ICU Cockpit: a platform for collecting multimodal waveform data, AI-based computational disease modeling and real-time decision support in the intensive care unit.

ICU Cockpit: a secure, fast, and scalable platform for collecting multimodal waveform data, online and historical data visualization, and online validation of algorithms in the intensive care unit. We present a network of software services that continuously stream waveforms from ICU beds to databases and a web-based user interface. Machine learning algorithms process the data streams and send outputs to the user interface. The architecture and capabilities of the platform are described. Since 2016, the platform has processed over 89 billion data points (N = 979 patients) from 200 signals (0.5-500 Hz) and laboratory analyses (once a day). We present an infrastructure-based framework for deploying and validating algorithms for critical care. The ICU Cockpit is a Big Data platform for critical care medicine, especially for multimodal waveform data. Uniquely, it allows algorithms to seamlessly integrate into the live data stream to produce clinical decision support and predictions in clinical practice.

Unraveling the deep learning gearbox in optical coherence tomography image segmentation towards explainable artificial intelligence.

Machine learning has greatly facilitated the analysis of medical data, while the internal operations usually remain intransparent. To better comprehend these opaque procedures, a convolutional neural network for optical coherence tomography image segmentation was enhanced with a Traceable Relevance Explainability (T-REX) technique. The proposed application was based on three components: ground truth generation by multiple graders, calculation of Hamming distances among graders and the machine learning algorithm, as well as a smart data visualization ('neural recording'). An overall average variability of 1.75% between the human graders and the algorithm was found, slightly minor to 2.02% among human graders. The ambiguity in ground truth had noteworthy impact on machine learning results, which could be visualized. The convolutional neural network balanced between graders and allowed for modifiable predictions dependent on the compartment. Using the proposed T-REX setup, machine learning processes could be rendered more transparent and understandable, possibly leading to optimized applications.

Validation of automated artificial intelligence segmentation of optical coherence tomography images.

PURPOSE: To benchmark the human and machine performance of spectral-domain (SD) and swept-source (SS) optical coherence tomography (OCT) image segmentation, i.e., pixel-wise classification, for the compartments vitreous, retina, choroid, sclera. METHODS: A convolutional neural network (CNN) was trained on OCT B-scan images annotated by a senior ground truth expert retina specialist to segment the posterior eye compartments. Independent benchmark data sets (30 SDOCT and 30 SSOCT) were manually segmented by three classes of graders with varying levels of ophthalmic proficiencies. Nine graders contributed to benchmark an additional 60 images in three consecutive runs. Inter-human and intra-human class agreement was measured and compared to the CNN results. RESULTS: The CNN training data consisted of a total of 6210 manually segmented images derived from 2070 B-scans (1046 SDOCT and 1024 SSOCT; 630 C-Scans). The CNN segmentation revealed a high agreement with all grader groups. For all compartments and groups, the mean Intersection over Union (IOU) score of CNN compartmentalization versus group graders' compartmentalization was higher than the mean score for intra-grader group comparison. CONCLUSION: The proposed deep learning segmentation algorithm (CNN) for automated eye compartment segmentation in OCT B-scans (SDOCT and SSOCT) is on par with manual segmentations by human graders.

Maternal social stress modulates the development of prepulse inhibition of startle in infants.

BACKGROUND: Stress during rearing has negative effects on the maturation of information processing in rodent offspring, but similar evidence in humans is absent. Prepulse inhibition (PPI) of startle is a measure reflecting the integrity of information processing. PPI does not depend on active cooperation, making it a suitable measure for studying newborns and infants. This study investigated whether postnatal development of infant PPI is influenced by self-reported stress in the mother. METHODS: 49 healthy term-born infants were studied twice, four days after birth and again at four months. PPI was assessed by presentation of acoustic startle stimuli (95dB) either alone or preceded (SOA 120ms) by a prepulse (75dB). Mother's social stress levels were assessed with the modified Trier Inventory for the Assessment of Chronic Stress (TICS). Cortisol saliva samples were collected from mothers and their children. RESULTS: ANOVA revealed a different development of PPI in infants whose mothers reported enhanced stress levels due to social isolation and reduced social recognition. Cortisol levels were related to mothers' self-report stress, but not to PPI development in infants. CONCLUSIONS: Maternal stress experience has an impact on the maturation of human infants' information processing in the first four months after birth.

Interactive multiscale tensor reconstruction for multiresolution volume visualization.

Large scale and structurally complex volume datasets from high-resolution 3D imaging devices or computational simulations pose a number of technical challenges for interactive visual analysis. In this paper, we present the first integration of a multiscale volume representation based on tensor approximation within a GPU-accelerated out-of-core multiresolution rendering framework. Specific contributions include (a) a hierarchical brick-tensor decomposition approach for pre-processing large volume data, (b) a GPU accelerated tensor reconstruction implementation exploiting CUDA capabilities, and (c) an effective tensor-specific quantization strategy for reducing data transfer bandwidth and out-of-core memory footprint. Our multiscale representation allows for the extraction, analysis and display of structural features at variable spatial scales, while adaptive level-of-detail rendering methods make it possible to interactively explore large datasets within a constrained memory footprint. The quality and performance of our prototype system is evaluated on large structurally complex datasets, including gigabyte-sized micro-tomographic volumes.

Harris lines revisited: prevalence, comorbidities, and possible etiologies.

OBJECTIVES: The occurrence of transverse radiopaque lines in long bones-Harris lines (HLs)-is correlated with episodes of temporary arrest of longitudinal growth and has been used as an indicator of health and nutritional status of modern and historical populations. However, the interpretation of HLs as a stress indicator remains debatable. The aim of this article is to evaluate the perspectives and the limitations of HLs analyses and to examine their reliability as a stress indicator. METHODS: The study was conducted on 241 tibiae from a medieval Swiss skeletal material and was carried out using a standardized, semiautomated HL detection and analysis tool developed by the authors. We compared four different age-at-formation estimation methods and analyzed the correlation of HL occurrence to life expectancy, mean-age-at-death, stature, tibia length, and metabolic disorders as expressed by linear enamel hypoplasia and hypothyroidism. RESULTS: The evaluation of the age-at-formation estimation methods showed statistical significant differences. Therefore, a mathematical framework for the conversion between the methods has been developed. Remodeling had eliminated about half of the HLs formed during adolescence, and a further half of the remaining ones during early adulthood, whereas no association between the aforementioned conditions and HL prevalence could be determined. The peaks of high HL frequency among various populations were found to parallel normal growth spurts and growth hormone secretion. CONCLUSIONS: We suggest a reconsideration of HLs as more of a result of normal growth and growth spurts, rather than a pure outcome of nutritional or pathologic stress.

Differential effect of ill-being and chronic stress on cradling behavior of first and multi-time parents.

A preference for cradling infants on the left side has been demonstrated in women, as has a relation of reduced left-cradling and stress/negative affect. This relation has not yet been investigated in male participants. Due to less left-cradling in non-fathers compared to fathers it was suggested that fatherhood might have an influence on cradling behavior. The present study investigated the cradling preference of first- and multi-time parents before and after birth, and its relation to ill-being and stress. Results revealed that cradling behavior of first-time fathers was not different before and after the birth of the infant. Thus, fatherhood does not seem to have an acute influence on cradling behavior. Furthermore, cradling behavior of first- and multi-time parents was differentially influenced by ill-being and stress. These results present new information about the course of cradling preference from pregnancy to postpartum and indicate that the relation of cradling and ill-being/stress is more complex for parents than for non-parents.

Pre- and perinatal predictors of startle eye blink reaction and prepulse inhibition in healthy neonates.

The present study examined the startle eye blink reflex and prepulse inhibition (PPI) in 65 healthy term-born neonates. Although the startle eye blink is already present at birth, some relevant neuronal structures are not fully mature. We therefore investigated the relationship between prenatal maturation and perinatal stress experience on startle eye blink and PPI. Eye blinks were evoked by unilaterally presented acoustic broadband white noise (50 ms, 95 dB, prepulse 75 dB). Startle response magnitude and percent PPI were calculated for ipsilateral and contralateral side of stimulation. Neonates exhibited stronger startle responses ipsilaterally than contralaterally, and a significant PPI. Neonates with more prenatal growth and less perinatal stress had greater startle magnitudes. Neonates with more stress had more PPI contralaterally. Results suggest that startle eye blinks may be useful as indicators of prenatal maturation and perinatal stress.

Left side cradling of an appetitive doll is associated with higher heart rate variability and attenuated startle in nulliparous females.

Cradling represents a unique type of mother-infant interaction. A bias towards left side cradling of infants and baby-like dolls has been demonstrated in human females, irrespective of handedness. One explanation for this behavioural bias involves right hemispheric specialisation of decoding visual, acoustic, and tactile emotional signals of left perceptual field origin. This implies that emotional signals from the child could have a greater impact on the caregiver's affective state when originating in the left than right perceptual fields. This may represent a key reinforcing mechanism responsible for left side cradling, but this has never been tested. In the present study, sixty-two never-pregnant female volunteers held an appetitive baby-like doll on the left or the right arm while reflexive startle eye blinks to binaural acoustic noise probes, as well as heart rate variability (HRV), were assessed. During left side cradling startle eye blink magnitude was attenuated, and low frequency HRV was decreased while high-frequency HRV was significantly increased. Attenuation of startle occurs in positive affective contexts, and high-frequency HRV is a reliable marker of vagal activity known to increase in appetitive, non-stressful contexts. Thus, our results suggest that appetitive infant signals have more positive effects on affective processes of the female caregiver when presented in her left perceptual fields.

Cradling side preference is associated with lateralized processing of baby facial expressions in females.

Women's cradling side preference has been related to contralateral hemispheric specialization of processing emotional signals; but not of processing baby's facial expression. Therefore, 46 nulliparous female volunteers were characterized as left or non-left holders (HG) during a doll holding task. During a signal detection task they were then asked to detect the emotional baby faces in a series of baby portraits with neutral and emotional facial expressions, presented either to the left or the right visual field (VFP). ANOVA revealed a significant HG x VFP interaction on response bias data (p < .05). Response bias was lowest when emotional baby faces were presented in the visual field of cradling side preference, suggesting that women's cradling side preference may have evolved to save cognitive resources during monitoring emotional baby face signals.

Functional expression of connexin30 and connexin31 in the polarized human airway epithelium.

Gap junctions are documented in the human airway epithelium but the functional expression and molecular identity of their protein constituents (connexins, Cx) in the polarized epithelium is not known. To address this question, we documented the expression of a family of epithelial Cx (Cx26, Cx30, Cx30.3, Cx31, Cx31.1, Cx32, Cx37, Cx40, and Cx43) in primary human airway epithelial cells (AEC) grown on porous supports. Under submerged conditions, AEC formed a monolayer of airway cells whereas the air-liquid interface induced within 30-60 days AEC differentiation into a polarized epithelium for up to 6-9 months. Maturation of AEC was associated with the down-regulation of Cx26 and Cx43. The well-differentiated airway epithelium exhibited gap junctional communication between ciliated and between ciliated and basal cells. Interestingly, Cx30 was mostly present between ciliated cells whereas Cx31 was found between basal cells. These results are supportive of the establishment of signal-selective gap junctions with maturation of AEC, likely contributing to support airway epithelium function. These results lay the ground for studying the role of Cx-mediated cell-cell communication during repair following AEC injury and exploring Cx-targeted interventions to modulate the healing process.

Cold pressor stress reduces left cradling preference in nulliparous human females.

The left cradling preference refers to the finding that women hold their infants more frequently on the left side of their own bodies. Several observational studies showed reduced left cradling during stressful circumstances, such as mother-infant separation, or domestic violence. However, until now no experimental study was conducted to investigate the immediate impact of stress on cradling behaviour. Half of the 64 female subjects participating were randomly assigned to a stressful bilateral cold pressor test. The remaining subjects performed a non-stressful control procedure. Before and after this intervention, cradling behaviour was assessed using a baby-like doll. Subjects showed a left cradling preference prior to the intervention. The cold pressor test increased blood pressure and heart rate significantly. A repeated ANOVA revealed an interaction of intervention (cold pressor vs. control) X assessment period (pre- vs. post-intervention), indicating that cold pressor stress reduces left cradling behaviour in female volunteers. Our data indicate that stress influences cradling preference. This may be of relevance for caregiver-infant interactions.

Gap junctional communication does not contribute to the interaction between neutrophils and airway epithelial cells.

Cystic fibrosis (CF) is characterized by intense neutrophil migration into the airways. Increasing evidence indicates that interaction between neutrophils and airway epithelial cells contributes to the modulation of the inflammatory response. Blood neutrophils were reported to express connexins and form gap junctions with endothelial cells, thereby establishing gap junctional communication. We tested whether altered communication between human neutrophils and airway epithelial cells may contribute to the exaggerated inflammatory response observed in CF patients. Microinjections did not reveal dye coupling between activated blood neutrophils. By contrast, diffusion of calcein between neutrophils and airway epithelial cells of CF or non-CF origin was observed in transmigration and adhesion assays. This diffusion was prevented with probenicid, an inhibitor of ATP-dependent organic anion pumps, but not with gap junction blockers. Finally, RT-PCR failed to detect mRNAs for six connexins in blood neutrophils. These results suggest that gap junctional communication does not contribute to neutrophil-airway epithelial cell interaction.

Long-term cultures of polarized airway epithelial cells from patients with cystic fibrosis.

The poor ability of respiratory epithelial cells to proliferate and differentiate in vitro into a pseudostratified mucociliated epithelium limits the general use of primary airway epithelial cell (AEC) cultures generated from patients with rare diseases, such as cystic fibrosis (CF). Here, we describe a procedure to amplify AEC isolated from nasal polyps and generate long-term cultures of the respiratory epithelium. AEC were seeded onto microporous permeable supports that carried on their undersurface a preformed feeder layer of primary human airway fibroblasts. The use of fibroblast feeder layers strongly stimulated the proliferation of epithelial cells, allowing the expansion of the cell pool with successive passages. AEC at increasing passage were seeded onto supports undercoated with airway fibroblasts and exposed to air. Either freshly isolated or amplified AEC could differentiate into a pseudostratified mucociliated epithelium for at least 10 mo. Thus, CF epithelia cultures showed elevated Na+ transport, drastic hyperabsorption of surface liquid, and absence of cAMP-induced Cl- secretion as compared with non-CF cultures. They were also characterized by thick apical secretion that hampered the movement of cell surface debris by cilia. However, CF respiratory epithelia did not show increased production of mucins or IL-8. The method described here is now routinely used in our laboratory to establish long-term cultures of well differentiated respiratory epithelia from human airway biopsies.

[Physical exercise and bone development in chronically ill children]. / Exercice physique et développement osseux de l'enfant malade chronique.

Children with chronic diseases are at increased risk of sub-optimal bone mineral acquisition and osteoporosis, especially those who have a growth and pubertal delay, reduced physical activity, inadequate nutrition, malabsorption or take medications which may influence bone development. Weight-bearing physical activity has a beneficial effect on bone development of healthy children but little is known in children with chronic diseases. Preliminary results of our cross-sectional study in children with juvenile idiopathic arthritis (JIA) suggest that hip bone mineral density is positively related with physical fitness and muscle strength and is reduced at the more affected side. We have initiated two randomized controlled trials to determine the effects of a moderate impact exercise training program on bone mineral density of children with JIA and type 1 diabetes mellitus.

Src signaling links mediators of inflammation to Cx43 gap junction channels in primary and transformed CFTR-expressing airway cells.

Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) is associated with recurrent pulmonary infections and inflammation. We previously reported that tumor necrosis factor (TNF)-alpha decreases gap junction connectivity in cell lines derived from the airway epithelium of non-cystic fibrosis (non-CF) subjects, a mechanism that was defective in cells derived from CF patients, and identified the tyrosine kinase c-Src as a possible bridge between TNF-alpha and Cx43. To examine whether this modulation also takes place in primary epithelial cells, the functional expression of Cx43 was studied in non-CF and CF airway cells, obtained from surgical polypectomies and turbinectomies, which were grown either on culture dishes or permeable filters. Expression of Cx43 was detected by immunofluorescence on cells grown under both culture conditions. Non-CF and CF airway cells also showed intercellular diffusion of Lucifer Yellow. Dye coupling was rapidly abolished in non-CF cells in the presence of TNF-alpha, lipopolysaccharide and lysophosphatidic acid, and could be prevented by tyrphostin47, an inhibitor of Src tyrosine kinases. This down-regulation, however, was not detected in CF airway cells. These data indicate that CFTR dysfunction is associated with altered Src signaling, resulting in the persistence of gap junction connectivity in primary and transformed CF airway cells.

Severe acute pancreatitis and reduced acinar cell apoptosis in the exocrine pancreas of mice deficient for the Cx32 gene.

BACKGROUND & AIMS: The early events leading to acinar cell injury during acute pancreatitis are poorly characterized. Signaling through gap junction channels contributes to the homeostasis of the exocrine pancreas by coordinating acinar cell activity within an acinus. To explore the role of gap junctional communication in acinar cell response to injury, we analyzed the course of acute pancreatitis induced by injection of cerulein in mice deficient for Cx32, the major gap junction protein expressed in the exocrine pancreas. METHODS: The severity of pancreatitis was evidenced by measuring serum amylase activity, pancreatic edema, acinar cell necrosis, pancreatic tumor necrosis factor alpha concentration, and myeloperoxidase activity. Acinar cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL), caspase-3 activity, and Bax/Bcl-2 expression. Expression and function of connexin were evaluated by immunofluorescence and dye coupling. RESULTS: Cx32-deficient mice exhibited a deleterious course of acute pancreatitis with increased necrosis, edema, and inflammation of the exocrine pancreas. In addition, the exocrine pancreas of Cx32-deficient mice showed a decreased number of TUNEL-positive acinar cells and decreased caspase-3 activity but no change in Bax or Bcl-2 pancreatic expression. Interestingly, chemicals known to induce apoptosis in vivo had no effect on Cx32-deficient pancreatic acinar cells. CONCLUSIONS: Deficiency of a pancreatic connexin converts a mild reversible form of acute pancreatitis into a severe disease and decreases the sensitivity of acinar cells to apoptotic stimuli. The results show that acinar cell-to-cell communication plays a key role in the modulation of severity of acute pancreatitis.

Defective activation of c-Src in cystic fibrosis airway epithelial cells results in loss of tumor necrosis factor-alpha-induced gap junction regulation.

Tumor necrosis factor-alpha (TNF-alpha) signaling is central to the transmission of the innate immune response and subsequent activation of the adaptive immune system. The functioning of both systems is required for optimal clearance of pathogens from the airways. In cystic fibrosis (CF), dysfunction of the CF transmembrane conductance regulator (CFTR) is associated with recurrent pulmonary infections despite an intense inflammatory and immune response. We reported recently that TNF-alpha decreased gap junction connectivity in non-CF airway cells, a mechanism that was absent in CF cells expressing the DeltaPhe-508 mutant of CFTR. We have now identified the tyrosine kinase c-Src as a possible pathway between the mediators of inflammation and the gap junction protein connexin43 (Cx43). Indeed, TNF-alpha increased the proportion of activated c-Src in non-CF airway cells. Moreover, pharmacological antagonists and expression in non-CF cells of a dominant negative construct of c-Src prevented Cx43 channel closure by TNF-alpha. Finally, gap junction channel closure was prevented by expression of a Cx43 mutant lacking tyrosine phosphorylation sites for c-Src. Additional experiments showed that activation of c-Src was defective in CF airway cells but rescued in CFTR-corrected CF cells. These data suggest that CFTR dysfunction is associated with altered TNF-alpha signaling, resulting in the persistence of gap junction connectivity in CF airway cells. We propose that altered regulation of c-Src may contribute to the dysregulated inflammatory response that is characteristic of the CF phenotype.

Characterization of a novel chemotactic factor for neutrophils in the bronchial secretions of patients with cystic fibrosis.

Chronic airway inflammation is a hallmark of cystic fibrosis (CF). Biological products with chemotactic activity are essential for neutrophil recruitment to sites of inflammation. The presence of a factor with chemotactic activity higher than that of interleukin (IL)-8 in the bronchial secretions of patients with CF has recently been reported. This article reports that the chemotactic activity of this factor remained unaffected by a variety of physical treatments and could be distinguished from those of IL-8, formylmethionylleucylphenylalanine, leukotreine B4, and platelet-activating factor. The factor induced chemotaxis and chemokinesis locomotion of neutrophils, and its chemotactic activity was sensitive to pertussis toxin and thapsigargin. Semipurified preparation of the chemotactic factor increased transiently intracellular Ca(2+) concentration but failed to stimulate the release of neutrophil primary granules and the production of superoxide, suggesting that the semipurified chemotactic factor is a Ca(2+)-dependent chemoattractant of neutrophils, acting via pertussin toxin-sensitive G protein-coupled surface receptors, that directs neutrophil movement toward the airway epithelium.