Indirect Effects Model Research Articles

Pharmacodynamic Models of Indirect Effects and Irreversible Inactivation with Turnover: Applicability to Mechanism-Based Modeling of Gene Silencing and Targeted Protein Degradation

Indirect response (IDR) and turnover with inactivation (TI) comprise two arrays of mechanism-based pharmacodynamic (PD) models widely used to describe delayed drug effects. IDR Model-IV (stimulation of response loss) and TI (irreversible loss) have been described with discerning “signature” profiles; classical IDR-IV response-time profiles display slow declines where peak response shifts later with increasing dose, whereas TI profiles feature steep response declines with earlier-shifting nadirs. Herein, we demonstrate mathematical convergence of IDR-IV and TI models upon implementation with identical linear versus nonlinear pharmacologic effect terms. Time of peak response in IDR-IV can in fact shift earlier or later depending on PK or PD parameters (e.g., kel, Smax) and effect type. A generalized dynamic model linking mRNA and protein turnover is proposed. Applicability of IDR-IV and TI, with either linear or nonlinear terms acting on degradation/catabolism/loss of response, is demonstrated through model-fitting PK-PD effects of three proteolysis-targeting chimeras (PROTACs) and two ligand-conjugated small interfering RNAs (siRNA). This work clarifies mathematical properties, convergence, and expected responses of IDR-IV and TI, demonstrates their applicability for targeted gene-silencing and protein-degrading agents, and illustrates how well-designed in vivo studies covering broad dose ranges with richly sampled time-points can influence PK-PD model structure and parameter resolution.

Gender Differences in Older Adults’ Muscle Strength and Depressive Symptoms: A Relationship Mediated Through Perceived Stress

Purpose: Preventing the effects of physical vulnerability is a practical approach to improving older adults’ depressive symptoms. This study aims to examine the relationship between gender differences related to muscle strength and depressive symptoms mediated by perceived stress. Methods: In this cross-sectional study, data from 2,705 older adults (65 years old or older) from the Korea National Health and Nutrition Examination Survey VII 2016 and 2018 were analyzed. The moderated mediation model was developed; the outcome, independent, mediation, and moderated mediation variables in the literature-based research model were depressive symptoms, muscle strength, perceived stress, and gender, respectively. Results: Perceived stress had a mediating effect on the relationship between muscle strength and depressive symptoms. The indirect effect of muscle strength on depressive symptoms mediated by perceived stress was β = -.02 (95% CI:-0.03~-0.01). The moderated mediation model demonstrated that the interaction term of handgrip strength and gender negatively affected perceived stress, which indicated that gender moderated the mediating model of perceived stress on the association of muscle strength and depressive symptoms (β = -.01, p <.05). The conditional indirect effect model was insignificant in the male group (β = -.00, 95% CI:-0.01~0.01) but significant in the female group (β = -.01, 95% CI: -0.02~0.00). Conclusions: Perceived stress mediated the relationship between muscle strength and depressive symptoms. However, the effect differed by gender. A stress-mediated depressive symptoms intervention program for older adults should be developed to consider women’s needs.

Associations between social engagement, internalizing symptoms, and delusional ideation in the general population.

Delusions are a hallmark feature of psychotic disorders and lead to significant clinical and functional impairment. Internalizing symptoms-such as symptoms of depression, anxiety, and trauma exposure-are commonly cited to be related to delusions and delusional ideation and are often associated with deficits in social functioning. While emerging studies are investigating the impact of low social engagement on psychotic-like experiences, little work has examined the relationship between social engagement, internalizing symptoms, and delusional ideation, specifically. Using general population data from the Nathan Kline Institute-Rockland (NKI-Rockland) database (N = 526), we examined the relationships between self-reported delusional ideation, internalizing symptoms, and social engagement and tested four indirect effect models to understand how these factors interrelate. Delusional ideation was significantly associated with both increased internalizing symptoms (r = 0.41, p < 0.001) and lower social engagement (r = -0.14, p = 0.001). Within aspects of social engagement, perceived emotional support showed the strongest relationship with delusional ideation (r = -0.17, p < 0.001). Lower social engagement was also significantly associated with increased internalizing symptoms (r = -0.29, p < 0.001). Cross-sectional models suggest that internalizing symptoms have a significant indirect effect on the association between delusional ideation and social engagement. These findings reveal that elevated delusional ideation in the general population is associated with lower social engagement. Elevated internalizing symptoms appear to play a critical role in reducing engagement, possibly exacerbating delusional thinking. Future work should examine the causal and temporal relationships between these factors.

Digitalization and energy: How could digital economy eliminate energy poverty in China?

Energy poverty has threatened the sustainability of countries. Meanwhile, digital economy is reshaping the global energy system, and its impacts on energy poverty deserves attention and exploration. Energy poverty by province in China is reassessed between 2007 and 2019, multiple estimation methods are applied to test the impacts of digital economy on energy poverty, and the varied impacts are investigated using heterogeneity analyses. Based on the technological innovation perspective, indirect effect model and dynamic panel threshold model are further constructed to test the indirect and nonlinear effects of digital economy on energy poverty. The results indicate that digital economy significantly reduces energy poverty in China. Specifically, such positive impact is more pronounced in the eastern China, and the government's energy planning reinforces it. Besides, the energy poverty reduction impact of digital economy is mainly reflected in affordability and efficiency of energy, and cleanliness of energy consumption. Further, digital economy may alleviate energy poverty by enhancing technological innovation, under the technological innovation threshold constraint, its impact is nonlinear. This study provides policy insights for accelerating poverty eradication in China and also offers evidence that digital economy empowers sustainable development.

Supportive leadership and job satisfaction at the European Court of Auditors

This article draws on theories of person–organisation fit and leadership behaviour to explore how supportive leadership is related to communication practices, collaborative working practices and performance management practices and how these three practices, in turn, relate to public servants’ job satisfaction. A model of supportive leadership's direct and indirect effects on employees’ job satisfaction is empirically tested using responses to a survey administered to the European Court of Auditors (ECA) staff. The findings show that communication and collaborative working practices mediate the relationship between supportive leadership and job satisfaction. Supportive leadership positively relates to performance management practices, but these practices have no significant association with job satisfaction. While addressing a theoretical void in the field, this study also makes an empirical contribution by unveiling how a professional European public audit institution manages its human resources and the means it uses. Points for practitioners Elaborating on the relationship between leadership behaviour and person–organisation fit in the context of a supranational public entity helps to explain what motivates public servants. The relationship between supportive leadership and public servants’ job satisfaction is mediated by two organisational practices: communication and collaborative working practices. Transparent performance management practices do not mediate the relationship between supportive leadership and job satisfaction. Public sector organisations with professional staff can centre their human resource management around effective communication and collaborative working practices to ensure greater employee satisfaction in the workplace.

The Relationship Between Autistic Traits and Quality of Life: Investigation of Indirect Effects Through Self-Determination.

Self-determination, described broadly as experiencing causal agency, is positively associated with quality of life (QoL) and increases through satisfaction of three basic psychological needs: autonomy (feeling able to make choices free from pressure), competence (perceived self-efficacy), and relatedness (social connection). Both unsupportive environments and challenges with social interaction can interfere with satisfaction of psychological needs. Social challenges are a key trait for autism diagnosis, and unsupportive environments are also known to adversely affect QoL for autistic people. Autistic people report, on average, lower self-determination than non-autistic people. Therefore, it is hypothesized that higher levels of autistic traits may reduce opportunities to develop self-determination, affecting QoL. We tested a parallel indirect effects model where we hypothesized that the relationships between autistic traits and four domains of QoL (psychological, social, physical, and environmental) would be indirectly influenced through self-determination (represented through satisfaction of the basic psychological needs for autonomy, competence, and relatedness). This study drew participants from the general population (N = 262; M AGE = 37.6, standard deviation = 11.92; 1.9% reported an autism diagnosis and 2.7% identified as autistic without a diagnosis). Participants completed an online survey. Higher levels of autistic traits were associated with lower levels of self-determination and lower levels of QoL, and there was a significant indirect effect between autistic traits and QoL via self-determination. More specifically, we found a significant indirect effect between autistic traits and all QoL domains via competence; between autistic traits and the environmental, social, and psychological QoL domains via relatedness; and between autistic traits and the physical and environmental QoL domains through autonomy. Our results suggest that supporting satisfaction of the needs for autonomy, competence, and relatedness may represent an important element in designing effective programs to support the development of self-determination in people with higher levels of autistic traits (potentially including autistic individuals) and also to support these people to improve their QoL.

Social support, self-efficacy, self-esteem, and well-being during COVID-19 lockdown: A two-wave study of Danish students.

Societal lockdown due to the COVID-19 pandemic has transformed everyday life across the globe, including requirements of social distancing that might limit the social support people derive from social interaction. Social support has proven to be a vital resource for well-being (i.e., perceived stress and satisfaction with life) and coping during societal challenges. The present study examined how social support is associated with perceived stress and life satisfaction through self-efficacy and self-esteem among Danish students (N = 204). These psychological constructs were examined both during and after lockdown, assessing the possible aversive psychological effects of the COVID-19 pandemic. Results did not yield any significant changes in either the mean scores of the constructs or the indirect effects model across the two time points. Moreover, the results indicate that social support derived from a significant person, family, and friends - but not student peers - is negatively linked with perceived stress and positively associated with life satisfaction through both self-efficacy and self-esteem. Although societal lockdown did not yield significant psychological impact, the results highlight the importance of social support among students, both during and after lockdown.

Relationship Between Fear of COVID-19, Conspiracy Beliefs About Vaccines and Intention to Vaccinate Against COVID-19: A Cross-National Indirect Effect Model in 13 Latin American Countries.

The present study explored the predictive capacity of fear of COVID-19 on the intention to be vaccinated against COVID-19 and the influence in this relationship of conspiracy beliefs as a possible mediating psychological variable, in 13 Latin American countries. A total of 5779 people recruited through non-probabilistic convenience sampling participated. To collect information, we used the Fear of COVID-19 Scale, Vaccine conspiracy beliefs Scale-COVID-19 and a single item of intention to vaccinate. A full a priori Structural Equation Model was used; whereas, cross-country invariance was performed from increasingly restricted structural models. The results indicated that, fear of COVID-19 positively predicts intention to vaccinate and the presence of conspiracy beliefs about COVID-19 vaccines. The latter negatively predicted intention to vaccinate against COVID-19. Besides, conspiracy beliefs about COVID-19 vaccines had an indirect effect on the relationship between fear of COVID-19 and intention to vaccinate against COVID-19 in the 13 countries assessed. Finally, the cross-national similarities of the mediational model among the 13 participating countries are strongly supported. The study is the first to test a cross-national mediational model across variables in a large number of Latin American countries. However, further studies with other countries in other regions of the world are needed.

Anti-inflammatory effects of dexamethasone in COVID-19 patients: Translational population PK/PD modeling and simulation.

Dexamethasone (DEX) given at a dose of 6 mg once-daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID-19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti-inflammatory effects in COVID-19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed-effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France). Published data for DEX PK in patients with COVID-19 exhibited moderate variability with a clearance of about half that in healthy adults. No accumulation of the drug was expected even with daily oral doses of 12 mg. Indirect effect models of DEX inhibition of TNFα, IL-6, and CRP plasma concentrations were enacted and simulations performed for DEX given at 1.5, 3, 6, and 12 mg daily for 10 days. The numbers of individuals that achieved specified reductions in inflammatory biomarkers were compared among the treatment groups. The simulations indicate the need for 6 or 12 mg daily doses of DEX for 10 days for simultaneous reductions in TNFα, IL-6, and CRP. Possibly beneficial is DEX given at a dose of 12 mg compared to 6 mg. The PopPK/PD model may be useful in the assessment of other anti-inflammatory compounds as well as drug combinations in the treatment of cytokine storms.

Entrainment Makes Pollution More Likely to Weaken Deep Convective Updrafts Than Invigorate Them

AbstractAre the results of aerosol invigoration studies that neglect entrainment valid for diluted deep convective clouds? We address this question by applying an entraining parcel model to soundings from tropical and midlatitude convective environments, wherein pollution is assumed to increase parcel condensate retention. Invigoration of 5%–10% and &lt;2% is possible in undiluted tropical and midlatitude parcels respectively when freezing is rapid. This occurs because the positive buoyancy contribution from freezing is larger than the negative buoyancy contribution from condensate loading, leading to positive net condensate contribution to buoyancy. However, aerosol‐induced weakening is more likely when realistic entrainment rates occur because water losses from entrainment more substantially reduce the latent heating relative to the loading contribution. This leads to larger net negative buoyancy contribution from condensates in polluted than in clean entraining parcels. Our results demonstrate that accounting for entrainment is critical in conceptual models of aerosol indirect effects in deep convection.

0683 Sleep disturbance, social functioning, and suicidal ideation among preadolescent children admitted to intensive psychiatric care

Abstract Introduction Research on preadolescent childhood suicidality is sparse, with recent population-based studies providing support for sociodemographic and diagnostic correlates of preadolescent suicidal ideation. Sleep disturbance is of particular interest in the examination of preadolescent suicidal ideation because sleep health is interlinked with childhood psychosocial functioning; further, there are changes in preadolescent homeostatic regulation of sleep-wake and intrinsic circadian rhythm (i.e., delayed sleep onset), and psychosocial pressures in preadolescence, such as bedtime autonomy, that are increasingly manifested. There is a need to test models that begin to delineate associations between sleep disturbance and childhood suicidal ideation, specifically among youth with early-onset psychopathology. One possible explanatory factor in the association between sleep disturbance and suicidal ideation, grounded in existing theoretical frameworks of suicide, is social functioning (e.g., developmentally appropriate peer interactions and connectedness). The current study tested an indirect effects model in which sleep disturbance is associated with suicidal ideation via social functioning. Methods 223 children (ages 7–12) with severe psychopathology who presented for intensive hospital-based treatment and their caregivers completed an assessment battery at admission, including the parent-reported sleep disturbances via the Children’s Sleep Habits Questionnaire, and child-reported dysregulated negative affect, social functioning, and suicidal ideation. Indirect effects were examined via the PROCESS macro for SPSS Version 4.0. Binary logistic regression was used when suicidality served as the dependent variable. All models controlled for youth age and dysregulated negative affect. Results Higher levels of parent-reported youth sleep disturbances were related to lower levels of youth-report social functioning. Further, lower levels of social functioning and higher levels of sleep disturbances were associated with higher odds of endorsing suicidal ideation. Indirect effects analyses indicated that higher levels of sleep disturbances was associated with increased odds of reporting suicidal ideation via the detrimental impact of sleep disturbances on social functioning. Conclusion The findings support the novel extension of explanatory models of suicide to children and highlight the possible role of sleep disturbance in the etiology of early suicidality. Documenting these associations provides the impetus for fine-grained examination of sleep health and social functioning among children who experience suicidal ideation and severe psychopathology. Support (if any)

Conditional role of parental controlling mediation on the relationship between escape, daily game time, and gaming disorder.

Parental mediation to protect children from gaming disorders may have unintended consequences. According to the self-determination theory, parental mediation with psychological control may exacerbate problem behavior. Therefore, investigating the indirect effects of parental controlling mediation on gaming disorders is worthwhile. This study aimed to examine the conditional effect of parental controlling mediation on the relationship between escape motivation and gaming disorder, mediated by daily game time. The following research questions were investigated: whether escape motivation has an indirect effect on gaming disorder through daily game time, and whether parental controlling mediation moderates the relationship between gaming disorder and daily gaming time. The convenience sample included 501 mid-school students (251 male and 250 female) in grades 5-7. The conditional indirect effects model was developed using Hayes's model 14 and Process Macro. The results showed that escape motivation was positively related to gaming disorder through daily game time, and parental controlling mediation had a moderating effect on the relationship between daily game time and gaming disorder. These findings suggest that parental mediation to protect children from excessive gaming may be related to gaming disorder when implemented with psychological control. Higher parental controlling mediation may be a risk factor for gaming disorder even when their children play games less frequently. These findings are discussed in light of the literature.

The relations between students' belongingness, self-efficacy, and response to active learning in science, math, and engineering classes

ABSTRACT Despite numerous benefits, students do not always respond positively and engage in active learning in STEM courses. Understanding the factors that influence how students’ respond to active learning is important to devising interventions that support their learning, especially for students from historically underrepresented groups. This study examines the influence of students’ belongingness and self-efficacy on their affective and behavioural response to active learning and the moderating influence of students’ gender-identity. We surveyed 579 students from 25 Science, Engineering, and Computer Science courses across 14 universities. Using a latent indirect-effect model, we found that belongingness and self-efficacy independently predicted students’ affective response to active learning and evaluation of the class. Belongingness also predicted students’ self-reports of their behavioural participation in active learning. Using measurement invariance, we also found that, despite mean differences in value, positivity, and distraction, there were no gender differences in the strength of relations between variables. These findings suggest that belongingness and self-efficacy play an important role in how all students respond to active learning and that fostering an atmosphere that supports both may reduce student’s resistance to engaging in active learning.

The benefits of making peace with pain: chronic pain acceptance moderates the indirect effect of perceived burdensomeness between pain severity and suicidal cognitions.

The purpose of this study was (1) to examine the degree to which perceived burdensomeness mediates the relationship between pain severity and suicidal cognitions and (2) to determine whether this mediated relationship was moderated by pain acceptance. We predicted that high levels of pain acceptance would buffer relationships on both paths of the indirect effect. Two-hundred seven patients with chronic pain completed an anonymous self-report battery of measures, including the Chronic Pain Acceptance Questionnaire, the Interpersonal Needs Questionnaire, the Suicidal Cognitions Scale, and the pain severity subscale of the West Haven-Yale Multidimensional Pain Inventory. Conditional process models were examined with Mplus. Chronic pain acceptance significantly moderated both paths of the mediation model. Results from the conditional indirect effect model indicated that the indirect effect was significant for those with low (b = 2.50, P = .004) and medium (b = 0.99, P = .01) but not high (b = 0.08, P = .68) levels of pain acceptance and became progressively stronger as pain acceptance scores decreased. The nonlinear indirect effect became nonsignificant at acceptance scores 0.38 standard deviation above the mean-a clinically attainable treatment target. Higher acceptance mitigated the relationship between pain severity and perceived burdensomeness and the relationship between perceived burdensomeness and suicidal cognitions in this clinical sample of patients experiencing chronic pain. Findings indicate that any improvement in pain acceptance can be beneficial, and they provide clinicians with a clinical cut-point that might indicate lower vs higher suicide risk.

Executive Functions and Morphological Awareness Explain the Shared Variance between Word Reading and Listening Comprehension

ABSTRACT Purpose A large body of literature showed that word reading and listening comprehension-two proximal predictors of reading comprehension according to the simple view of reading – are related. Grounded on the direct and indirect effects model of reading, we examined the extent to which the relation is explained by domain-general cognitions or executive functions (working memory and attentional control) and emergent literacy skills (language and code-related skills including morphological awareness, phonological awareness, orthographic pattern recognition, letter naming fluency, and rapid automatized naming). Method Data were from English-speaking children in Grade 1 (N = 372; 52% boys; 60% White children, 26% African American children, 6% multiracial children, 6% Hispanic children, and 2% Asian American children). Results Results from structural equation models showed that word reading and listening comprehension were moderately related (.54). When working memory and attentional control were included as predictors, the relation became weaker (.39). When morphological awareness was additionally included, they were no longer related (.05). The other emergent literacy skills did not add explanatory power beyond executive functions and morphological awareness. Conclusion These results indicate that executive functions and morphological awareness largely explain the shared variance between word reading and listening comprehension for English-speaking beginning readers.

Protean career processes in young adults: Relationships with perceived future employability, educational performance, and commitment

Protean career processes of vocational identity awareness, career adaptability, and career agency have been hypothesized to mediate the relationships between protean career orientation and career-related outcomes. To date, the role of these process mechanisms has not been assessed directly in young adults, and little attention has been paid to educational outcomes, which are important career-related goals for young people on the way to their desired career. To address this gap, we tested this indirect-effects model in a sample of young adult undergraduates (N = 396; Mage = 20.19, SD = 2.99; 72.2% women) and included career-related goals (perceived future employability, educational performance, and commitment) as outcomes. Identity awareness and career adaptability partially explained the relationship between protean career orientation and perceived future employability and completely explained the relationships with educational performance and commitment. Contrary to protean career theory, there were no significant indirect paths via career agency to any of the outcomes.

Identity processing styles and personal growth initiative in college students: The mediating role of cultural tightness–looseness

Cultural norms and their regulation in society account for individual behaviour and related psychological processes. This study investigated if and how cultural norm regulation mediated the relationship between identity processing styles and intentional personal growth. A sample of 613 students (mean age = 19.72 years, SD = 1.67 years; female = 454, 74.1%) completed the Revised Identity Styles Inventory-5; the Personal Growth Initiative Scale-2; and the Cultural Tightness– Looseness Scale. To investigate the hypothesised mediation, we tested direct and indirect effects models in Mplus. Of the 14 possible direct effects between the two viable identity styles (informational and diffuse-avoidant) and four dimensions of personal growth initiative (readiness for change, planfulness, using resources, and intentional behaviour), 12 were significant. And of the 12 pathways, only three were mediated by cultural tightness, namely informational style to readiness for change, planfulness, and intentional behaviour. The findings demonstrate the value of strict cultural norm regulation in facilitating intentional personal growth in this group.

A systems-level model of direct and indirect links between environmental health, socioeconomic factors, and human mortality

Major efforts are being made to better understand how human health and ecosystem health are influenced by climate and other environmental factors. However, studies that simultaneously address human and ecosystem health within a systems-level framework that accounts for both direct and indirect effects are rare. Using path analysis and a large database of environmental and socioeconomic variables, we create a systems-level model of direct and indirect effects on human and ecosystem health in counties throughout the conterminous United States. As indicators of human and ecosystem health, we use age-adjusted mortality rate and an index of biological integrity in streams and rivers, respectively. We show that: (i) geology and climate set boundary conditions for all other variables in the model; (ii) hydrology and land cover have predictable but distinct effects on human and ecosystem health; and (iii) forest cover is a key link between the environment and the socioeconomic variables that directly influence human health.

The Role of Anxiety Sensitivity in the Association Between Childhood Maltreatment and Sleep Disturbance Among Adults in Psychiatric Inpatient Treatment.

The present investigation examined associations of childhood maltreatment, anxiety sensitivity (AS), and sleep disturbance among a diverse sample of adults in psychiatric inpatient treatment. We hypothesized that childhood maltreatment would be indirectly associated with greater sleep disturbance through elevated AS. Exploratory analyses examined the indirect effect models with three AS subscales ( i.e. , physical, cognitive, and social concerns) as parallel mediators. A sample of adults in acute-care psychiatric inpatient treatment ( N = 88; 62.5% male; Mage = 33.32 years, SD = 11.07; 45.5% White) completed a series of self-report measures. After accounting for theoretically relevant covariates, childhood maltreatment was indirectly associated with sleep disturbance through AS. Parallel mediation analyses revealed that no individual subscale of AS significantly accounted for this association. These findings suggest that heightened levels of AS may explain the association between childhood maltreatment and sleep disturbance among adults in psychiatric inpatient treatment. Interventions targeting AS can be brief and efficacious and have the potential to improve clinical outcomes among psychiatric populations.

Racial discrimination, depressive symptoms, and parenting in African American families

AbstractObjectiveThe goal was to examine direct and indirect associations between racial discrimination and parenting among African American mothers and fathers.BackgroundExperiences of racial discrimination are common among African Americans, with well‐documented effects on individual functioning. Greater attention to associations between racial discrimination and family functioning, including parenting, is needed, as are tests of whether these associations might arise indirectly through depressive symptoms.MethodData from 346 African American families were used to examine correlations between racial discrimination and nurturant involved parenting, consistent discipline, and educational involvement among mothers and fathers, and to examine indirect effect models testing linkages through depressive symptoms.ResultsThere was minimal evidence of significant direct (bivariate) associations between racial discrimination and parenting. There were, however, significant negative indirect effects from racial discrimination to nurturant involved parenting and to consistent discipline through depressive symptoms for mothers and fathers.ConclusionHigher levels of racial discrimination were associated with lower levels of nurturant involved parenting and consistent discipline through higher depressive symptoms.ImplicationsConceptual models describing the effects of racial discrimination on families should integrate indirect effects through individual functioning. Interventions focused on supporting African American parents should address the harmful effects of racial discrimination on individual and family well‐being.