Uncertainty quantification in mechanistic epidemic models via cross-entropy approximate Bayesian computation.

This paper proposes a data-driven approximate Bayesian computation framework for parameter estimation and uncertainty quantification of epidemic models, which incorporates two novelties: (i) the identification of the initial conditions by using plausible dynamic states that are compatible with observational data; (ii) learning of an informative prior distribution for the model parameters via the cross-entropy method. The new methodology's effectiveness is illustrated with the aid of actual data from the COVID-19 epidemic in Rio de Janeiro city in Brazil, employing an ordinary differential equation-based model with a generalized SEIR mechanistic structure that includes time-dependent transmission rate, asymptomatics, and hospitalizations. A minimization problem with two cost terms (number of hospitalizations and deaths) is formulated, and twelve parameters are identified. The calibrated model provides a consistent description of the available data, able to extrapolate forecasts over a few weeks, making the proposed methodology very appealing for real-time epidemic modeling.

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Data-driven modelling of social forces and collective behaviour in zebrafish.

Zebrafish are rapidly emerging as a powerful model organism in hypothesis-driven studies targeting a number of functional and dysfunctional processes. Mathematical models of zebrafish behaviour can inform the design of experiments, through the unprecedented ability to perform pilot trials on a computer. At the same time, in-silico experiments could help refining the analysis of real data, by enabling the systematic investigation of key neurobehavioural factors. Here, we establish a data-driven model of zebrafish social interaction. Specifically, we derive a set of interaction rules to capture the primary response mechanisms which have been observed experimentally. Contrary to previous studies, we include dynamic speed regulation in addition to turning responses, which together provide attractive, repulsive and alignment interactions between individuals. The resulting multi-agent model provides a novel, bottom-up framework to describe both the spontaneous motion and individual-level interaction dynamics of zebrafish, inferred directly from experimental observations.

Depression and the Link with Cardiovascular Disease.

This review provides an outline of the association between major depressive disorder (MDD) and coronary heart disease (CHD). Much is known about the two individual clinical conditions; however, it is not until recently, biological mechanisms have been uncovered that link both MDD and CHD. The activation of stress pathways have been implicated as a neurochemical mechanism that links MDD and CHD. Depression is known to be associated with poorer outcomes of CHD. Psychological factors, such as major depression and stress, are now known as risk factors for developing CHD, which is as important and is independent of classic risk factors, such as hypertension, diabetes mellitus, and cigarette smoking. Both conditions have great socioeconomic importance given that depression and CHD are likely to be two of the three leading causes of global burden of disease. Better understanding of the common causal pathways will help us delineate more appropriate treatments.

Examining Endothelial Function and Platelet Reactivity in Patients with Depression before and after SSRI Therapy.

Although it is recognized that patients with major depressive disorder (MDD) are at increased risk of developing cardiovascular disease (CVD) the mechanisms responsible remain unknown. Endothelial dysfunction is one of the first signs of CVD. Using two techniques, flow-mediated dilatation in response to reactive hyperemia and laser Doppler velocimetry with iontophoresis, we examined endothelial function in the forearm before and after serotonin-specific reuptake inhibitor (SSRI) treatment in 31 patients with MDD. Measurement of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, soluble P-selectin, and noradrenaline in plasma was also performed. Prior to treatment, markers of endothelial and vascular function and platelet reactivity were within the normal range. Following SSRI therapy (95 ± 5 days) symptoms of depression were reduced (paired difference between pre- and post-treatment Hamilton rating -18 ± 1, P < 0.001) with 19 patients recovered and 4 remitted. There occurred no significant change in markers of endothelial or vascular function following SSRI therapy. The improvement in Hamilton depression rating in response to therapy could be independently predicted by the baseline arterial plasma noradrenaline concentration (r (2) = 0.36, P = 0.003). In this cohort of patients with MDD, SSRI therapy did not influence endothelial function or markers of vascular or platelet reactivity. Patient response to SSRI therapy could be predicted by the initial circulating level of noradrenaline, with noradrenaline levels being lower in responders.

Health-related quality of life and blood pressure 12 months after renal denervation.

AIM: To examine the effect of renal denervation (RDN) on blood pressure (BP) and health-related quality of life (QoL) in patients with resistant hypertension, pseudoresistant hypertension due to a white-coat effect and in patients with uncontrolled masked hypertension. METHODS: Using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), Beck Depression Inventory (BDI) and Spielberger's state and trait anxiety questionnaires, we examined QoL, symptoms of depression and anxiety prior to and 12 months following RDN. BP was assessed from clinic and ambulatory blood pressure monitoring (ABPM) recordings. RESULTS: Patients with uncontrolled masked hypertension had the highest BDI and anxiety scores among all groups at baseline. Twelve months following RDN clinic and ambulatory BP were reduced only in those patients with resistant hypertension (delta SBP: clinic -16 ±â€Š3 mmHg, ABPMday -8 ±â€Š2 mmHg, ABPMnight -8 ±â€Š2 mmHg, all P < 0.01). Clinic BP was reduced in the pseudoresistant group (-17 ±â€Š6 mmHg, P < 0.01) but was elevated in the uncontrolled masked group (+13 ±â€Š6 mmHg, P = 0.02). In all patients, trait anxiety (P < 0.05), BDI scores (P < 0.05) and the SF-36 mental component summary (MCS) score (P < 0.001) were improved. The improvement in the SF-36 MCS was confined to those patients with resistant hypertension (+4.0 ±â€Š1.1, P < 0.01). The change in clinic BP after RDN was related to the baseline clinic BP (systolic: r = 0.54, P < 0.001; diastolic r = 0.43, P < 0.001), the number of ablations delivered (both clinic and mean day ABPM systolic r = 0.24, P < 0.05) and to the change in SF-36 MCS score (systolic: r = 0.25, P = 0.01; diastolic r = 0.24, P = 0.02). CONCLUSION: These results indicate that in patients with confirmed resistant hypertension, RDN is associated with a reduction in BP and a sustained improvement in mental health-related aspects of QoL.

Data-driven stochastic modelling of zebrafish locomotion.

In this work, we develop a data-driven modelling framework to reproduce the locomotion of fish in a confined environment. Specifically, we highlight the primary characteristics of the motion of individual zebrafish (Danio rerio), and study how these can be suitably encapsulated within a mathematical framework utilising a limited number of calibrated model parameters. Using data captured from individual zebrafish via automated visual tracking, we develop a model using stochastic differential equations and describe fish as a self propelled particle moving in a plane. Based on recent experimental evidence of the importance of speed regulation in social behaviour, we extend stochastic models of fish locomotion by introducing experimentally-derived processes describing dynamic speed regulation. Salient metrics are defined which are then used to calibrate key parameters of coupled stochastic differential equations, describing both speed and angular speed of swimming fish. The effects of external constraints are also included, based on experimentally observed responses. Understanding the spontaneous dynamics of zebrafish using a bottom-up, purely data-driven approach is expected to yield a modelling framework for quantitative investigation of individual behaviour in the presence of various external constraints or biological assays.

Analytical modelling of the spread of disease in confined and crowded spaces.

Since 1927 and until recently, most models describing the spread of disease have been of compartmental type, based on the assumption that populations are homogeneous and well-mixed. Recent models have utilised agent-based models and complex networks to explicitly study heterogeneous interaction patterns, but this leads to an increasing computational complexity. Compartmental models are appealing because of their simplicity, but their parameters, especially the transmission rate, are complex and depend on a number of factors, which makes it hard to predict how a change of a single environmental, demographic, or epidemiological factor will affect the population. Therefore, in this contribution we propose a middle ground, utilising crowd-behaviour research to improve compartmental models in crowded situations. We show how both the rate of infection as well as the walking speed depend on the local crowd density around an infected individual. The combined effect is that the rate of infection at a population scale has an analytically tractable non-linear dependency on crowd density. We model the spread of a hypothetical disease in a corridor and compare our new model with a typical compartmental model, which highlights the regime in which current models may not produce credible results.

Addressing the needs of adolescents with treatment resistant depressive disorders: a systematic review of rTMS.

BACKGROUND: Depressive disorders are among the most commonly experienced mental health concerns and a leading cause of mortality in adolescence. Current treatment guidelines recommend the use of antidepressant medication, cognitive behavioral therapy or both treatments. Unfortunately 40­60% of adolescents fail to respond to these treatments, therefore a new effective alternative treatment modality would be of particular benefit. rTMS is effective in addressing treatment resistant depression in adults and investigation into its effectiveness with adolescent populations has begun. OBJECTIVE: To examine the existing literature regarding the efficacy and safety of rTMS treatment with adolescents experiencing depressive symptoms, especially research conducted since the last published review. METHODS: A systematic review was conducted in accordance with PRISMA guidelines. The databases of OVID PsycINFO, PubMed, Ovid Medline and Web of Science were searched for research utilizing rTMS treatment with adolescents experiencing depressive symptomology. RESULTS: The review identified seven studies that examined rTMS as a treatment for depressive symptomology in adolescence. Findings indicate rTMS is likely to be an effective treatment for young people with preliminary longitudinal results suggesting maintenance of effects 3 years post-treatment. Reported side effects have included headaches, scalp discomfort and single incidences of hypomania and seizure. All side effects were transitory and did not recur. CONCLUSION: Preliminary results suggest rTMS is an effective and well tolerated antidepressant treatment for adolescents with treatment resistant depressive symptomology. Further research allowing for comparison across studies is necessary to establish the efficacy of rTMS in adolescent depression.

Effects of selective serotonin reuptake inhibitor treatment on plasma oxytocin and cortisol in major depressive disorder.

BACKGROUND: Oxytocin is known for its capacity to facilitate social bonding, reduce anxiety and for its actions on the stress hypothalamopituitary adrenal (HPA) axis. Since oxytocin can physiologically suppress activity of the HPA axis, clinical applications of this neuropeptide have been proposed in conditions where the function of the HPA axis is dysregulated. One such condition is major depressive disorder (MDD). Dysregulation of the HPA system is the most prominent endocrine change seen with MDD, and normalizing the HPA axis is one of the major targets of recent treatments. The potential clinical application of oxytocin in MDD requires improved understanding of its relationship to the symptoms and underlying pathophysiology of MDD. Previous research has investigated potential correlations between oxytocin and symptoms of MDD, including a link between oxytocin and treatment related symptom reduction. The outcomes of studies investigating whether antidepressive treatment (pharmacological and non-pharmacological) influences oxytocin concentrations in MDD, have produced conflicting outcomes. These outcomes suggest the need for an investigation of the influence of a single treatment class on oxytocin concentrations, to determine whether there is a relationship between oxytocin, the HPA axis (e.g., oxytocin and cortisol) and MDD. Our objective was to measure oxytocin and cortisol in patients with MDD before and following treatment with selective serotonin reuptake inhibitors, SSRI. METHOD: We sampled blood from arterial plasma. Patients with MDD were studied at the same time twice; pre- and post- 12 weeks treatment, in an unblinded sequential design (clinicaltrials.govNCT00168493). RESULTS: Results did not reveal differences in oxytocin or cortisol concentrations before relative to following SSRI treatment, and there were no significant relationships between oxytocin and cortisol, or these two physiological variables and psychological symptom scores, before or after treatment. CONCLUSIONS: These outcomes demonstrate that symptoms of MDD were reduced following effective treatment with an SSRI, and further, stress physiology was unlikely to be a key factor in this outcome. Further research is required to discriminate potential differences in underlying stress physiology for individuals with MDD who respond to antidepressant treatment, relative to those who experience treatment resistance.

Health-related quality of life after renal denervation in patients with treatment-resistant hypertension.

Recent studies have demonstrated the effectiveness of radiofrequency ablation of the renal sympathetic nerves in reducing blood pressure (BP) in patients with resistant hypertension. The effect of renal denervation on health-related quality of life (QoL) has not been evaluated. Using the Medical Outcomes Study 36-Item Short-Form Health Survey and Beck Depression Inventory-II, we examined QoL before and 3 months after renal denervation in patients with uncontrolled BP. For baseline comparisons, matched data were extracted from the Australian Diabetes, Obesity, and Lifestyle database. Before renal denervation, patients with resistant hypertension (n = 62) scored significantly worse in 5 of the eight 36-Item Short-Form Health Survey domains and the Mental Component Summary score. Three months after denervation (n = 40), clinic BP was reduced (change in systolic and diastolic BP, -16 ± 4 and -6 ± 2 mm Hg, respectively; P<0.01). The Mental Component Summary score improved (47.6 ± 1.1 versus 52 ± 1; P = 0.001) as a result of increases in the vitality, social function, role emotion, and mental health domains. Beck Depression Inventory scores were also improved, particularly with regard to symptoms of sadness (P = 0.01), tiredness (P<0.001), and libido (P<0.01). The magnitude of BP reduction or BP level achieved at 3 months bore no association to the change in QoL. Renal denervation was without a detrimental effect on any elements of the 36-Item Short-Form Health Survey. These results indicate that patients with severe hypertension resistant to therapy present with a marked reduction in subjective QoL. In this pre- and post-hypothesis generating study, several aspects of QoL were improved after renal denervation; however, this was not directly associated with the magnitude of BP reduction.

Single-unit muscle sympathetic nervous activity and its relation to cardiac noradrenaline spillover.

Recent work using single-unit sympathetic nerve recording techniques has demonstrated aberrations in the firing pattern of sympathetic nerves in a variety of patient groups. We sought to examine whether nerve firing pattern is associated with increased noradrenaline release. Using single-unit muscle sympathetic nerve recording techniques coupled with direct cardiac catheterisation and noradrenaline isotope dilution methodology we examined the relationship between single-unit firing patterns and cardiac and whole body noradrenaline spillover to plasma. Participants comprised patients with hypertension (n=6), depression (n=7) and panic disorder (n =9) who were drawn from our ongoing studies. The patient groups examined did not differ in their single-unit muscle sympathetic nerve firing characteristics nor in the rate of spillover of noradrenaline to plasma from the heart. The median incidence of multiple spikes per beat was 9%. Patients were stratified according to the firing pattern: low level of incidence (less than 9% incidence of multiple spikes per beat) and high level of incidence (greater than 9% incidence of multiple spikes per beat). High incidence of multiple spikes within a cardiac cycle was associated with higher firing rates (P <0.0001) and increased probability of firing (P <0.0001). Whole body noradrenaline spillover to plasma and (multi-unit) muscle sympathetic nerve activity in subjects with low incidence of multiple spikes was not different to that of those with high incidence of multiple spikes. In those with high incidence of multiple spikes there occurred a parallel activation of the sympathetic outflow to the heart, with cardiac noradrenaline spillover to plasma being two times that of subjects with low nerve firing rates (11.0 ± 1.5 vs. 22.0 ± 4.5 ng min⁻¹, P <0.05). This study indicates that multiple within-burst firing and increased single-unit firing rates of the sympathetic outflow to the skeletal muscle vasculature is associated with high cardiac noradrenaline spillover.

How to turn a genetic circuit into a synthetic tunable oscillator, or a bistable switch.

Systems and Synthetic Biology use computational models of biological pathways in order to study in silico the behaviour of biological pathways. Mathematical models allow to verify biological hypotheses and to predict new possible dynamical behaviours. Here we use the tools of non-linear analysis to understand how to change the dynamics of the genes composing a novel synthetic network recently constructed in the yeast Saccharomyces cerevisiae for In-vivo Reverse-engineering and Modelling Assessment (IRMA). Guided by previous theoretical results that make the dynamics of a biological network depend on its topological properties, through the use of simulation and continuation techniques, we found that the network can be easily turned into a robust and tunable synthetic oscillator or a bistable switch. Our results provide guidelines to properly re-engineering in vivo the network in order to tune its dynamics.

Cardiovascular abnormalities in patients with major depressive disorder: autonomic mechanisms and implications for treatment.

This article provides a detailed review of the association of major depression with coronary heart disease (CHD), examines the biological variables underpinning the linkage and discusses the clinical implications for treatment. When considering the co-morbidity between major depressive disorder (MDD) and CHD it is important to differentiate between (i) the prevalence and impact of MDD in those with existing CHD and (ii) MDD as a risk factor for the development of CHD. Whether the same biological mechanisms are at play in these two instances remains unknown. Depression is common in patients with CHD. Importantly, depression in these patients increases mortality. There is also consistent evidence that MDD is a risk factor for the development of CHD. The relative risk of developing CHD is proportional to the severity of depression and is independent of smoking, obesity, hypercholesterolaemia, diabetes mellitus and hypertension. There is a clear need to identify the underlying neurochemical mechanisms responsible for MDD and their linkage to the heart and vascular system. Of particular interest are activation of stress pathways, including both the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, and inflammatory-mediated atherogenesis. Elevated sympathetic activity, reduced heart rate variability and increased plasma cortisol levels have been documented in patients with MDD. In addition to direct effects on the heart and vasculature, activation of stress pathways may also be associated with increased release of inflammatory cytokines such as interleukin-6 and tumour necrosis factor-alpha. Elevated levels of C-reactive protein are commonly observed in patients with MDD. The majority of investigations examining treatment of depression following myocardial infarction have focused on safety and efficacy; there is little evidence to indicate that treating depression in these patients improves survival. Given that strategies for preventive therapy remain incompletely formulated, future research should focus on generating a better understanding of the neurobiology of MDD and heart disease as a basis for rational and effective therapy.

Elevated brain serotonin turnover in patients with depression: effect of genotype and therapy.

CONTEXT: The biological basis for the development of major depressive disorder (MDD) remains incompletely understood. OBJECTIVE: To quantify brain serotonin (5-hydroxytryptamine [5-HT]) turnover in patients with MDD. DESIGN: Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated. SETTING: Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. PARTICIPANTS: Studies were performed in 21 patients fulfilling the DSM-IV and International Statistical Classification of Diseases, 10th Revision diagnostic criteria for MDD and in 40 healthy volunteers. INTERVENTIONS: Treatment for patients consisted of SSRI administration for approximately 12 weeks. MAIN OUTCOME MEASURES: Brain serotonin turnover before and after SSRI therapy. RESULTS: Brain serotonin turnover was significantly elevated in unmedicated patients with MDD compared with healthy subjects (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 4.4 [4.3] vs 1.6 [2.4] nmol/L, respectively; P = .003). Analysis of the influence of the 5-HTT genotype in MDD indicated that carriage of the s allele compared with the l allele was associated with greater than a 2-fold increase in brain serotonin turnover (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.5 [4.7] vs 2.7 [2.9] nmol/L, respectively; P = .04). Following SSRI therapy, brain serotonin turnover was substantially reduced (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.0 [4.0] nmol/L prior to treatment vs 2.0 [3.3] nmol/L following therapy; P = .008). CONCLUSIONS: Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD.

Sympathetic activity in major depressive disorder: identifying those at increased cardiac risk?

BACKGROUND: Evidence exists linking major depressive disorder (MDD) with clinical cardiovascular events. The importance of the sympathetic nervous system in the generation of cardiac risk in other contexts is established. OBJECTIVE: To examine the importance of the sympathetic nervous system in the generation of cardiac risk in patients with major depressive disorder (MDD). METHODS: Studies were performed in 39 patients meeting the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for MDD and in 76 healthy subjects. Treatment for patients consisted of selective serotonin reuptake inhibition (SSRI) for 12 weeks. Whole body and cardiac sympathetic activity were examined using noradrenaline isotope dilution methodology and sympathetic nerve recording techniques. Measurement of the extraction of infused tritiated noradrenaline by the heart, and estimation of cardiac dihydroxyphenylglycol production provided direct quantification of neuronal noradrenaline reuptake. RESULTS: Sympathetic activity, particularly in the heart and for the whole body, in patients with MDD followed a bimodal distribution. Elevated values were observed in patients with co-morbid panic disorder (P = 0.006). Consistent with a defect in noradrenaline reuptake, the cardiac extraction of tritiated noradrenaline (0.80 +/- 0.01 versus 0.56 +/- 0.04%, P < 0.001) and cardiac dihydroxyphenylglycol overflow (109 +/- 8 versus 73 +/- 11, P = 0.01) were reduced in patients with MDD. SSRI therapy abolished the excessive sympathetic activation, with whole body noradrenaline spillover falling from 518 +/- 83 to 290 +/- 41 ng/min (P = 0.008). CONCLUSIONS: We have identified a subset of patients with MDD in whom sympathetic nervous activity is extraordinarily high, including in the sympathetic outflow to the heart. Treatment with an SSRI may reduce sympathetic activity in a manner likely to reduce cardiac risk.

Specific serotonin reuptake inhibition in major depressive disorder adversely affects novel markers of cardiac risk.

There exists a growing body of evidence linking depression with cardiovascular events, although the mechanisms responsible remain unknown. We investigated the role of the autonomic nervous system and inflammation in the link between coronary heart disease and major depressive disorder (MDD), and examined the cardiac risk modification following pharmacological treatment of depression. We measured cardiac baroreflex function, heart rate variability, pulse pressure and high sensitivity C-reactive protein (hsCRP), all of which have an impact on cardiac risk, pre- and post-treatment in 25 patients with MDD, with no history of coronary heart disease, and in 15 healthy subjects. Treatment consisted of selective serotonin reuptake inhibitors for approximately 12 weeks. No significant differences were observed between untreated MDD patients and healthy subjects in blood pressure, heart rate, baroreflex sensitivity or heart rate variability. Pulse pressure and hsCRP, however, were significantly elevated in patients with MDD prior to treatment (p=0.023 and p=0.025, respectively). Moreover, while pharmacotherapy was effective in alleviating depression, surprisingly, each of cardiac baroreflex function, heart rate variability, pulse pressure and hsCRP was modified (p<0.05) in a manner likely to increase cardiac risk. In conclusion, this study demonstrated higher pulse pressure and hsCRP plasma levels in patients with MDD, which might contribute to increased cardiac risk. Following treatment vagal activity was reduced, as indicated by reductions in baroreflex sensitivity and heart rate variability, accompanied by increases in pulse pressure and plasma hsCRP levels. Mechanisms potentially responsible for generating cardiac risk in patients treated with selective serotonin reuptake inhibitors may need to be therapeutically targeted to reduce the incidence of coronary heart disease in this population.