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Decreased heart rate variability (HRV) is considered a common marker of autonomic dysfunction that contributes to poor health outcomes. While some studies have suggested that children with autism spectrum disorder (ASD) show reduced HRV, research is yet to consider whether this may be associated with medication use and symptom severity. This study examined the relationship between resting state HRV, medication use and symptom severity in children diagnosed with ASD. Children with ASD (N = 86), aged between 3 and 12 years (M = 8.09), were compared to 44 neurotypical children of similar age (M = 7.15). Laboratory assessment of HRV involved 5 min of non‐invasive baseline electrocardiogram assessments while participants viewed an age‐appropriate non‐verbal animated video. Time‐domain and frequency‐domain HRV measures were analyzed. ASD symptom severity was assessed using the Autism Diagnostic Observation Schedule‐Second Edition (ADOS‐2) and Social Responsiveness Scale (SRS‐2). Results indicated that children with ASD exhibited reduced resting HRV relative to neurotypical children. Subsequent analyses within the ASD group suggested that this group difference was greater in children who were taking psychotropic medication (N = 36). Our data also provides tentative evidence of a relationship between HRV and social impairment symptoms in children with ASD, with more severe repetitive behaviors (as measured by the ADOS‐2) associated with decreased resting HRV. Overall, these findings suggest that HRV may be atypical in children with ASD and suggest the importance of exploring HRV as a risk factor for cardiovascular health in this group. Lay Summary: Cardiac activity, such as heart rate variability (HRV), can provide insight into the autonomic nervous system. This study reports on the association between resting‐state HRV and autonomic nervous system activity in young children with autism spectrum disorder (ASD) compared to neurotypical children. These results may help us understand what underlies autonomic nervous system dysfunction and the potential pathophysiological mechanisms leading to increased cardiovascular risk in ASD. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme (ACE) polymorphism has been shown to be important in hypertension progression and also in diabetes complications, especially associated with heart disease. Heart rate variability (HRV) is an established measure for classification of autonomic function regulating heart rate, based on the interbeat interval time series derived from a raw ECG recording. Results of this paper show that the length (number of interbeat intervals) and preprocessing of the tachogram affect the HRV analysis outcome. The comparison was based on tachogram lengths of 250, 300, 350, and 400 RR-intervals and five preprocessing approaches. An automated adaptive preprocessing method for the heart rate biosignal and tachogram length of 400 interbeat intervals provided the best classification. HRV results differed for the Type 2 Diabetes Mellitus (T2DM) group between the I/I genotype and the I/D and D/D genotypes, whereas for controls there was no significant difference in HRV between genotypes. Selecting an appropriate length of recording and automated preprocessing has confirmed that there is an effect of ACE polymorphism including the I/I genotype and that I/I should not be combined with I/D genotype in determining the extent of autonomic modulation of the heart rate. [ABSTRACT FROM PUBLISHER]

Lithium salts are used widely for treatment of bipolar and other mental disorders. Lithium therapy is accompanied frequently by renal side effects, such as nephrogenic diabetes insipidus or chronic kidney disease (CKD), but the molecular mechanisms underlying these effects are still poorly understood. In the present study we examined the effect of lithium on the activity of the osmosensitive transcriptional activator nuclear factor of activated T cells 5 (NFAT5, also known as TonEBP), which plays a key role in renal cellular osmoprotection and urinary concentrating ability. Interestingly, we found different effects of lithium on NFAT5 activity, depending on medium osmolality and incubation time. When cells were exposed to lithium for a relative short period (24 h), NFAT5 activity was significantly increased, especially under isosmotic conditions, resulting in an enhanced expression of the NFAT5 target gene heat shock protein 70 (HSP70). Further analysis revealed that the increase of NFAT5 activity depended primarily on an enhanced activity of the c-terminal transactivation domain (TAD), while NFAT5 protein abundance was largely unaffected. Enhanced activity of the TAD is probably mediated by lithium-induced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK-3β), which is in accordance with previous studies. When cells were exposed to lithium for a longer period (96 h), cellular NFAT5 activity and subsequently expression of HSP70 significantly decreased under hyperosmotic conditions, due to diminished NFAT5 protein abundance, also resulting from GSK-3β inhibition. Taken together, our results provide evidence that lithium has opposing effects on NFAT5 activity, depending on environmental osmolality and exposure duration. The potential impacts of these observations on the diverse effects of lithium on kidney function are discussed. [ABSTRACT FROM AUTHOR]

Context: There is evidence that heart rate variability (HRV) is reduced in major depressive disorder (MDD), although there is debate about whether this effect is caused by medication or the disorder per se. MDD is associated with a two to fourfold increase in the risk of cardiac mortality, and HRV is a robust predictor of cardiac mortality; determining a direct link between HRV and not only MDD, but common comorbid anxiety disorders, will point to psychiatric indicators for cardiovascular risk reduction. Objective: To determine in physically healthy, unmedicated patients whether (1) HRV is reduced in MDD relative to controls, and (2) HRV reductions are driven by MDD alone, comorbid generalized anxiety disorder (GAD, characterized by anxious anticipation), or comorbid panic and posttraumatic stress disorders (PD/PTSD, characterized by anxious arousal). Design, Setting, and Patients: A case-control study in 2006 and 2007 on 73 MDD patients, including 24 without anxiety comorbidity, 24 with GAD, and 14 with PD/PTSD. Seventy-three MDD and 94 healthy age- and sex-matched control participants were recruited from the general community. Participants had no history of drug addiction, alcoholism, brain injury, loss of consciousness, stroke, neurological disorder, or serious medical conditions. There were no significant differences between the four groups in age, gender, BMI, or alcohol use. Main Outcome Measures: HRV was calculated from electrocardiography under a standardized short-term resting state condition. Results: HRV was reduced in MDD relative to controls, an effect associated with a medium effect size. MDD participants with comorbid generalized anxiety disorder displayed the greatest reductions in HRV relative to controls, an effect associated with a large effect size. Conclusions: Unmedicated, physically healthy MDD patients with and without comorbid anxiety had reduced HRV. Those with comorbid GAD showed the greatest reductions. Implications for cardiovascular risk reduction strategies in otherwise healthy patients with psychiatric illness are discussed. [ABSTRACT FROM AUTHOR]

Associations between uncoupling protein (UCP) expression and functional changes in myocardial mitochondrial bio-energetics have not been well studied during periods of starvation stress. Our aim was to study the effects of acute starvation, for 24 or 48 h, on combined cardiac mitochondrial function and UCP expression in mice. Isolated heart mitochondria from female mice starved for 48 h compared to that from mice fed revealed a significantly ( p < 0.05) decreased adenosine diphosphate-to-oxygen ratio, a significantly increased proton leak and an increased GTP inhibition on palmitic acid-induced state 4 oxygen consumption ( p < 0.05). These bio-energetic functional changes were associated with increases in mitochondrial UCP2 and UCP3 protein expression. In conclusion, our findings suggest that increased UCP2 and UCP3 levels may contribute to decreased myocardial mitochondrial bio-energetic function due to starvation. [ABSTRACT FROM AUTHOR]

A response by Vidya Perera and colleagues to a letter to the editor about their article "The Impact of Frailty on the Utilisation of Antithrombotic Therapy in Older Patients With Arterial Fibrillation," published in the 2009 issue is presented.

The Ames test is a gold standard mutagenicity assay that utilizes various Salmonella typhimurium strains with and without S9 fraction to provide insights into the mechanisms by which a chemical can mutate DNA. Multitask deep learning is an ideal framework for developing QSAR models with multiple end points, such as the Ames test, as the joint training of multiple predictive tasks may synergistically improve the prediction accuracy of each task. This work investigated how toxicology domain knowledge can be used to handcraft task groupings that better guide the training of multitask neural networks compared to a naïve ungrouped multitask neural network developed on a complete set of tasks. Sixteen S. typhimurium ± S9 strain tasks were used to generate groupings based on mutagenic and metabolic mechanisms that were reflected in correlation data analyses. Both grouped and ungrouped multitask neural networks predicted the 16 strain tasks with a higher balanced accuracy compared with single task controls, with grouped multitask neural networks consistently featuring incremental increases in predictivity over the ungrouped approach. We conclude that the main variable driving these performance improvements is the general multitask effect with mechanistic task groupings acting as an enhancement step to further concentrate synergistic training signals united by a common biological mechanism. This approach enables incorporation of toxicology domain knowledge into multitask QSAR model development allowing for more transparent and accurate Ames mutagenicity prediction.

The prediction of Ames mutagenicity continues to be a concern in both regulatory and pharmacological toxicology. Traditional quantitative structure-activity relationship (QSAR) models of mutagenicity make predictions based on molecular descriptors calculated on a chemical data set used in their training. However, it is known that molecules such as aromatic amines can be non-mutagenic themselves but metabolically activated by S9 rodent liver enzyme in Ames tests forming molecules such as iminoquinones or amine substituents that better stabilize mutagenic nitrenium ions in known pathways of mutagenicity. Modern in silico modeling methods can implicitly model these metabolites through consideration of the structural elements relevant to their formation but do not include explicit modeling of these metabolites' potential activity. These metabolites do not have a known individual mutagenicity label and, in their current state, cannot be fitted into a traditional QSAR model. Multiple instance learning (MIL) however can be applied to a group of metabolites and their parent under a single mutagenicity label. Here we trained MIL models on Ames data, first with an aromatic amines data set ( n = 457), a class known to require metabolic activation, and subsequently on a larger data set ( n = 6505) incorporating multiple molecular species. MIL was shown to be able to predict Ames mutagenicity with performance in line with previously established models (balanced accuracy = 0.778), suggesting its potential utility in Ames prediction applications. Furthermore, the MIL model predicted well on identified hard-to-predict molecule groups relative to the models in which these molecule groups were identified. These results are presumably due to the increased consideration of the metabolic contribution to the mutagenic outcome. Further exploration of MIL as a supplement to existing models could aid in the prediction of chemicals where implicit modeling of metabolites cannot fully grasp their characteristics. This paper demonstrates the potential of an MIL approach to modeling Ames tests with S9 and is particularly relevant to metabolically activated xenobiotic mutagens.

Decreased heart rate variability (HRV) is considered a common marker of autonomic dysfunction that contributes to poor health outcomes. While some studies have suggested that children with autism spectrum disorder (ASD) show reduced HRV, research is yet to consider whether this may be associated with medication use and symptom severity. This study examined the relationship between resting state HRV, medication use and symptom severity in children diagnosed with ASD. Children with ASD (N = 86), aged between 3 and 12 years (M = 8.09), were compared to 44 neurotypical children of similar age (M = 7.15). Laboratory assessment of HRV involved 5 min of non-invasive baseline electrocardiogram assessments while participants viewed an age-appropriate non-verbal animated video. Time-domain and frequency-domain HRV measures were analyzed. ASD symptom severity was assessed using the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) and Social Responsiveness Scale (SRS-2). Results indicated that children with ASD exhibited reduced resting HRV relative to neurotypical children. Subsequent analyses within the ASD group suggested that this group difference was greater in children who were taking psychotropic medication (N = 36). Our data also provides tentative evidence of a relationship between HRV and social impairment symptoms in children with ASD, with more severe repetitive behaviors (as measured by the ADOS-2) associated with decreased resting HRV. Overall, these findings suggest that HRV may be atypical in children with ASD and suggest the importance of exploring HRV as a risk factor for cardiovascular health in this group. LAY SUMMARY: Cardiac activity, such as heart rate variability (HRV), can provide insight into the autonomic nervous system. This study reports on the association between resting-state HRV and autonomic nervous system activity in young children with autism spectrum disorder (ASD) compared to neurotypical children. These results may help us understand what underlies autonomic nervous system dysfunction and the potential pathophysiological mechanisms leading to increased cardiovascular risk in ASD., (© 2020 International Society for Autism Research and Wiley Periodicals LLC.)

GABA-containing tea has gained popularity as an accessible intervention to reduce the impact of chronic stress-induced autonomic imbalance and increased risk for cardiovascular disease despite a lack of evidence concerning the γ-aminobutyric acid (GABA) content in a cup of the tea and its effects on physiological and psychological stress as measures of cognitive function. We aimed to measure the effects of GABA-fortified tea consumption on heart rate variability (HRV) and stress in 30 participants using a pre-post cohort study design. Ten minute lead II ECG recordings were analyzed with Kubios software. Frequency domain parameters including total power, high and low frequency power, along with heart rate, were determined. A control group that consumed a non-fortified tea was included in the research. Statistical analysis was by two-way ANOVA for two-group comparison with time as an interaction and a significance level of p < 0.05. Oolong tea consumption led to a significant decrease in the immediate stress score and a significant improvement in HRV. We conclude that autonomic imbalance and HRV in people with acute stress is significantly reduced following a cup of GABA fortified oolong tea and highlights the complex interaction between autonomic nervous system function and mood.

Aims: Effective transfer of information is vital for rational drug therapy. This is particularly important for older patients, who have a high prevalence of polypharmacy and are managed by multidisciplinary teams. We aimed to assess medicine information exchange (MIE) networks in geriatric medicine wards and whether they are associated with prescribing patterns., Methods: We conducted network analysis in acute geriatric medicine wards from four hospitals to characterize MIE networks among multidisciplinary team members. Corresponding patient data were collected to analyze high-risk prescribing in conjunction with network characteristics., Results: We found that junior doctors, senior nurses and pharmacists were central to MIE across all four hospitals. Doctors were more likely than other professions to receive medicines information in three hospitals. Reciprocity and the tendency to communicate within one's own profession also influenced network formation. No difference was observed in prescribing practice between hospitals., Conclusions: Understanding MIE networks can identify gaps in multidisciplinary communication that can be addressed. Networks may identify targets for dissemination of interventions to improve prescribing., (© 2016 The British Pharmacological Society.)

Heart Rate Variability (HRV) is extensively used to investigate general Autonomic Nervous System (ANS) function and is affected by many factors including age, gender, pathology such as diabetes and genetic polymorphisms. One of these genetic polymorphisms is the Angiotensin Converting Enzyme (ACE) polymorphism corresponding to insertion (I) or deletion (D) of a 287-base pair sequence of DNA in intron 16 of the ACE gene (rs4340). Some studies have addressed the relationship between HRV and D/D, I/D and I/I ACE polymorphism while others combined I/D and I/I ACE groups. In this study HRV is determined for diabetic and control individuals with different ACE polymorphism considering either separate or combined I/D and I/I genotypes. Linear time domain parameters, entropy, low frequency and total power of HRV were found to be significantly different between diabetic and control individuals with combined I/I and I/D ACE polymorphism, while only entropy was different for diabetic and control subjects with D/D ACE genotype. Separate analysis of I/I and I/D genotypes was preferred for a thorough investigation of HRV and ACE polymorphism, as the combined analysis masked some differences in HRV parameters such as Poincaré plot between ACE polymorphisms and diabetes status. Furthermore, a separate analysis demonstrated that most of the significant differences for HRV were between the diabetic group with I/I genotype and I/D and D/D groups.

Associations between uncoupling protein (UCP) expression and functional changes in myocardial mitochondrial bio-energetics have not been well studied during periods of starvation stress. Our aim was to study the effects of acute starvation, for 24 or 48 h, on combined cardiac mitochondrial function and UCP expression in mice. Isolated heart mitochondria from female mice starved for 48 h compared to that from mice fed revealed a significantly (p < 0.05) decreased adenosine diphosphate-to-oxygen ratio, a significantly increased proton leak and an increased GTP inhibition on palmitic acid-induced state 4 oxygen consumption (p < 0.05). These bio-energetic functional changes were associated with increases in mitochondrial UCP2 and UCP3 protein expression. In conclusion, our findings suggest that increased UCP2 and UCP3 levels may contribute to decreased myocardial mitochondrial bio-energetic function due to starvation.

Understanding patient decision making with respect to clinical trial participation has the potential to improve both the efficiency of recruitment for clinical trials and their management. In this mini-review we consider 3 key factors influencing clinical trial recruitment outcomes that include; 1) patient personal characteristics, 2) enabling factors that involve patient centered attitudes or circumstances, and 3) aversion. These factors are explored across both Australian rural and urban settings and contrasted to reported outcomes from research across other countries. Australia has the lowest number of publications on rural clinical trial participation when compared to rural research in America and Canada. Across Australian urban areas where all 3 factors have been studied, trends are similar to those reported in other developed countries. In conclusion we suggest that trial participation could be improved if participants are better informed about a trial as this is a valuable factor to enable recruitment.