Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

NetMets: software for quantifying and visualizing errors in biological network segmentation

One of the major goals in biomedical image processing is accurate segmentation of networks embedded in volumetric data sets. Biological networks are composed of a meshwork of thin filaments that span large volumes of tissue. Examples of these structures include neurons and microvasculature, which can take the form of both hierarchical trees and fully connected networks, depending on the imaging modality and resolution. Network function depends on both the geometric structure and connectivity. Therefore, there is considerable demand for algorithms that segment biological networks embedded in three-dimensional data. While a large number of tracking and segmentation algorithms have been published, most of these do not generalize well across data sets. One of the major reasons for the lack of general-purpose algorithms is the limited availability of metrics that can be used to quantitatively compare their effectiveness against a pre-constructed ground-truth. In this paper, we propose a robust metric for measuring and visualizing the differences between network models. Our algorithm takes into account both geometry and connectivity to measure network similarity. These metrics are then mapped back onto an explicit model for visualization

Whole-body tissue stabilization and selective extractions via tissue-hydrogel hybrids for high-resolution intact circuit mapping and phenotyping

To facilitate fine-scale phenotyping of whole specimens, we describe here a set of tissue fixation-embedding, detergent-clearing and staining protocols that can be used to transform excised organs and whole organisms into optically transparent samples within 1–2 weeks without compromising their cellular architecture or endogenous fluorescence. PACT (passive CLARITY technique) and PARS (perfusion-assisted agent release in situ) use tissue-hydrogel hybrids to stabilize tissue biomolecules during selective lipid extraction, resulting in enhanced clearing efficiency and sample integrity. Furthermore, the macromolecule permeability of PACT- and PARS-processed tissue hybrids supports the diffusion of immunolabels throughout intact tissue, whereas RIMS (refractive index matching solution) grants high-resolution imaging at depth by further reducing light scattering in cleared and uncleared samples alike. These methods are adaptable to difficult-to-image tissues, such as bone (PACT-deCAL), and to magnified single-cell visualization (ePACT). Together, these protocols and solutions enable phenotyping of subcellular components and tracing cellular connectivity in intact biological networks

Optimal blood pressure in patients with atrial fibrillation (from the AFFIRM Trial)

Many medications used to treat atrial fibrillation (AF) also reduce blood pressure (BP). The relation between BP and mortality is unclear in patients with AF. We performed a post hoc analysis of 3,947 participants from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management trial. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at baseline and follow-up were categorized by 10-mm Hg increments. The end points were all-cause mortality (ACM) and secondary outcome (combination of ACM, ventricular tachycardia and/or fibrillation, pulseless electrical activity, significant bradycardia, stroke, major bleeding, myocardial infarction, and pulmonary embolism). SBP and DBP followed a "U-shaped" curve with respect to primary and secondary outcomes after multivariate analysis. A nonlinear Cox proportional hazards model showed that the incidence of ACM was lowest at 140/78 mm Hg. Subgroup analyses revealed similar U-shaped curves. There was an increased ACM observed with BP <110/60 mm Hg (hazard ratio 2.4, p <0.01, respectively, for SBP and DBP). In conclusion, in patients with AF, U-shaped relation existed between BP and ACM. These data suggest that the optimal BP target in patients with AF may be greater than the general population and that pharmacologic therapy to treat AF may be associated with ACM or adverse events if BP is reduced to <110/60 mm Hg

Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity

10.1038/s41467-021-22397-5Nature Communications12

Optimal blood pressure in patients with atrial fibrillation (from the AFFIRM Trial).

Many medications used to treat atrial fibrillation (AF) also reduce blood pressure (BP). The relation between BP and mortality is unclear in patients with AF. We performed a post hoc analysis of 3,947 participants from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management trial. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at baseline and follow-up were categorized by 10-mm Hg increments. The end points were all-cause mortality (ACM) and secondary outcome (combination of ACM, ventricular tachycardia and/or fibrillation, pulseless electrical activity, significant bradycardia, stroke, major bleeding, myocardial infarction, and pulmonary embolism). SBP and DBP followed a U-shaped curve with respect to primary and secondary outcomes after multivariate analysis. A nonlinear Cox proportional hazards model showed that the incidence of ACM was lowest at 140/78 mm Hg. Subgroup analyses revealed similar U-shaped curves. There was an increased ACM observed with BP \u3c110/60 mm Hg (hazard ratio 2.4,

Contemporary Trends of Hospitalization for Atrial Fibrillation in the United States, 2000 Through 2010

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The associated morbidity and mortality make AF a major public health burden. Hospitalizations account for the majority of the economic cost burden associated with AF. The main objective of this study is to examine the trends of AF-related hospitalizations in the United States and to compare patient characteristics, outcomes, and comorbid diagnoses. With the use of the Nationwide Inpatient Sample from 2000 through 2010, we identified AF-related hospitalizations using International Classification of Diseases, 9th Revision, Clinical Modification code 427.31 as the principal discharge diagnosis. Overall AF hospitalizations increased by 23% from 2000 to 2010, particularly in patients ≥65 years of age. The most frequent coexisting conditions were hypertension (60.0%), diabetes mellitus (21.5%), and chronic pulmonary disease (20.0%). Overall in-hospital mortality was 1%. The mortality rate was highest in the group of patients ≥80 years of age (1.9%) and in the group of patients with concomitant heart failure (8.2%). In-hospital mortality rate decreased significantly from 1.2% in 2000 to 0.9% in 2010 (29.2% decrease; P<0.001). Although there was no significant change in mean length of stay, mean cost of AF hospitalization increased significantly from $6410 in 2001 to$8439 in 2010 (24.0% increase; P<0.001). Hospitalization rates for AF have increased exponentially among US adults from 2000 to 2010. The proportion of comorbid chronic diseases has also increased significantly. The last decade has witnessed an overall decline in hospital mortality; however, the hospitalization cost has significantly increased

Contemporary trends of hospitalization for atrial fibrillation in the United States, 2000 through 2010: implications for healthcare planning.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The associated morbidity and mortality make AF a major public health burden. Hospitalizations account for the majority of the economic cost burden associated with AF. The main objective of this study is to examine the trends of AF-related hospitalizations in the United States and to compare patient characteristics, outcomes, and comorbid diagnoses. METHODS AND RESULTS: With the use of the Nationwide Inpatient Sample from 2000 through 2010, we identified AF-related hospitalizations using International Classification of Diseases, 9th Revision, Clinical Modification code 427.31 as the principal discharge diagnosis. Overall AF hospitalizations increased by 23% from 2000 to 2010, particularly in patients ≥65 years of age. The most frequent coexisting conditions were hypertension (60.0%), diabetes mellitus (21.5%), and chronic pulmonary disease (20.0%). Overall in-hospital mortality was 1%. The mortality rate was highest in the group of patients ≥80 years of age (1.9%) and in the group of patients with concomitant heart failure (8.2%). In-hospital mortality rate decreased significantly from 1.2% in 2000 to 0.9% in 2010 (29.2% decrease; P CONCLUSIONS: Hospitalization rates for AF have increased exponentially among US adults from 2000 to 2010. The proportion of comorbid chronic diseases has also increased significantly. The last decade has witnessed an overall decline in hospital mortality; however, the hospitalization cost has significantly increased

Outcomes in atrial fibrillation patients with and without left ventricular hypertrophy when treated with a lenient rate-control or rhythm-control strategy

Although left ventricular (LV) hypertrophy has been proposed as a factor predisposing to atrial fibrillation (AF), its relevance to prognosis and selection of therapeutic strategies is unclear. We identified 2,105 patients with echocardiographic data on LV mass enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial. LV hypertrophy was defined as increased LV mass, stratified by American Society of Echocardiography criteria. The primary end point was all-cause mortality, secondary end point was as per AFFIRM trial definition, and tertiary end point was cardiovascular hospitalizations. We compared "strict" versus "lenient" rate control in patients with increased LV mass, and studied association of heart failure (HF) with preserved and decreased systolic function in patients with increased LV mass. Over 6 years, 332 deaths (15.7%) were reported. Adjusted hazard ratio (HR) of severely increased LV mass for all-cause mortality was 1.34 (95% confidence interval [CI] 1.01 to 1.79, p=0.045) for the overall population and 1.61 (95% CI 1.09 to 2.37, p=0.016) for the rhythm-control arm. Increased LV mass was a predictor of cardiovascular hospitalizations in the lenient rate-control group (HR 1.72, 95% CI 1.05 to 2.82, p=0.03) but not in the strict rate-control group. Severely increased LV mass was predictive of cardiovascular hospitalizations in patients with HF with preserved (HR 1.8, 95% CI 1.0 to 3.2, p=0.03) and decreased LV systolic function (HR 2.4, 95% CI 1.1 to 5.2, p=0.02). Thus, LV hypertrophy is a significant independent predictor of mortality in patients with AF, especially those managed with rhythm control. In patients with LV hypertrophy, strict rate control may be associated with better outcomes than lenient rate control. LV hypertrophy portends higher cardiovascular morbidity in patients with AF and HF

Outcomes in atrial fibrillation patients with and without left ventricular hypertrophy when treated with a lenient rate-control or rhythm-control strategy.

Although left ventricular (LV) hypertrophy has been proposed as a factor predisposing to atrial fibrillation (AF), its relevance to prognosis and selection of therapeutic strategies is unclear. We identified 2,105 patients with echocardiographic data on LV mass enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial. LV hypertrophy was defined as increased LV mass, stratified by American Society of Echocardiography criteria. The primary end point was all-cause mortality, secondary end point was as per AFFIRM trial definition, and tertiary end point was cardiovascular hospitalizations. We compared strict versus lenient rate control in patients with increased LV mass, and studied association of heart failure (HF) with preserved and decreased systolic function in patients with increased LV mass. Over 6 years, 332 deaths (15.7%) were reported. Adjusted hazard ratio (HR) of severely increased LV mass for all-cause mortality was 1.34 (95% confidence interval [CI] 1.01 to 1.79, p=0.045) for the overall population and 1.61 (95% CI 1.09 to 2.37, p=0.016) for the rhythm-control arm. Increased LV mass was a predictor of cardiovascular hospitalizations in the lenient rate-control group (HR 1.72, 95% CI 1.05 to 2.82, p=0.03) but not in the strict rate-control group. Severely increased LV mass was predictive of cardiovascular hospitalizations in patients with HF with preserved (HR 1.8, 95% CI 1.0 to 3.2, p=0.03) and decreased LV systolic function (HR 2.4, 95% CI 1.1 to 5.2, p=0.02). Thus, LV hypertrophy is a significant independent predictor of mortality in patients with AF, especially those managed with rhythm control. In patients with LV hypertrophy, strict rate control may be associated with better outcomes than lenient rate control. LV hypertrophy portends higher cardiovascular morbidity in patients with AF and HF