Within-person couplings play a prominent role in psychological research and previous studies have shown that interindividual differences in within-person couplings predict future behavior. For ...example, stress reactivity-operationalized as the within-person coupling of stress and positive or negative affect-is an important predictor of various (mental) health outcomes and has often been assumed to be a more or less stable personality trait. However, issues of reliability of these couplings have been largely neglected so far. In this work, we present an estimate for the reliability of within-person couplings that can be easily obtained using the user-modifiable R code accompanying this work. Results of a simulation study show that this index performs well even in the context of unbalanced data due to missing values. We demonstrate the application of this index in a measurement burst study targeting the reliability and test-retest correlation of stress reactivity estimates operationalized as within-person couplings in a daily diary design. Reliability and test-retest correlations of stress reactivity estimates were rather low, challenging the implicit assumption of stress reactivity as a stable person-level variable. We highlight key factors that researchers planning studies targeting interindividual differences in within-person couplings should consider to maximize reliability.
Dysregulations of the hypothalamic-pituitary-adrenal (HPA) and sympatho-adrenal medullary (SAM) axis are associated with mental and somatic illness. However, there is lack of knowledge regarding the ...molecular mechanisms underlying these effects. Epigenetic states in the serotonin transporter gene (SLC6A4) were shown to be associated with stress in various forms. We hypothesized that levels of DNA methylation (DNAm) of SLC6A4 would be associated with altered SAM- and HPA regulation in daily life. N = 74 healthy persons participated in the study. An ecological momentary assessment (EMA) approach was used to assess indicators of stress in daily life. Each day included six concurrent assessments of saliva, to quantify cortisol (sCort; HPA axis) and alpha-amylase (sAA; SAM axis), and to assess self-reports on subjective stress. To assess SLC6A4 DNAm, peripheral blood was drawn and analyzed via bisulfite pyrosequencing. All data were assessed in two waves three months apart, each including two days of EMA and the assessment of SLC6A4 DNAm. Data were analyzed using multilevel models. On the between-person level, higher average levels of SLC6A4 DNAm were associated with higher average levels of sAA, but not with average levels of sCort. On the within-person level, higher levels of SLC6A4 DNAm were associated with lower levels of sAA and sCort. There were no associations of subjective stress with SLC6A4 DNAm. The results help to clarify the association between environmental stress and stress axes regulation, pointing towards an important role of differential within- and between-person effects of SLC6A4 DNAm, which might shape this association.
•Repeated assessments of serotonin transporter gene methylation (SLC6A4 DNAm) and psychobiological stress in everyday life.•SLC6A4 DNAm is associated with psychobiological stress in everyday life.•Differential within- and between-person associations of SLC6A4 DNAm with psychobiological stress.•Higher SLC6A4 DNAm (within-person) is associated with a reduced output of salivary alpha-amylase and salivary cortisol.•Higher SLC6A4 DNAm (between-persons) is associated with an increased output of salivary alpha-amylase.
Abstract
Even though each adolescent is unique, some ingredients for development may still be universal. According to Self-Determination Theory, every adolescent’s well-being should benefit when ...parents provide warmth and autonomy. To rigorously test this idea that each family has similar mechanisms, we followed 159 Dutch parent-adolescent dyads (parent:
M
age
= 45.34, 79% mothers; adolescent:
M
age
= 13.31, 62% female) for more than three months, and collected 100 consecutive daily reports of parental warmth, autonomy support, positive and negative affect. Positive effects of parental warmth and autonomy support upon well-being were found in 91–98% of the families. Preregistered analysis of 14,546 daily reports confirmed that effects of parenting differed in strength (i.e., some adolescents benefited more than others), but were universal in their direction (i.e., in fewer than 1% of families effects were in an unexpected direction). Albeit stronger with child-reported parenting, similar patterns were found with parent-reports. Adolescents who benefited most from need-supportive parenting in daily life were characterized by higher overall sensitivity to environmental influences. Whereas recent work suggests that each child and each family have unique developmental mechanisms, this study suggests that need-supportive parenting promotes adolescent well-being in most families.
This study investigated if in-session reflective functioning (RF) of mothers improved between and within sessions of brief dyadic focused parent-infant psychotherapy (fPIP) for the treatment of ...regulatory disorders in infants.
In-session RF was coded for 44 therapy sessions from
= 11 mothers randomly selected from a RCT on the efficacy of fPIP as part of secondary analyses. A new rating system distinguished self-focused and child-focused in-session RF. Cumulative ordinal regression models were applied to analyze the dynamics of in-session RF within and across sessions, controlling for word count of each statement.
While in-session RF improved significantly within sessions, between-session RF improved significantly only in the second session compared to the first with a significant decrease observed in the last session. Child-focused in-session RF was significantly lower than self-focused in-session RF at the beginning of the sessions but improved significantly stronger than self-focused in-session RF during sessions.
In-session RF (particularly in child-focused statements) can be regarded as a dynamic change process relevant within each session of dyadic fPIP. Improvements made on a session-by-session basis may not be maintained until the next session. Implications for practitioners and in-session RF research are discussed.
Early experiences of childhood sexual or physical abuse are often associated with functional impairments, reduced well-being and interpersonal problems in adulthood. Prior studies have addressed ...whether the traumatic experience itself or adult psychopathology is linked to these limitations. To approach this question, individuals with posttraumatic stress disorder (PTSD) and healthy individuals with and without a history of child abuse were investigated. We used global positioning system (GPS) tracking to study temporal and spatial limitations in the participants' real-life activity space over the course of one week. The sample consisted of 228 female participants: 150 women with PTSD and emotional instability with a history of child abuse, 35 mentally healthy women with a history of child abuse (healthy trauma controls, HTC) and 43 mentally healthy women without any traumatic experiences in their past (healthy controls, HC). Both traumatized groups-i.e. the PTSD and the HTC group-had smaller movement radii than the HC group on the weekends, but neither spent significantly less time away from home than HC. Some differences between PTSD and HC in movement radius seem to be related to correlates of PTSD psychopathology, like depression and physical health. Yet group differences between HTC and HC in movement radius remained even when contextual and individual health variables were included in the model, indicating specific effects of traumatic experiences on activity space. Experiences of child abuse could limit activity space later in life, regardless of whether PTSD develops.
Music engagement is an essential part in many people's everyday life. A large body of research has provided evidence for the beneficial effects of music engagement on health and well-being, although ...studies on underlying mechanisms (e.g., flow experiences) have been scarce. Therefore, we examined in the present study the potential effects of the quality of motivation (autonomous vs. controlled) to engage in active hobby music making on flow and well-being. We tested the prediction by Self-Determination Theory that autonomous forms of motivation are related to higher well-being. Furthermore, we examined whether flow experiences during music making might account for this association in an online daily diary study with 975 hobby musicians. Daily autonomous motivation to make music, flow (two subscales: fluency and absorption), and subjective well-being (life satisfaction, positive and negative affect) were assessed each day for ten consecutive days. Multilevel structural equation models indicated that there was a positive effect of autonomous motivation on life satisfaction and positive affect that was mediated by both subscales of flow, with fluency of performance at both the within- and between person level and absorption only at the within-person level. Further, there was a negative indirect effect on negative affect via fluency on the within-person level. This study provides evidence for the importance of autonomous motivation in hobby music making with regard to subjective well-being and highlights investigating the effects on a within-person level. Results further suggest the experience of flow as a potential mediating mechanism.
•Investigated the role of stress anticipation in the modulation of the CAR using EMA.•CAR was higher on days after higher-than-usual stress anticipation (within persons).•The strength of this ...within-person relationship differed between persons.•Mean anticipatory stress did not predict mean CAR (between persons).
The cortisol awakening response (a rapid rise in cortisol concentration shortly after awakening) is hypothesized to prepare the organism to cope with upcoming demands, suggesting a key role for anticipatory stress in its regulation. Yet, no thorough test of this hypothesis incorporating temporal dynamics of the underlying processes has been conducted so far. To address this gap in the literature, the present study investigated the effects of anticipated stress for the next day (assessed in the evening) on an estimate of the cortisol awakening response (assessed in the following morning). In an ambulatory assessment paradigm, 42 participants (69% female; mean age = 22.8, range = 18–30 years) completed 5 consecutive days of assessments in their daily lives, collecting saliva samples at awakening and 30 min later. Using hierarchical linear modeling, associations with anticipatory stress were examined separately on the within- and between-person level. In line with our expectations, anticipatory stress predicted the post-awakening cortisol increase on the within-person level, implying an elevated cortisol rise on days for which more stress than usual had been anticipated. In contrast, on the between-person level higher average anticipatory stress did not predict an increased cortisol rise. Taken together, the findings confirm a key role of anticipatory stress in the regulation of the cortisol awakening response on the within-person level.
Summary Background Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 ...inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. Methods In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations ( FLT3mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov , number NCT02014558 , and is ongoing. Findings Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 39% of 252), anaemia (61 24%), thrombocytopenia (33 13%), sepsis (28 11%), and pneumonia (27 11%). Commonly reported treatment-related adverse events were diarrhoea (92 37% of 252), anaemia (86 34%), fatigue (83 33%), elevated aspartate aminotransferase (65 26%), and increased alanine aminotransferase (47 19%). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 39% of 252; five related to treatment), progressive disease (43 17%), sepsis (36 14%; two related to treatment), pneumonia (27 11%), acute renal failure (25 10%; five related to treatment), pyrexia (21 8%; three related to treatment), bacteraemia (14 6%; one related to treatment), and respiratory failure (14 6%). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism 200 mg/day, respiratory failure 120 mg/day, haemoptysis 80 mg/day, intracranial haemorrhage 20 mg/day, ventricular fibrillation 120 mg/day, septic shock 80 mg/day, and neutropenia 120 mg/day). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission Interpretation Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Funding Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.
BCR-ABL overexpression and stem cell quiescence supposedly contribute to the failure of imatinib mesylate (IM) to eradicate chronic myeloid leukemia (CML). However, BCR-ABL expression levels of ...persisting precursors and the impact of long-term IM therapy on the clearance of CML from primitive and mature bone marrow compartments are unclear. Here, we have shown that the number of BCR-ABL–positive precursors decreases significantly in all bone marrow compartments during major molecular remission (MMR). More importantly, we were able to demonstrate substantially lower BCR-ABL expression levels in persisting MMR colony-forming units (CFUs) compared with CML CFUs from diagnosis. Critically, lower BCR-ABL levels may indeed cause IM insensitivity, because primary murine bone marrow cells engineered to express low amounts of BCR-ABL were substantially less sensitive to IM than BCR-ABL–overexpressing cells. BCR-ABL overexpression in turn catalyzed the de novo development of point mutations to a greater extent than chemical mutagenesis. Thus, MMR is characterized by the persistence of CML clones with low BCR-ABL expression that may explain their insensitivity to IM and their low propensity to develop IM resistance through kinase point mutations. These findings may have implications for future treatment strategies of residual disease in CML.
Rumination and worry are common forms of perseverative cognition in children. Research has started to target perseverative cognitions in the everyday life of children, however, valid measurement ...instruments reliably capturing rumination and worry in children's daily life are still missing. We conducted two ambulatory assessment studies validating short scales suitable for the measurement of rumination and worry in children's daily life. Results of the first study (N = 110, 8-11 year-olds, 31 days, up to 4 daily measurements) supported a unidimensional structure of the rumination scale. Rumination was associated with negative affect (but not positive affect) on the within- and on the between-person level. On the between-person level, children who ruminated more showed poorer working memory performance. In the second study (N = 84, 8-10 year-olds, 21 days, up to 3 daily measurements), findings of Study 1 were largely replicated. Moreover, we established a unidimensional worry scale in Study 2 reliably capturing worry in children's daily life. Importantly, Study 2 showed that worry and rumination share common variance but can be differentiated in children. On the within-person level, higher levels of worry were associated with higher levels of negative affect and lower levels of positive affect. On the between-person level, worry was associated with higher levels of negative affect and lower working memory performance. Altogether, findings of both studies demonstrated that the short scales had excellent psychometric properties suggesting that they are helpful tools for the assessment of rumination and worry in children's daily life.
Public Significance Statement
The present work evaluated two short scales measuring rumination and worry in children's daily life. Results supported the validity and reliability of the two short scales and showed that fluctuations of rumination and worry are related but distinct phenomena in children. These measurement instruments provide valuable tools for research on children's experiences in everyday life. They might also be useful in clinical studies that track intervention-related changes in worry and rumination.
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