Association of complement pathways with COVID-19 severity and outcomes.

OBJECTIVES: Complement activation has been implicated in COVID-19 pathogenesis. This study aimed to assess the levels of complement activation products and full-length proteins in hospitalized patients with COVID-19, and evaluated whether complement pathway markers are associated with outcomes. METHODS: Longitudinal measurements of complement biomarkers from 89 hospitalized adult patients, grouped by baseline disease severity, enrolled in an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial and treated with intravenous sarilumab (200 mg or 400 mg) or placebo (NCT04315298), were performed. These measurements were then correlated with clinical and laboratory parameters. RESULTS: All complement pathways were activated in hospitalized patients with COVID-19. Alternative pathway activation was predominant earlier in the disease course. Complement biomarkers correlated with multiple variables of multi-organ dysfunction and inflammatory injury. High plasma sC5b-9, C3a, factor Bb levels, and low mannan-binding lectin levels were associated with increased mortality. Sarilumab treatment showed a modest inhibitory effect on complement activation. Moreover, sera from patients spontaneously deposited C5b-9 complex on the endothelial surface ex vivo, suggesting a microvascular thrombotic potential. CONCLUSION: These results advance our understanding of COVID-19 disease pathophysiology and demonstrate the importance of specific complement pathway components as prognostic biomarkers in COVID-19.

The Activin/FLRG Pathway Associates with Poor COVID-19 Outcomes in Hospitalized Patients.

A subset of hospitalized COVID-19 patients, particularly the aged and those with comorbidities, develop the most severe form of the disease, characterized by acute respiratory disease syndrome (ARDS), coincident with experiencing a "cytokine storm." Here, we demonstrate that cytokines which activate the NF-κB pathway can induce activin A. Patients with elevated activin A, activin B, and FLRG at hospital admission were associated with the most severe outcomes of COVID-19, including the requirement for mechanical ventilation, and all-cause mortality. A prior study showed that activin A could decrease viral load, which indicated there might be a risk to giving COVID-19 patients an inhibitor of activin. To evaluate this, the role for activin A was examined in a hamster model of SARS-CoV-2 infection, via blockade of activin A signaling. The hamster model demonstrated that use of an anti-activin A antibody did not worsen the disease and there was no evidence for increase in lung viral load and pathology. The study indicates blockade of activin signaling may be beneficial in treating COVID-19 patients experiencing ARDS.

Baseline Severe Acute Respiratory Syndrome Viral Load Is Associated With Coronavirus Disease 2019 Severity and Clinical Outcomes: Post Hoc Analyses of a Phase 2/3 Trial.

BACKGROUND: Elucidating the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and clinical outcomes is critical for understanding coronavirus disease 2019 (COVID-19). METHODS: The SARS-CoV-2 levels were analyzed by quantitative real-time polymerase chain reaction (RT-qPCR) of nasopharyngeal or oropharyngeal swab specimens collected at baseline, and clinical outcomes were recorded over 60 days from 1362 COVID-19 hospitalized patients enrolled in a multicenter, randomized, placebo-controlled phase 2/3 trial of sarilumab for COVID-19 (ClinicalTrials.gov NCT04315298). RESULTS: In post hoc analyses, higher baseline viral load, measured by both RT-qPCR cycle threshold and log10 copies/mL, was associated with greater supplemental oxygenation requirements and disease severity at study entry. Higher baseline viral load was associated with higher mortality, lower likelihood of improvement in clinical status and supplemental oxygenation requirements, and lower rates of hospital discharge. Viral load was not impacted by sarilumab treatment over time versus placebo. CONCLUSIONS: These data support viral load as an important determinant of clinical outcomes in hospitalized patients with COVID-19 requiring supplemental oxygen or assisted ventilation.

Associations of depression severity with heart rate and heart rate variability in young adults across normative and clinical populations.

Limitations of current depression treatments may arise from a lack of knowledge about unique psychophysiological processes that contribute to depression across the full range of presentations. This study examined how individual variations in heart rate (HR) and heart rate variability (HRV) are related to depressive symptoms across normative and clinical populations in 152 young adults (aged 18-35 years). Moderating effects of sex and antidepressant medication status were considered. Electrocardiogram data were collected during "vanilla" baseline and in response to positive and negative emotional cues. Linear regressions and repeated-measures mixed models were used to assess the relationships between Beck Depression Inventory-II (BDI-II) scores, sex, antidepressant use, and cardiovascular outcomes. Baseline models yielded significant main effects of BDI-II and sex on HR and significant interactions between antidepressant medication status and BDI-II on HRV outcomes. The main effects of BDI-II and sex on HR were no longer significant after controlling for cardiorespiratory fitness. Participants who denied current antidepressant use (n = 137) exhibited a negative association and participants who endorsed current antidepressant (n = 15) use exhibited a positive association between BDI-II scores and HRV. Emotional reactivity models were largely non-significant with the exception of a significant main effect of antidepressant medication status on high-frequency HRV reactivity. Results indicated antidepressant medication use may moderate the relationship between depression severity and cardiovascular functioning, but this requires replication given the modest proportion of medicated individuals in this study. Overall, findings suggest cardiovascular processes and cardiorespiratory fitness are linked to depression symptomatology and may be important to consider in depression treatment.

Lower resting cardiac autonomic balance in young adults with current major depression.

Research on cardiac autonomic function in major depressive disorder (MDD) has predominantly examined cardiac vagal control and adopted a model of reciprocal autonomic balance. A proposed bivariate autonomic continuum uses cardiac autonomic balance (CAB) and cardiac autonomic regulation (CAR) models, derived from normalized values of respiratory sinus arrhythmia and pre-ejection period, to more adequately index patterns of autonomic control. The purpose of this study was to assess resting levels of CAB and CAR among young adults with and without a current diagnosis of major depression. One hundred forty-two young adults (n = 65 MDD, n = 77 healthy controls; 20.8 ± 2.6 years) completed a structured diagnostic interview, cardiovascular assessment, and a maximal aerobic fitness test. The findings revealed that CAB, but not CAR, significantly predicted current MDD status (OR = 0.70, 95% CI [0.53, 0.93]), an effect that remained after controlling for aerobic fitness and body mass index. Although CAB was found to be a significant predictor of current MDD status among a sample of young adults, there remained substantial variation in autonomic control that was not captured by the traditional model of reciprocal autonomic balance.

Using Multilevel Modeling to Examine Blunted Neural Responses to Reward in Major Depression.

BACKGROUND: Major depressive disorder (MDD) is a pernicious disorder characterized by deficits in reward processing. A better understanding of these deficits may help to elucidate the underlying pathophysiology and guide treatment development. METHODS: This study assessed reward positivity and feedback negativity event-related potentials and their difference scores elicited in response to monetary gains and losses among 100 young adults (52 with MDD). Multilevel modeling was used to assess individual- and trial-level change in neural responses over time. RESULTS: Trial-level analyses indicated that a diagnosis of MDD and depressive symptom severity significantly moderated the trajectory of reward positivity, with individuals with higher symptoms of depression demonstrating less sensitivity to rewards over time. CONCLUSIONS: These results provide further support for reward dysfunction in MDD and highlight important individual differences in the trajectory of neural responses to reward. Future studies are warranted to investigate reward sensitivity over time to elucidate important individual- and trial-level differences in reward processing.

A history of sport-related concussion is associated with sustained deficits in conflict and error monitoring.

Previous research has demonstrated long-term deficits in neurocognitive function in individuals with a history of sport-related concussion. The purpose of this study was to examine the relationship between a history of concussion and behavioral and event-related potential (ERP) indices of pre- and post-response conflict and error monitoring. A secondary aim was to determine whether years of high risk sport participation were related to impairments in these cognitive control processes. Forty-seven former athletes (age = 20.8 ±â€¯2.2 years) with (n = 25; 5 females) and without (n = 22; 9 females) a history of concussion completed a modified flanker task while behavioral performance, N2, error-related negativity (ERN), and error positivity (Pe) components were assessed. An increase in post-response error-related (ERN) brain activity and a nonsignificant trend of increased pre-response conflict (N2) was observed in individuals with a prior sport-related concussion relative to non-concussed controls; however, no behavioral performance differences were found between groups. No significant associations were found between ERP and behavioral measures and the number of years of high-risk sport participation; however, time since last head injury was associated with shorter N2 latency. Together, these findings suggest a persistent impairment in cognitive control and error-related processing in individuals with a history of concussion. These findings are interpreted within the framework of the compensatory error-monitoring hypothesis.

Do sport-related concussions result in long-term cognitive impairment? A review of event-related potential research.

Sport-related concussions have become a major public health concern although the long-term effects on cognitive function remain largely unknown. Event-related potentials (ERPs) are ideal for studying the long-term impact of sport-related concussions, as they have excellent temporal precision and provide insight that cannot be obtained from behavioral or neuropsychological measures alone. We reviewed all available published studies that have used stimulus or response-locked ERPs to document cognitive control processes in individuals with a history of concussion. Collectively, cross-sectional evidence suggests consistent reductions in P3 amplitude in previously concussed individuals, as well as a possible impairment in cognitive processing speed (P3 latency) and error monitoring processes (ERN). The persistent neurophysiological changes found may be related to the number of previous concussions sustained and the time since injury. Future studies incorporating prospective research designs are warranted before definitive statements can be offered regarding the long-term impact of sport-related concussions on cognitive control.

A randomized trial of aerobic exercise on cognitive control in major depression.

OBJECTIVE: The aim of this study was to examine the effects of an 8-week moderate-intensity aerobic exercise training intervention on cognitive control in individuals with major depressive disorder (MDD). METHODS: Participants with a current diagnosis of MDD (n=30; 21.1±2.0years) were stratified by depressive symptoms and randomized to an 8-week intervention of aerobic exercise (AE) or placebo exercise (PE). AE consisted of three sessions/week of moderate-intensity exercise training while PE consisted of three sessions/week of light-intensity stretching. Cognitive control was assessed pre- and post-treatment using behavioral performance (i.e., reaction time and accuracy) and event-related potentials (i.e., N2 amplitude). Depressive symptoms and rumination were also assessed before and after the intervention. RESULTS: Compared with PE, the AE treatment arm was associated with an increase in N2 amplitude to incongruent flanker task trials, reflecting an increase in cognitive control processes. Symptoms of depression also decreased after AE although the treatments did not differ in their effects on rumination. Exploratory mediation analysis indicated that changes in N2 amplitude did not mediate pre-to-post treatment reductions in depressive symptoms. CONCLUSIONS: An 8-week moderate-intensity AE program is associated with improved neural indices of conflict monitoring and reduced depressive symptoms among individuals with MDD. SIGNIFICANCE: Future research examining the influence of exercise in combination with behavioral and pharmacological treatments for neurocognitive function in MDD is warranted.

Active Workstations Do Not Impair Executive Function in Young and Middle-Age Adults.

PURPOSE: This study aimed to examine the effects of self-selected low-intensity walking on an active workstation on executive functions (EF) in young and middle-age adults. METHODS: Using a within-subjects design, 32 young (20.6 ± 2.0 yr) and 26 middle-age (45.6 ± 11.8 yr) adults performed low-intensity treadmill walking and seated control conditions in randomized order on separate days, while completing an EF test battery. EF was assessed using modified versions of the Stroop (inhibition), Sternberg (working memory), Wisconsin Card Sorting (cognitive flexibility), and Tower of London (global EF) cognitive tasks. Behavioral performance outcomes were assessed using composite task z-scores and traditional measures of reaction time and accuracy. Average HR and step count were also measured throughout. RESULTS: The expected task difficulty effects were found for reaction time and accuracy. No significant main effects or interactions as a function of treadmill walking were found for tasks assessing global EF and the three individual EF domains. Accuracy on the Tower of London task was slightly impaired during slow treadmill walking for both age-groups. Middle-age adults displayed longer planning times for more difficult conditions of the Tower of London during walking compared with sitting. A 50-min session of low-intensity treadmill walking on an active workstation resulted in accruing approximately 4500 steps. CONCLUSIONS: These findings suggest that executive function performance remains relatively unaffected while walking on an active workstation, further supporting the use of treadmill workstations as an effective approach to increase physical activity and reduce sedentary time in the workplace.

Dose-Response and Time Course Effects of Acute Resistance Exercise on Executive Function.

The purpose of this study was to examine possible dose-response and time course effects of an acute bout of resistance exercise on the core executive functions of inhibition, working memory, and cognitive flexibility. Twenty-eight participants (14 female; Mage = 20.5 ± 2.1 years) completed a control condition and resistance exercise bouts performed at 40%, 70%, and 100% of their individual 10-repetition maximum. An executive function test battery was administered at 15 min and 180 min postexercise to assess immediate and delayed effects of exercise on executive functioning. At 15 min postexercise, high-intensity exercise resulted in less interference and improved reaction time (RT) for the Stroop task, while at 180 min low- and moderate-intensity exercise resulted in improved performance on plus-minus and Simon tasks, respectively. These findings suggest a limited and task-specific influence of acute resistance exercise on executive function in healthy young adults.