmental organization workers or those who work in the manufacturing, or services sector are more likely to be abused in the workplace. The study also concludes that the number of workers employed, and the hazardous workplace environment may be related to the probability of being abused. Furthermore, this study shows that full-time workers, workers who are employed temporarily or have an oral contract may face abuse in the workplace more.

Breaking the Cycle of Intergenerational Childhood Maltreatment: Effects on Offspring Mental Health.

This study evaluated how continuities and discontinuities in the intergenerational transmission of maltreatment affect offspring psychopathology. Data from a multigenerational prospective, longitudinal study were used to compare the severity of offspring psychopathology in families with no history of maltreatment (controls) and those in which parents, offspring, or both experienced childhood maltreatment (cycle breakers, initiators, and maintainers, respectively). Participants included 454 parents (Mage = 47.1, SDage = 3.4) and their 697 offspring (Mage = 22.3, SDage = 6.3). Offspring of cycle breakers reported less psychopathology than offspring of cycle maintainers and did not report more psychopathology than offspring of controls. Offspring of cycle initiators and maintainers reported comparable levels of psychopathology. Results suggest that breaking the cycle of maltreatment buffers offspring from risk for psychopathology associated with parental maltreatment, with no enduring or additive effects of maltreatment across generations. Our findings highlight the need for maltreatment prevention programs and further research to identify conditions and characteristics that reduce the probability of intergenerational transmission.

Anxiety-Related Frontocortical Activity Is Associated With Dampened Stressor Reactivity in the Real World.

Negative affect is a fundamental dimension of human emotion. When extreme, it contributes to a variety of adverse outcomes, from physical and mental illness to divorce and premature death. Mechanistic work in animals and neuroimaging research in humans and monkeys have begun to reveal the broad contours of the neural circuits governing negative affect, but the relevance of these discoveries to everyday distress remains incompletely understood. Here, we used a combination of approaches-including neuroimaging assays of threat anticipation and emotional-face perception and more than 10,000 momentary assessments of emotional experience-to demonstrate that individuals who showed greater activation in a cingulo-opercular circuit during an anxiety-eliciting laboratory paradigm experienced lower levels of stressor-dependent distress in their daily lives (ns = 202-208 university students). Extended amygdala activation was not significantly related to momentary negative affect. These observations provide a framework for understanding the neurobiology of negative affect in the laboratory and in the real world.

Sunitinib in Patients with Metastatic Colorectal Cancer (mCRC) with FLT-3 Amplification: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

BACKGROUND: TAPUR is a pragmatic, phase II basket study evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Sunitinib is an oral multikinase inhibitor of FMS-like tyrosine kinase-3 (FLT-3), among other targets. Results from a cohort of patients with metastatic colorectal cancer (mCRC) with FLT-3 amplification treated with sunitinib are reported. OBJECTIVE: This study aimed to investigate whether patients with mCRC with FLT-3 amplification would be responsive to sunitinib, an oral multikinase inhibitor. METHODS: Eligible patients received a standard sunitinib dose of 50 mg orally for 4 weeks followed by 2 weeks off. Simon's two-stage design was used with the primary study endpoint of objective response (OR) or stable disease (SD) at 16 weeks based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints were progression-free survival, overall survival, and safety. RESULTS: Ten patients were enrolled from November 2016 to April 2018. All patients had mCRC with FLT-3 amplification. No ORs were observed. Although two patients had SD at 16 weeks, one died because of disease progression shortly thereafter and the cohort was closed. A single grade 3 adverse event of diarrhea was reported as possibly related to sunitinib. CONCLUSIONS: Monotherapy with sunitinib does not have clinical activity in patients with mCRC with FLT-3 amplification and should not be prescribed for off-label use. Other treatments should be considered for these patients, including treatments offered in clinical trials. CLINICAL TRIAL REGISTRATION: NCT02693535 (26 February 2016).

Palbociclib in Patients With Non-Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non-small-cell lung cancer (NSCLC) with CDKN2A alterations treated with palbociclib are reported. METHODS: Eligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC with CDKN2A alterations and no Rb mutations received palbociclib 125 mg orally once daily for 21 days, followed by 7 days off. Simon's two-stage design was used with a primary study end point of objective response or stable disease (SD) of at least 16 weeks in duration. Secondary end points are progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Twenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting. CONCLUSION: Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with CDKN2A alterations. Additional investigation is necessary to confirm efficacy and utility of palbociclib in this population.

Social context and the real-world consequences of social anxiety.

BACKGROUND: Social anxiety lies on a continuum, and young adults with elevated symptoms are at risk for developing a range of psychiatric disorders. Yet relatively little is known about the factors that govern the hour-by-hour experience and expression of social anxiety in the real world. METHODS: Here we used smartphone-based ecological momentary assessment (EMA) to intensively sample emotional experience across different social contexts in the daily lives of 228 young adults selectively recruited to represent a broad spectrum of social anxiety symptoms. RESULTS: Leveraging data from over 11 000 real-world assessments, our results highlight the central role of close friends, family members, and romantic partners. The presence of such close companions was associated with enhanced mood, yet socially anxious individuals had fewer confidants and spent less time with the close companions that they do have. Although higher levels of social anxiety were associated with a general worsening of mood, socially anxious individuals appear to derive larger benefits - lower levels of negative affect, anxiety, and depression - from their close companions. In contrast, variation in social anxiety was unrelated to the amount of time spent with strangers, co-workers, and acquaintances; and we uncovered no evidence of emotional hypersensitivity to these less-familiar individuals. CONCLUSIONS: These findings provide a framework for understanding the deleterious consequences of social anxiety in emerging adulthood and set the stage for developing improved intervention strategies.

Integrated Duo Wavelength VCSEL Using an Electrically Pumped GaInAs/AlGaAs 980 nm Cavity at the Bottom and an Optically Pumped GaInAs/AlGaInAs 1550 nm Cavity on the Top.

In this work, an integrated single chip dual cavity VCSEL has been designed which comprises an electrically pumped 980 nm bottom VCSEL section fabricated using GaInAs/AlGaAs MQW active region and a 1550 nm top VCSEL section constructed using GaInAs/AlGaInAs MQW active region but optically pumped using half of the produced 980 nm light entering into it from the electrically pumped bottom cavity. In this design, the active region of the intracavity structure 980 nm VCSEL consists of 3 quantum wells (QWs) using Ga0.847In0.153As, 2 barriers using Al0.03Ga0.97As, and 2 separate confinement heterostructures (SCH) using the same material as the barrier. The active region of the top emitting 1550 nm VCSEL consists of 3 QWs using Ga0.47In0.52As, 2 barriers using Al0.3Ga0.17In0.53As, and 2 SCHs using the same material as the barrier. The top DBR and the bottom DBR mirror systems of the 1550 nm VCSEL section plus the top and bottom DBR mirror systems of the 980 nm VCSEL section have been formed using GaAs/Al0.8Ga0.2As. Computations show that the VCSEL is capable of producing 8.5 mW of power at 980 nm from the bottom side and 2 mW of power at the 1550 nm from top side.