Mortality Time-Trends of Different Cardiovascular Diseases in a Practically Extinct Cohort of Italian Middle-Aged Men Followed-Up for 61 Years: A Possible Etiological Explanation?

PURPOSE: To study a male Italian cohort (initially aged 40-59, n = 1712) during 61 years and the natural history of major CVD mortality categories including coronary heart disease (CHD), stroke and other heart diseases of uncertain etiology (HDUE), including congestive heart failure) along with their risk factor relationships. METHODS AND RESULTS: Cox models were run with 12 covariates as possible predictors measured at entry to the study. About 93% of all CVD deaths were covered by the three major groups selected here (N = 751): 37.4% of them were diagnosed as CHD, 30.6% as stroke and 28.5% as HDUE. CHD declined in the last 20 years of follow-up, while a sharp increase in HDUE mortality was seen. Baseline mean levels of serum cholesterol were 209.6, 204.2 and 198.0 mg/dL, respectively, for CHD, stroke and HDUE deaths: the multivariable coefficients of serum cholesterol were positive and significant for CHD (p < 0.0001), and stroke (p = 0.0203) and not significant for HDUE (p = 0.3467). In Fine-Gray models, the algebraic signs of cholesterol coefficients were opposite for CHD versus the other mortality categories (t = 3.13). The predictive performances of remaining risk factors were varied whereas that of Cox models was not very good, probably due to the attrition phenomenon and possible competing risks. CONCLUSION: Large differences in natural history and risk factors were found comparing the three CVD conditions, potentially indicating different etiologies and pointing to the need of not mixing them up in a grouped CVD category.

Competing Risks of Coronary Heart Disease Mortality versus Other Causes of Death in 10 Cohorts of Middle-Aged Men of the Seven Countries Study Followed for 60 Years to Extinction.

OBJECTIVES: To assess whether competing risks help explain why regions with initially high serum cholesterol have higher mortality from coronary heart disease (CHD) and lower mortality from stroke and other major heart diseases, while the reverse is found for those with initially lower serum cholesterol. MATERIAL AND METHODS: Ten cohorts of men (N = 9063) initially aged 40-59 in six countries were examined and followed for fatal outcomes for 60 years. Major cardiovascular disease (CVD) groups were CHD, stroke, and other Heart Diseases of Uncertain Etiology (HDUE), or the combination of stroke and HDUE (STHD), along with all other causes of death. Fine-Gray competing risk analysis was applied with CHD versus all other causes of death or STHD (direct mode) and all other causes of death or STHD versus CHD (inverse mode), and the effects of 19 covariates (of which 3 references) on the cause-specific hazard of the outcomes were assessed, thus investigating potential etiologic roles. A systematic comparison with results obtained by running the Cox model in direct and inverse modes with the same end-point results was also performed and illustrated graphically. RESULTS: CHD mortality is bound to different risk factor relationships when compared with all other causes of death and with STHD. The role of serum cholesterol is crucial since, in both comparisons, by Fine-Gray, its coefficients are positive and significant for CHD and negative and significant for all other causes of death and STHD. Risk factor capabilities in specific outcome types of the CVD domain (CHD versus STHD) are different depending on the outcome types considered. Risk factor coefficients are smaller in Fine-Gray modelling and larger in the Cox model. Fine-Gray detects different risk factors whose coefficients may have opposite algebraic signs. CONCLUSIONS: This is the first report whereby a large group of risk factors are investigated in connection with life-long CVD outcomes by Fine-Gray competing risk analysis, and a systematic comparison is performed with results obtained by Cox models in both direct and inverse modes. Subtypes of CVD mortality should be summed with full awareness that some risk factors vary by pathology, and they should at least be disentangled into CHD and STHD.

Multi-modal analysis of infant cry types characterization: Acoustics, body language and brain signals.

BACKGROUND: Infant crying is the first attempt babies use to communicate during their initial months of life. A misunderstanding of the cry message can compromise infant care and future neurodevelopmental process. METHODS: An exploratory study collecting multimodal data (i.e., crying, electroencephalography (EEG), near-infrared spectroscopy (NIRS), facial expressions, and body movements) from 38 healthy full-term newborns was conducted. Cry types were defined based on different conditions (i.e., hunger, sleepiness, fussiness, need to burp, and distress). Statistical analysis, Machine Learning (ML), and Deep Learning (DL) techniques were used to identify relevant features for cry type classification and to evaluate a robust DL algorithm named Acoustic MultiStage Interpreter (AMSI). RESULTS: Significant differences were found across cry types based on acoustics, EEG, NIRS, facial expressions, and body movements. Acoustics and body language were identified as the most relevant ML features to support the cause of crying. The DL AMSI algorithm achieved an accuracy rate of 92%. CONCLUSIONS: This study set a precedent for cry analysis research by highlighting the complexity of newborn cry expression and strengthening the potential use of infant cry analysis as an objective, reliable, accessible, and non-invasive tool for cry interpretation, improving the infant-parent relationship and ensuring family well-being.

How can cry acoustics associate newborns' distress levels with neurophysiological and behavioral signals?

Introduction: Even though infant crying is a common phenomenon in humans' early life, it is still a challenge for researchers to properly understand it as a reflection of complex neurophysiological functions. Our study aims to determine the association between neonatal cry acoustics with neurophysiological signals and behavioral features according to different cry distress levels of newborns. Methods: Multimodal data from 25 healthy term newborns were collected simultaneously recording infant cry vocalizations, electroencephalography (EEG), near-infrared spectroscopy (NIRS) and videos of facial expressions and body movements. Statistical analysis was conducted on this dataset to identify correlations among variables during three different infant conditions (i.e., resting, cry, and distress). A Deep Learning (DL) algorithm was used to objectively and automatically evaluate the level of cry distress in infants. Results: We found correlations between most of the features extracted from the signals depending on the infant's arousal state, among them: fundamental frequency (F0), brain activity (delta, theta, and alpha frequency bands), cerebral and body oxygenation, heart rate, facial tension, and body rigidity. Additionally, these associations reinforce that what is occurring at an acoustic level can be characterized by behavioral and neurophysiological patterns. Finally, the DL audio model developed was able to classify the different levels of distress achieving 93% accuracy. Conclusion: Our findings strengthen the potential of crying as a biomarker evidencing the physical, emotional and health status of the infant becoming a crucial tool for caregivers and clinicians.

Geometry Does Impact on the Plane Strain Directions of the Human Left Ventricle, Irrespective of Disease.

The directions of primary strain lines of local deformation in Epicardial and Endocardial layers have been the subject of debate in recent years. Different methods led to different conclusions and a complete assessment of strain direction patterns in large and variable (in terms of pathology) cohorts of healthy and diseased patients is still lacking. Here, we use local deformation tensors in order to evaluate the angle of strain lines with respect to the horizontal circumferential direction in both Epi- and Endo-layers. We evaluated this on a large group of 193 subjects including 82 healthy control and 111 patients belonging to a great variety of pathological conditions. We found that Epicardial strain lines obliquely directed while those of Endocardium are almost circumferential. This result occurs irrespective of pathological condition. We propose that the geometric vinculum characterizing Endocardium and Epicardium in terms of different lever arm length and orientation of muscular fibers during contraction inescapably requires Endocardial strain lines to be circumferentially oriented and this is corroborated by experimental results. Further investigations on transmural structure of myocytes could couple results presented here in order to furnish additional experimental explanations.

Correction: A new, fast method to search for morphological convergence with shape data.

[This corrects the article DOI: 10.1371/journal.pone.0226949.].

Old African fossils provide new evidence for the origin of the American crocodiles.

Molecular and morphological phylogenies concur in indicating that the African lineages formerly referred to Crocodylus niloticus are the sister taxon the four Neotropical crocodiles (Crocodylus intermedius, C. moreleti, C. acutus and C. rhombifer), implying a transoceanic dispersal from Africa to America. So far the fossil record did not contribute to identify a possible African forerunner of the Neotropical species but, curiously, the oldest remains referred to the African C. niloticus are Quaternary in age, whereas the oldest American fossils of Crocodylus are older, being dated to the early Pliocene, suggesting that another species could be involved. We re-described, also thanks to CT imaging, the only well-preserved topotipic skull of Crocodylus checchiai Maccagno, 1947 from the late Miocene (Messinian) African site of As Sahabi in Libya. As previously suggested on the basis of late Miocene material from Tanzania, C. checchiai is a valid, diagnosable species. According to our phylogenetic analyses, C. checchiai is related to the Neotropical taxa and could be even located at the base of their radiation, therefore representing the missing link between the African and the American lineages.

Local and global energies for shape analysis in medical imaging.

In a previous contribution, a new Riemannian shape space, named TPS space, was introduced to perform statistics on shape data. This space was endowed with a Riemannian metric and a flat connection, with torsion, compatible with the given metric. This connection allows the definition of a Parallel Transport of the deformation compatible with the three-fold decomposition in spherical, deviatoric, and non-affine components. Such a parallel transport also conserves the Γ-energy, strictly related to the total elastic strain energy stored by the body in the original deformation. A new approach is here presented in order to calculate the bending energy on the body alone (body bending energy) and to restrict it exclusively within physical boundaries of objects involved in the deformation analysis. The novelty of this new procedure resides in the fact that we propose a new metric to be preserved during the TPS direct transport. This allows transporting the shape change more coherently with the mechanical meaning of the deformation. The geometry of the TPS space is then further discussed in order to better represent the relationship between the Γ-energy, the strain energy, and the so-called bending energy densities.

A 450 million years long latitudinal gradient in age-dependent extinction.

Leigh Van Valen famously stated that under constant conditions extinction probability is independent of species age. To test this 'law of constant extinction', we developed a new method using deep learning to infer age-dependent extinction and analysed 450 myr of marine life across 21 invertebrate clades. We show that extinction rate significantly decreases with age in > 90% of the cases, indicating that most species died out soon after their appearance while those which survived experienced ever decreasing extinction risk. This age-dependent extinction pattern is stronger towards the Equator and holds true when the potential effects of mass extinctions and taxonomic inflation are accounted for. These results suggest that the effect of biological interactions on age-dependent extinction rate is more intense towards the tropics. We propose that the latitudinal diversity gradient and selection at the species level account for this exceptional, yet little recognised, macroevolutionary and macroecological pattern.

A new, fast method to search for morphological convergence with shape data.

Morphological convergence is an intensely studied macroevolutionary phenomenon. It refers to the morphological resemblance between phylogenetically distant taxa. Currently available methods to explore evolutionary convergence either: rely on the analysis of the phenotypic resemblance between sister clades as compared to their ancestor, fit different evolutionary regimes to different parts of the tree to see whether the same regime explains phenotypic evolution in phylogenetically distant clades, or assess deviations from the congruence between phylogenetic and phenotypic distances. We introduce a new test for morphological convergence working directly with non-ultrametric (i.e. paleontological) as well as ultrametric phylogenies and multivariate data. The method (developed as the function search.conv within the R package RRphylo) tests whether unrelated clades are morphologically more similar to each other than expected by their phylogenetic distance. It additionally permits using known phenotypes as the most recent common ancestors of clades, taking full advantage of fossil information. We assessed the power of search.conv and the incidence of false positives by means of simulations, and then applied it to three well-known and long-discussed cases of (purported) morphological convergence: the evolution of grazing adaptation in the mandible of ungulates with high-crowned molars, the evolution of mandibular shape in sabertooth cats, and the evolution of discrete ecomorphs among anoles of Caribbean islands. The search.conv method was found to be powerful, correctly identifying simulated cases of convergent morphological evolution in 95% of the cases. Type I error rate is as low as 4-6%. We found search.conv is some three orders of magnitude faster than a competing method for testing convergence.

Impact of transition to a subterranean lifestyle on morphological disparity and integration in talpid moles (Mammalia, Talpidae).

BACKGROUND: Understanding the mechanisms promoting or constraining morphological diversification within clades is a central topic in evolutionary biology. Ecological transitions are of particular interest because of their influence upon the selective forces and factors involved in phenotypic evolution. Here we focused on the humerus and mandibles of talpid moles to test whether the transition to the subterranean lifestyle impacted morphological disparity and phenotypic traits covariation between these two structures. RESULTS: Our results indicate non-subterranean species occupy a significantly larger portion of the talpid moles morphospace. However, there is no difference between subterranean and non-subterranean moles in terms of the strength and direction of phenotypic integration. CONCLUSIONS: Our study shows that the transition to a subterranean lifestyle significantly reduced morphological variability in talpid moles. However, this reduced disparity was not accompanied by changes in the pattern of traits covariation between the humerus and the mandible, suggesting the presence of strong phylogenetic conservatism within this pattern.

Non-invasive prediction of genotype positive-phenotype negative in hypertrophic cardiomyopathy by 3D modern shape analysis.

NEW FINDINGS: What is the central question of this study? Can impaired deformational indicators for genotype positive for hypertrophic cardiomyopathy in subjects that do not exhibit a left-ventricular wall hypertrophy condition (G+LVH-) be determined using non-invasive 3D echocardiography? What is the main finding and its importance? Using 3D-STE and modern shape analysis, peculiar deformational impairments can be detected in G+LVH- subjects that can be classified with good accuracy. Moreover, the patterns of impairment are located mainly on the apical region in agreement with other evidence coming from previous biomechanical investigations. ABSTRACT: We propose a non-invasive procedure for predicting genotype positive for hypertrophic cardiomyopathy (HCM) in subjects that do not exhibit a left-ventricular wall hypertrophy condition (G+LVH-); the procedure is based on the enhanced analysis of medical imaging from 3D speckle tracking echocardiography (3D-STE). 3D-STE, due to its low quality images, has not been used so far to detect effectively the G+LVH- condition. Here, we post-processed echocardiographic images exploiting the tools of modern shape analysis, and we studied the motion of the left ventricle (LV) during an entire cycle. We enrolled 82 controls, 21 HCM patients and 11 G+LVH- subjects. We followed two steps: (i) we selected the most impaired regions of the LV by analysing its strains; and (ii) we used shape analysis on these regions to classify the subjects. The G+LVH- subjects showed different trajectories and deformational attributes. We found high classification performance in terms of area under the receiver operating characteristic curve (∼90), sensitivity (∼78) and specificity (∼79). Our results showed that (i) G+LVH- subjects present important deformational impairments relative to healthy controls and (ii) modern shape analysis can efficiently predict genotype by means of a non-invasive and inexpensive technique such as 3D-STE.

Are developmental shifts the main driver of phenotypic evolution in Diplodus spp. (Perciformes: Sparidae)?

BACKGROUND: Sparid fishes of the genus Diplodus show a complex life history. Juveniles have adaptations well suited to life in the water column. When fishes recruit into the adult population, individuals develop a radically differentiated shape that reflects their adaptation to the new benthic environment typical of the adult. A comparative analysis of ontogenetic trajectories was performed to assess the presence of divergence in the developmental pattern. By using a geometric morphometric approach, we investigated the pattern of shape variation across ontogenetic stages that span from early settlement to the adult stage in four species of the genus Diplodus. Landmarks were collected on the whole body of fishes to quantify the phenotypic variation along two well defined life stages, i.e. juvenile and adult. A comparative analysis of ontogenetic trajectories was performed to assess the presence of divergence in the developmental pattern. Subsequently, we investigated the patterns of integration and modularity as proxy for the alteration of the developmental processes. This have allowed to give an insight in morphological developmental patterns across ecologically and ontogenetically differentiated life stages and to investigate the process leading to the adult shape. RESULT: Our results suggest that the origin of morphological novelties in Diplodus spp. arise from shifts of the ontogenetic trajectories during development. During the settlement phase, the juveniles' morphological shapes converge towards similar regions of the morphospace. When the four species approach the transition between settlement and recruitment, we observe the lowest level of inter- and intra-specific disparity. After this transition we detect an abrupt shift of ontogenetic trajectories, i.e. the path taken by species during development, that led to highly divergent adult phenotypes. DISCUSSION: We suggest that the evolution of new ecomorphologies, better suited to exploit different niches (pelagic vs. benthonic) and reduce inter-specific competition in Diplodus spp., are related to the shift in the ontogenetic trajectory that in turn is associated to changes in modularity and integration pattern.

The decomposition of deformation: New metrics to enhance shape analysis in medical imaging.

In landmarks-based Shape Analysis size is measured, in most cases, with Centroid Size. Changes in shape are decomposed in affine and non affine components. Furthermore the non affine component can be in turn decomposed in a series of local deformations (partial warps). If the extent of deformation between two shapes is small, the difference between Centroid Size and m-Volume increment is barely appreciable. In medical imaging applied to soft tissues bodies can undergo very large deformations, involving large changes in size. The cardiac example, analyzed in the present paper, shows changes in m-Volume that can reach the 60%. We show here that standard Geometric Morphometrics tools (landmarks, Thin Plate Spline, and related decomposition of the deformation) can be generalized to better describe the very large deformations of biological tissues, without losing a synthetic description. In particular, the classical decomposition of the space tangent to the shape space in affine and non affine components is enriched to include also the change in size, in order to give a complete description of the tangent space to the size-and-shape space. The proposed generalization is formulated by means of a new Riemannian metric describing the change in size as change in m-Volume rather than change in Centroid Size. This leads to a redefinition of some aspects of the Kendall's size-and-shape space without losing Kendall's original formulation. This new formulation is discussed by means of simulated examples using 2D and 3D platonic shapes as well as a real example from clinical 3D echocardiographic data. We demonstrate that our decomposition based approaches discriminate very effectively healthy subjects from patients affected by Hypertrophic Cardiomyopathy.

Statistical shape modeling of the left ventricle: myocardial infarct classification challenge.

Statistical shape modeling is a powerful tool for visualizing and quantifying geometric and functional patterns of the heart. After myocardial infarction (MI), the left ventricle typically remodels in response to physiological challenges. Several methods have been proposed in the literature to describe statistical shape changes. Which method best characterizes left ventricular remodeling after MI is an open research question. A better descriptor of remodeling is expected to provide a more accurate evaluation of disease status in MI patients. We therefore designed a challenge to test shape characterization in MI given a set of three-dimensional left ventricular surface points. The training set comprised 100 MI patients, and 100 asymptomatic volunteers (AV). The challenge was initiated in 2015 at the Statistical Atlases and Computational Models of the Heart workshop, in conjunction with the MICCAI conference. The training set with labels was provided to participants, who were asked to submit the likelihood of MI from a different (validation) set of 200 cases (100 AV and 100 MI). Sensitivity, specificity, accuracy and area under the receiver operating characteristic curve were used as the outcome measures. The goals of this challenge were to (1) establish a common dataset for evaluating statistical shape modeling algorithms in MI, and (2) test whether statistical shape modeling provides additional information characterizing MI patients over standard clinical measures. Eleven groups with a wide variety of classification and feature extraction approaches participated in this challenge. All methods achieved excellent classification results with accuracy ranges from 0.83 to 0.98. The areas under the receiver operating characteristic curves were all above 0.90. Four methods showed significantly higher performance than standard clinical measures. The dataset and software for evaluation are available from the Cardiac Atlas Project website1.

Re-calibration of coronary risk prediction: an example of the Seven Countries Study.

We aimed at performing a calibration and re-calibration process using six standard risk factors from Northern (NE, N = 2360) or Southern European (SE, N = 2789) middle-aged men of the Seven Countries Study, whose parameters and data were fully known, to establish whether re-calibration gave the right answer. Greenwood-Nam-D'Agostino technique as modified by Demler (GNDD) in 2015 produced chi-squared statistics using 10 deciles of observed/expected CHD mortality risk, corresponding to Hosmer-Lemeshaw chi-squared employed for multiple logistic equations whereby binary data are used. Instead of the number of events, the GNDD test uses survival probabilities of observed and predicted events. The exercise applied, in five different ways, the parameters of the NE-predictive model to SE (and vice-versa) and compared the outcome of the simulated re-calibration with the real data. Good re-calibration could be obtained only when risk factor coefficients were substituted, being similar in magnitude and not significantly different between NE-SE. In all other ways, a good re-calibration could not be obtained. This is enough to praise for an overall need of re-evaluation of most investigations that, without GNDD or another proper technique for statistically assessing the potential differences, concluded that re-calibration is a fair method and might therefore be used, with no specific caution.

The evolution of cranial base and face in Cercopithecoidea and Hominoidea: Modularity and morphological integration.

The evolutionary relationship between the base and face of the cranium is a major topic of interest in primatology. Such areas of the skull possibly respond to different selective pressures. Yet, they are often said to be tightly integrated. In this paper, we analyzed shape variability in the cranial base and the facial complex in Cercopithecoidea and Hominoidea. We used a landmark-based approach to single out the effects of size (evolutionary allometry), morphological integration, modularity, and phylogeny (under Brownian motion) on skull shape variability. Our results demonstrate that the cranial base and the facial complex exhibit different responses to different factors, which produces a little degree of morphological integration between them. Facial shape variation appears primarily influenced by body size and sexual dimorphism, whereas the cranial base is mostly influenced by functional factors. The different adaptations affecting the two modules suggest they are best studied as separate and independent units, and that-at least when dealing with Catarrhines-caution must be posed with the notion of strong cranial integration that is commonly invoked for the evolution of their skull shape.

Morphologically normalized left ventricular motion indicators from MRI feature tracking characterize myocardial infarction.

We characterized motion attributes arising from LV spatio-temporal analysis of motion distributions in myocardial infarction. Time-varying 3D finite element shape models were obtained in 300 Controls and 300 patients with myocardial infarction. Inter-individual left ventricular shape differences were eliminated using parallel transport to the grand mean of all cases. The first three principal component (PC) scores were used to characterize trajectory attributes. Scores were tested with ANOVA/MANOVA using patient disease status (Infarcts vs. Controls) as a factor. Infarcted patients had significantly different magnitude, orientation and shape of left ventricular trajectories in comparison to Controls. Significant differences were found for the angle between PC scores 1 and 2 in the endocardium, and PC scores 1 and 3 in the epicardium. The largest differences were found in the magnitude of endocardial motion. Endocardial PC scores in shape space showed the highest classification power using support vector machine, with higher total accuracy in comparison to previous methods. Shape space performed better than size-and-shape space for both epicardial and endocardial features. In conclusion, LV spatio-temporal motion attributes accurately characterize the presence of infarction. This approach is easily generalizable to different pathologies, enabling more precise study of the pathophysiological consequences of a wide spectrum of cardiac diseases.

Homeostatic Left Heart integration and disintegration links atrio-ventricular covariation's dyshomeostasis in Hypertrophic Cardiomyopathy.

Left ventricle and left atrium are and have been practically always analyzed separately in common clinically and non-clinically oriented cardiovascular investigations. Both classic and speckle tracking echocardiographic data contributed to the knowledge about deformational impairments occurring in systo-diastolic differences. Recently new trajectory based approaches allowed a greater awareness about the entire left ventricle or left atrium revolution and on their deficiencies that take place in presence of hypertrophic cardiomyopathy. However, surprisingly, the concomitant function of the two left heart chambers has not been analyzed for their geometrical/mechanical relationship. For the first time we study here, by acquiring left ventricle and left atrial geometries on the same heartbeat, the trajectory attributes of the entire left heart treated as a whole shape and the shape covariation of its two subunits. We contrasted healthy subjects with patients affected by hypertrophic cardiomyopathy. We found impaired left heart trajectory mainly in terms of orientation and size. More importantly, we found profound differences in the direction of morphological covariation of left ventricle and left atrium. These findings open to new perspectives in pathophysiological evaluation of different diseases by allowing the appreciation of concomitant functioning of both left heart whole geometry and of its two chambers.

Lifetime competing risks between coronary heart disease mortality and other causes of death during 50years of follow-up.

OBJECTIVES: To study coronary heart disease (CHD) death versus 11 other causes of death using the cumulative incidence function (CIF) and the competing risks procedures to disentangle the differential role of risk factors for different end-points. MATERIAL AND METHODS: Standard Cox and Fine-Gray models among 1712 middle-aged men were compared during 50years of follow-up. CHD death was the primary event, while deaths from 11 selected causes, mutually exclusive from the primary end-point, were considered as secondary events. Reverse solutions were also performed. We considered 10 selected risk factors. RESULTS: CHD death risk was the second highest among 12 mostly specific causes of death. Some risk factors were specific: serum cholesterol for CHD death whereas, systolic blood pressure, cigarette smoking and age may have a differential role in other causes of death. Application of the Fine-Gray model based on CIF enabled to dissect, at least in part, the respective role that baseline covariates may have to segregate the probabilities of two types of death in contrast from each other. They also point to the absence of contributing significance for some of the selected risk factors and this calls for a parsimonious approach in predictions. CONCLUSIONS: The relative rarity of competing risk challenges when defining the risk factors role at long-term needs now be corrected since we have clearly shown, with Fine-Gray model, at direct or reverse use, that comparing different end-points heavily influences the risk factor predictive capacity.