Repeatability of fractional flow reserve despite variations in systemic and coronary hemodynamics

Objectives This study classified and quantified the variation in fractional flow reserve (FFR) due to fluctuations in systemic and coronary hemodynamics during intravenous adenosine infusion. Background Although FFR has become a key invasive tool to guide treatment, questions remain regarding its repeatability and stability during intravenous adenosine infusion because of systemic effects that can alter driving pressure and heart rate. Methods We reanalyzed data from the VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice) study, which enrolled consecutive patients who were infused with intravenous adenosine at 140 μg/kg/min and measured FFR twice. Raw phasic pressure tracings from the aorta (Pa) and distal coronary artery (Pd) were transformed into moving averages of Pd/Pa. Visual analysis grouped Pd/Pa curves into patterns of similar response. Quantitative analysis of the Pd/Pa curves identified the “smart minimum” FFR using a novel algorithm, which was compared with human core laboratory analysis. Results A total of 190 complete pairs came from 206 patients after exclusions. Visual analysis revealed 3 Pd/Pa patterns: “classic” (sigmoid) in 57%, “humped” (sigmoid with superimposed bumps of varying height) in 39%, and “unusual” (no pattern) in 4%. The Pd/Pa pattern repeated itself in 67% of patient pairs. Despite variability of Pd/Pa during the hyperemic period, the “smart minimum” FFR demonstrated excellent repeatability (bias −0.001, SD 0.018, paired p = 0.93, r2 = 98.2%, coefficient of variation = 2.5%). Our algorithm produced FFR values not significantly different from human core laboratory analysis (paired p = 0.43 vs. VERIFY; p = 0.34 vs. RESOLVE). Conclusions Intravenous adenosine produced 3 general patterns of Pd/Pa response, with associated variability in aortic and coronary pressure and heart rate during the hyperemic period. Nevertheless, FFR – when chosen appropriately – proved to be a highly reproducible value. Therefore, operators can confidently select the “smart minimum” FFR for patient care. Our results suggest that this selection process can be automated, yet comparable to human core laboratory analysis

Developmental trajectories of autistic social traits in the general population

BACKGROUND: Autistic people show diverse trajectories of autistic traits over time, a phenomenon labelled 'chronogeneity'. For example, some show a decrease in symptoms, whilst others experience an intensification of difficulties. Autism spectrum disorder (ASD) is a dimensional condition, representing one end of a trait continuum that extends throughout the population. To date, no studies have investigated chronogeneity across the full range of autistic traits. We investigated the nature and clinical significance of autism trait chronogeneity in a large, general population sample. METHODS: Autistic social/communication traits (ASTs) were measured in the Avon Longitudinal Study of Parents and Children using the Social and Communication Disorders Checklist (SCDC) at ages 7, 10, 13 and 16 (N = 9744). We used Growth Mixture Modelling (GMM) to identify groups defined by their AST trajectories. Measures of ASD diagnosis, sex, IQ and mental health (internalising and externalising) were used to investigate external validity of the derived trajectory groups. RESULTS: The selected GMM model identified four AST trajectory groups: (i) Persistent High (2.3% of sample), (ii) Persistent Low (83.5%), (iii) Increasing (7.3%) and (iv) Decreasing (6.9%) trajectories. The Increasing group, in which females were a slight majority (53.2%), showed dramatic increases in SCDC scores during adolescence, accompanied by escalating internalising and externalising difficulties. Two-thirds (63.6%) of the Decreasing group were male. CONCLUSIONS: Clinicians should note that for some young people autism-trait-like social difficulties first emerge during adolescence accompanied by problems with mood, anxiety, conduct and attention. A converse, majority-male group shows decreasing social difficulties during adolescence

Altered engagement of autobiographical memory networks in adult offspring of postnatally depressed mothers

Maternal depression is associated with increased risk for offspring mood and anxiety disorders. One possible impact of maternal depression during offspring development is on the emotional autobiographical memory system. We investigated the neural mechanisms of emotional autobiographical memory in adult offspring of mothers with postnatal depression (N = 16) compared to controls (N = 21). During fMRI, recordings of participants describing one pleasant and one unpleasant situation with their mother and with a companion, were used as prompts to re-live the situations. Compared to controls we predicted the PND offspring would show: greater activation in medial and posterior brain regions implicated in autobiographical memory and rumination; and decreased activation in lateral prefrontal cortex and decreased connectivity between lateral prefrontal and posterior regions, reflecting reduced control of autobiographical recall. For negative situations, we found no group differences. For positive situations with their mothers, PND offspring showed higher activation than controls in left lateral prefrontal cortex, right frontal pole, cingulate cortex and precuneus, and lower connectivity of right middle frontal gyrus, left middle temporal gyrus, thalamus and lingual gyrus with the posterior cingulate. Our results are consistent with adult offspring of PND mothers having less efficient prefrontal regulation of personally relevant pleasant autobiographical memories

Audiovisual Processing is Abnormal in Parkinson\u27s Disease and Correlates with Freezing of Gait and Disease Duration

Background: Sensory and perceptual disturbances progress with disease duration in Parkinson’s disease (PD) and probably contribute to motor deficits such as bradykinesia and gait disturbances, including freezing of gait (FOG). Simple reaction time tests are ideal to explore sensory processing, as they require little cognitive processing. Multisensory integration is the ability of the brain to integrate sensory information from multiple modalities into a single coherent percept, which is crucial for complex motor tasks such as gait. 9 10 11 12 13 Objectives: The aims of this study were to: 1. Assess differences in unisensory (auditory and visual) and multisensory processing speed in people with PD and age-matched healthy controls. 2. Compare relative differences in unisensory processing in people with PD with disease duration and freezing of gait status taking into account the motor delays, which are invariably present in PD. 3. Compare relative differences in multisensory (audiovisual) processing between the PD cohort and age-matched controls. 14 15 16 17 Methods: 39 people with PD (23 with FOG) and 17 age-matched healthy controls performed a reaction time task in response to unisensory (auditory-alone, visual-alone) and multisensory (audiovisual) stimuli. 18 19 Results: The PD group were significantly slower than controls for all conditions compared with healthy controls but auditory reaction times were significantly faster than visual for the PD group only. These relative unisensory differences are correlated with disease duration and divide the PD group by FOG status, but these factors are co-dependent. Although multisensory facilitation occurs in PD, it is significantly less enhanced than in healthy controls. 20 21 22 23 Conclusion: There are significant unisensory and multisensory processing abnormalities in PD. The relative differences in unisensory processing are specific to PD progression, providing a link between these sensory abnormalities and a motor feature of PD. Sensory disturbances have previously been postulated to be central to FOG but this is the first study to predict audiovisual processing abnormalities using FOG status. The multisensory processing abnormalities are independent of disease duration and FOG status and may be a potential biomarker for the disease

Developmental pathways from toddler difficult temperament to child generalized psychopathology and adult functioning

BACKGROUND: Early difficult temperament and child mental health problems are consistently associated with impaired functioning in adulthood. We examined three potential pathways between difficult temperament in toddlerhood (age 2) and depressive symptoms (ages 21-23) and well-being (age 23): i) direct - early difficult temperament directly associates with these outcomes, ii) mediated - these direct effects are also mediated by a general psychopathology factor in late childhood/early adolescence (GPF; ages 7, 10,and 13), and iii) moderated-mediated - these mediated effects are also moderated by negative (age 42 months) and positive (age 33 months) parenting behaviors. METHODS: The analytic sample included 1892 mother-child dyads (33.4% male children) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Mothers reported on their child's difficult temperament, negative parenting, positive parenting, and child's mental health symptoms. In adulthood, participants reported their own depressive symptoms and well-being (i.e. mental well-being, life satisfaction, happiness). RESULTS: First, early difficult temperament associated directly and positively with depressive symptoms, but negatively with well-being in adulthood. Second, the GPF in late childhood/early adolescence mediated these direct associations. Third, the mediated pathways were not moderated by negative or positive parenting. LIMITATIONS: i) low risk community sample, ii) early risks are based on maternal reports. CONCLUSIONS: Temperament is a risk factor for impaired psychosocial functioning in adulthood, manifested through increased susceptibility to psychopathology in childhood/adolescence. Although more research is needed to test their generalizability, these findings suggest that targeting early difficult temperament may alleviate the risk for later mental health difficulties and may increase general well-being

PTSD symptoms and cortisol stress reactivity in adolescence: Findings from a high adversity cohort in South Africa

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in the pathophysiology of post-traumatic stress disorder (PTSD). However, there has been little study of HPA stress reactivity in association with PTSD symptoms (PTSS) in children; and there is limited research on PTSD in low and middle-income countries, where trauma exposure is more common and co-occurring stressors more likely. METHOD: We assessed the relationship between PTSS and cortisol stress reactivity in children aged 13 years (N = 291) from an impoverished South African community. HPA axis stress reactivity was indexed by salivary cortisol during the Trier Social Stress Test (TSST). RESULTS: In regression analyses both trauma exposure and PTSS showed small inverse associations with total cortisol output (area under the curve with respect to ground) during the TSST, but PTSS effects did not withstand correction for covariates. In addition, hierarchical linear modelling (HLM) found that PTSS were associated with alterations in the shape of the profile of cortisol reactivity that were moderated by sex. In girls, PTSS were associated with reduced linear slope but larger quadratic slopes, whereas the opposite pattern was found in boys. Thus, elevated PTSS were associated with overall blunted profiles of cortisol stress reactivity in girls, but a larger quadratic slope in boys reflects a steeper cortisol increase and decline in boys. There was no relationship between trauma exposure (with or without PTSS) and cortisol reactivity profiles in HLM analyses. CONCLUSION: In children from a high adversity, low and middle income country context, sex specific associations were found between PTSS and cortisol responses to psychosocial stress. Further research should probe HPA axis functioning more comprehensively in such populations to understand the biological associations of PTSS

The uniting of Europe and the foundation of EU studies: revisiting the neofunctionalism of Ernst B. Haas

This article suggests that the neofunctionalist theoretical legacy left by Ernst B. Haas is somewhat richer and more prescient than many contemporary discussants allow. The article develops an argument for routine and detailed re-reading of the corpus of neofunctionalist work (and that of Haas in particular), not only to disabuse contemporary students and scholars of the normally static and stylized reading that discussion of the theory provokes, but also to suggest that the conceptual repertoire of neofunctionalism is able to speak directly to current EU studies and comparative regionalism. Neofunctionalism is situated in its social scientific context before the theory's supposed erroneous reliance on the concept of 'spillover' is discussed critically. A case is then made for viewing Haas's neofunctionalism as a dynamic theory that not only corresponded to established social scientific norms, but did so in ways that were consistent with disciplinary openness and pluralism

Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vitro.

Eicosapentaenoic acid (EPA) has been shown to have an inhibitory effect on the growth of several pancreatic cancer cell lines in vitro. This study investigates the mechanism of growth inhibition and cytotoxicity of EPA on the pancreatic cancer cell line MIA PaCa-2. Cells were analysed for cell count, viability, cell cycle distribution and ultrastructural changes. There was a time- and dose-dependent decrease in cell count and viability in cultures of pancreatic cancer cells supplemented with EPA. Flow cytometric DNA analysis of MIA PaCa-2 cells incubated with EPA demonstrated the presence of sub G1 populations corresponding to the presence of apoptotic cells and the blockade of cell cycle progression in S-phase and G2/M-phase. The presence of apoptosis in EPA-supplemented cultures was further confirmed by DNA fragmentation and ultrastructural changes associated with apoptosis. Therefore, we conclude that EPA mediates its effect on the pancreatic cancer cell line MIA PaCa-2, at least in part, via cell cycle arrest and the induction of apoptosis