Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's RE searching COV ID to E nhance R ecovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of five cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study ( n =10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n=6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n=6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n=600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. Clinical Trialsgov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT05172011.

Sex differences in suicidal behaviors and aggression in US Veterans.

Female Veterans are the fastest growing demographic group in the Department of Veterans Affairs. Moreover, suicide rates in female Veterans are increasing, making suicide in female Veterans a topic of vital clinical and research significance. The current study examined the association between suicide, aggression, and mood symptoms by sex. Participants consisted of 264 Veterans (female=54, male=210) ages 18-55. Veterans completed well-validated measures of suicidal behaviors, aggression, anxiety, and depression. Male Veterans reported higher physical aggression, verbal aggression, anger, hostility, and total aggression compared to female Veterans. In male Veterans, lifetime suicidal behavior including ideation and attempts was correlated with total aggression and subscales of physical aggression, verbal aggression, anger, and hostility. However, in female Veterans lifetime suicidal behavior was significantly associated with hostility and anger. There were no between-group differences in measures of suicidal behaviors, anxious or depressive symptoms. These results suggest important differences in the association between aggression and suicidal behavior by sex. These data have significant clinical implications, as males with aggressive traits and females who endorse hostility and anger may be more likely to engage in suicidal behaviors.

Neurobiological evidence of sexual dimorphism in limbic circuitry of US Veterans.

BACKGROUND: Female Veterans are an increasing patient population in the Department of Veterans Affairs and may have distinct clinical and neurobiological features compared to males. METHODS: Nineteen female and 19 male Veterans who met diagnostic criteria for depression/posttraumatic stress disorder (MDD/PTSD) completed diagnostic interviews, symptom measures, and resting-state neuroimaging. Participants completed clinical measures of mood and aggression in addition to magnetic resonance imaging on a 3.0 Tesla Siemens scanner. RESULTS: Females showed increased functional connectivity between the left and right basolateral amygdala (BLA) and the left and right cerebellar and occipital lobes. Sex differences also were evident in the relationship between affective and clinical symptoms with BLA connectivity. Females showed a correlation between revenge planning and decreased connectivity between the left BLA and left occipital lobe and also a correlation between aggression and decreased connectivity between the right BLA and right mid cingulate, right and left medial frontal lobe, and right frontal lobe. Males evidenced a relationship between increased depressive symptoms and increased connectivity between the left BLA and right and left occipital lobe, left calcarine, and other areas associated with visual memory and processing, and interpretation of sensory information. Additionally, males reported higher levels of physical aggression and revenge planning compared to females. LIMITATIONS: This study included neuroimaging and self-report clinical measures. Further studies will benefit from multimodal measures, including behavioral measures of aggression. CONCLUSIONS: Results suggest that male Veterans report more aggression than females and symptoms of aggression and mood are differentially related to BLA connectivity by sex.

Alterations in anterior cingulate cortex myoinositol and aggression in veterans with suicidal behavior: A proton magnetic resonance spectroscopy study.

Studies investigating the neurochemical changes that correspond with suicidal behavior (SB) have not yielded conclusive results. Suicide correlates such as aggression have been used to explore risk factors for SB. Yet the neurobiological basis for the association between aggression and SB is unclear. Aggression and SB are both prevalent in veterans relative to civilian populations. The current study evaluated the relationship between brain chemistry in the anterior (ACC) and the posterior cingulate cortex (POC), as well as the relationship between aggression and SB in a veteran population using proton magnetic resonance spectroscopy (1H-MRS). Single-voxel MRS data at 3 Tesla (T) were acquired from the ACC and POC voxels using a 2-dimensional J-resolved point spectroscopy sequence and quantified using the ProFit algorithm. Participants also completed a structured diagnostic interview and a clinical battery. Our results showed that the myoinositol (mI)/H2O ratio in the ACC and POC was significantly higher in veterans who reported SB when compared to veterans who did not. The two groups did not differ significantly with regard to other metabolites. Second, verbal aggression and SB measures positively correlated with mI/H2O in the ACC. Finally, verbal aggression mediated the relationship between mI/H2O in the ACC and SB.

Suicide Behavior and Chronic Pain: An Exploration of Pain-Related Catastrophic Thinking, Disability, and Descriptions of the Pain Experience.

This study examined differences in suicidal ideation (SI) and suicide attempts (SAs) among veterans with chronic pain. Pain-specific variables, including catastrophic thinking, disability, and sensory, affective, and evaluative pain descriptors, were a focus. Structured diagnostic and clinical interviews were conducted to examine SI/SA and mental health. Veterans completed the Structured Clinical Interview for DSM-IV and the Columbia-Suicide Severity Rating Scale to assess Axis I symptoms and suicidal behavior(s). Self-report questionnaires were used to evaluate the participants' subjective experience of chronic pain, which included the McGill Pain Questionnaire, Pain Catastrophizing Scale, and Pain Disability Index. The findings add to previous literature by suggesting pain-related catastrophic thinking specifically is related to elevated risk for SA, whereas affective and sensory pain are associated with SI. The study results support the need to assess pain from a multifaceted perspective and to examine the different experiences of pain, such as sensory and affective constructs, when discussing suicide risk in veterans.

Enlarged thalamic volumes and increased fractional anisotropy in the thalamic radiations in veterans with suicide behaviors.

Post-mortem studies have suggested a link between the thalamus, psychiatric disorders, and suicide. We evaluated the thalamus and anterior thalamic radiations (ATR) in a group of Veterans with and without a history of suicidal behavior (SB) to determine if thalamic abnormalities were associated with an increased risk of SB. Forty Veterans with mild traumatic brain injury (TBI) and no SB (TBI-SB), 19 Veterans with mild TBI and a history of SB (TB + SB), and 15 healthy controls (HC) underwent magnetic resonance imaging scanning including a structural and diffusion tensor imaging scan. SBs were evaluated utilizing the Columbia Suicide Rating Scale and impulsivity was measured using the Barratt Impulsiveness Scale (BIS). Differences in thalamic volumes and ATR fractional anisotropy (FA) were examined between (1) TBI + SB versus HC and (2) TBI + SB versus combined HC and TBI-SB and (3) between TBI + SB and TBI-SB. Left and right thalamic volumes were significantly increased in those with TBI + SB compared to the HC, TBI-SB, and the combined group. Veterans with TBI + SB had increased FA bilaterally compared to the HC, HC and TBI-SB group, and the TBI-SB only group. Significant positive associations were found for bilateral ATR and BIS in the TBI + SB group. Our findings of thalamic enlargement and increased FA in individuals with TBI + SB suggest that this region may be a biomarker for suicide risk. Our findings are consistent with previous evidence indicating that suicide may be associated with behavioral disinhibition and frontal-thalamic-limbic dysfunction and suggest a neurobiologic mechanism that may increase vulnerability to suicide.