Use of capnography for prediction of obstruction severity in non-intubated COPD and asthma patients.

BACKGROUND: Capnography waveform contains essential information regarding physiological characteristics of the airway and thus indicative of the level of airway obstruction. Our aim was to develop a capnography-based, point-of-care tool that can estimate the level of obstruction in patients with asthma and COPD. METHODS: Two prospective observational studies conducted between September 2016 and May 2018 at Rabin Medical Center, Israel, included healthy, asthma and COPD patient groups. Each patient underwent spirometry test and continuous capnography, as part of, either methacholine challenge test for asthma diagnosis or bronchodilator reversibility test for asthma and COPD routine evaluation. Continuous capnography signal, divided into single breaths waveforms, were analyzed to identify waveform features, to create a predictive model for FEV1 using an artificial neural network. The gold standard for comparison was FEV1 measured with spirometry. MEASUREMENTS AND MAIN RESULTS: Overall 160 patients analyzed. Model prediction included 32/88 waveform features and three demographic features (age, gender and height). The model showed excellent correlation with FEV1 (R = 0.84), R2 achieved was 0.7 with mean square error of 0.13. CONCLUSION: In this study we have developed a model to evaluate FEV1 in asthma and COPD patients. Using this model, as a point-of-care tool, we can evaluate the airway obstruction level without reliance on patient cooperation. Moreover, continuous FEV1 monitoring can identify disease fluctuations, response to treatment and guide therapy. TRIAL REGISTRATION: clinical trials.gov, NCT02805114. Registered 17 June 2016, https://clinicaltrials.gov/ct2/show/NCT02805114.

Impact of Continuous Capnography in Ventilated Neonates: A Randomized, Multicenter Study.

OBJECTIVE: To compare the time spent within a predefined safe range of CO2 (30-60 mmHg) during conventional ventilation between infants who were monitored with distal end-tidal CO2 (dETCO2, or capnography) and those who were not. STUDY DESIGN: For this randomized, controlled multicenter study, ventilated infants with a double-lumen endotracheal tube were randomized to 1 of 2 groups: the open (monitored) group, in which data from the capnograph were recorded, displayed to the medical team, and used for patient care, and the masked group, in which data from the capnograph were recorded. However, the measurements were masked and not available for patient care. dETCO2 was compared with PaCO2 measurements recorded for patient care. RESULTS: Fifty-five infants (25 open, 30 masked) participated in the study (median gestational age, 28.6 weeks; range, 23.5-39.0 weeks). The 2 groups were comparable. dETCO2 was in good correlation (r = 0.73; P < .001) and adequate agreement (mean ± SD of the difference, 3.0 ± 8.5 mmHg) with PaCO2. Compared with infants in the masked group, those in the monitored group had significantly (P = .03) less time with an unsafe dETCO2 level (high: 3.8% vs 8.8% or low: 3.8% vs 8.9%). The prevalence of intraventricular hemorrhage or periventricular leukomalacia rate was lower in the monitored group (P = .02) and was significantly (P < .05) associated with the independent factors dETCO2 monitoring and gestational age. CONCLUSION: Continuous dETCO2 monitoring improved control of CO2 levels within a safe range during conventional ventilation in a neonatal intensive care unit. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01572272.

Precise temporal modulation in the response of the SOS DNA repair network in individual bacteria.

The SOS genetic network is responsible for the repair/bypass of DNA damage in bacterial cells. While the initial stages of the response have been well characterized, less is known about the dynamics of the response after induction and its shutoff. To address this, we followed the response of the SOS network in living individual Escherichia coli cells. The promoter activity (PA) of SOS genes was monitored using fluorescent protein-promoter fusions, with high temporal resolution, after ultraviolet irradiation activation. We find a temporal pattern of discrete activity peaks masked in studies of cell populations. The number of peaks increases, while their amplitude reaches saturation, as the damage level is increased. Peak timing is highly precise from cell to cell and is independent of the stage in the cell cycle at the time of damage. Evidence is presented for the involvement of the umuDC operon in maintaining the pattern of PA and its temporal precision, providing further evidence for the role UmuD cleavage plays in effecting a timed pause during the SOS response, as previously proposed. The modulations in PA we observe share many features in common with the oscillatory behavior recently observed in a mammalian DNA damage response. Our results, which reveal a hitherto unknown modulation of the SOS response, underscore the importance of carrying out dynamic measurements at the level of individual living cells in order to unravel how a natural genetic network operates at the systems level.

Auditory temporal processing, reading, and phonological awareness among aging adults.

Auditory temporal processing (ATP) has been related in the literature to both speech perception as well as reading and phonological awareness. In aging adults, it is known to be related to difficulties in speech perception. In the present study, we aimed to test whether an age-related deficit in ATP would also be accompanied by poor reading and phonological awareness. Thirty-eight aging adults were compared to 55 readers with dyslexia and 42 young normal readers on temporal order judgment (TOJ), speech perception, reading, and phonological awareness tests. Aging adults had longer TOJ thresholds than young normal readers, but shorter than readers with dyslexia; however, they had lower speech perception accuracy than both groups. Phonological awareness of the aging adults was better than readers with dyslexia, but poorer than young normal readers, although their reading accuracy was similar to that of the young controls. This is the first report on poor phonological awareness among aging adults. Suprisingly, it was not accompanied by difficulties in reading ability, and might instead be related to aging adults' difficulties in speech perception. This newly discovered relationship between ATP and phonological awareness among aging adults appears to extend the existing understanding of this relationship, and suggests it should be explored in other groups with ATP deficits.

Optimal gene partition into operons correlates with gene functional order.

Gene arrangement into operons varies between bacterial species. Genes in a given system can be on one operon in some organisms and on several operons in other organisms. Existing theories explain why genes that work together should be on the same operon, since this allows for advantageous lateral gene transfer and accurate stoichiometry. But what causes the frequent separation into multiple operons of co-regulated genes that act together in a pathway? Here we suggest that separation is due to benefits made possible by differential regulation of each operon. We present a simple mathematical model for the optimal distribution of genes into operons based on a balance of the cost of operons and the benefit of regulation that provides 'just-when-needed' temporal order. The analysis predicts that genes are arranged such that genes on the same operon do not skip functional steps in the pathway. This prediction is supported by genomic data from 137 bacterial genomes. Our work suggests that gene arrangement is not only the result of random historical drift, genome re-arrangement and gene transfer, but has elements that are solutions of an evolutionary optimization problem. Thus gene functional order may be inferred by analyzing the operon structure across different genomes.

Diagnostic accuracy of capnography during high-frequency ventilation in neonatal intensive care units.

BACKGROUND AND OBJECTIVE: High-frequency ventilation (HFV) is a powerful tool for CO2 elimination, and thus requires careful monitoring of CO2 . Our aim was to assess the diagnostic accuracy (correlation, agreement, and trending) of continuous distal capnography (dCap) with PaCO2 in infants ventilated with HFV. DESIGN: This was a prospective, observational, multicenter study. dCap was compared with simultaneous PaCO2 ("gold standard") drawn from indwelling arterial line for patient care in term and preterm infants ventilated with HFV. dCap was obtained via the side-port of a double-lumen endotracheal-tube by a Microstream capnograph with specially designed software for HFV. RESULTS: Twenty-four infants participated in the study (median [range] gestational age [GA]: 26.8 [23.6-38.6] weeks). Analysis included 332 measurements. dCap was in correlation (r = 0.70, P < 0.001) but with less than adequate agreement (mean difference ± SD of the differences: -11.7 ± 10.3 mmHg) with PaCO2 . Comparable findings were found in the subgroup of infants <1,000 g (n = 240 measurements). Correlations were maintained in severe lung disease. Changes in dCap and in PaCO2 for consecutive measurements within each patient were correlated (r = 0.63, P < 0.001). Area under the receiver operating curves (ROC) for dCap to detect high (>60 mmHg) or low (<30 mmHg) PaCO2 was 0.83 (CI: 0.76-0.90) and 0.88 (CI: 0.79-0.97), respectively; P < 0.001. CONCLUSIONS: Our prospective study suggests that continuous dCap in infants ventilated with HFV may be helpful for trends and alarm for unsafe levels of PaCO2 . dCap is only a complimentary tool and cannot replace PaCO2 sampling because the agreement between these measurements was less than adequate.

Continuous integrated distal capnography in infants ventilated with high frequency ventilation.

OBJECTIVE: To assess within a feasibility study the correlation, agreement, and trending of continuous integrated distal capnography (dCap) with PaCO(2) in infants on HFV. STUDY DESIGN: Sixteen premature infants [median (range) gestational age: 26.5 (24.7-34.7) weeks], ventilated with HFV (mean ± SD airway pressure: 8.1 ± 2.1 cmH(2) O, FiO(2) : 0.39 ± 0.21) for RDS, intubated with a double-lumen endotracheal-tube and whose data were recorded on a bedside computer participated in the study. Side-stream dCap was measured via the extra-port of a double-lumen endotracheal-tube by a Microstream capnograph, with a specially designed software for HFV and compared with simultaneous PaCO(2) . Integrated time-window analysis of the data was performed retrospectively on data collected prospectively. RESULTS: Analysis included 195 measurements. The correlation of dCap with PaCO(2) (r = 0.68, P < 0.0001) and the agreement (bias ± precision: -2.0 ± 10.7 mmHg) were adequate. Area under the ROC curves for dCap to detect high (>60 mmHg) or low (<35 mmHg) PaCO(2) was 0.79 (CI: 0.70-0.89) and 0.87 (CI: 0.73-1.00), respectively; P < 0.0001. Changes in dCap and in PaCO(2) for consecutive measurements within each patient were adequately correlated (r = 0.65, P < 0.0001). CONCLUSIONS: Continuous integrated dCap is feasible in premature infants ventilated with HFV and can be helpful for trends and alarm for unsafe levels of PaCO(2) .

Transcriptional response of steady-state yeast cultures to transient perturbations in carbon source.

To understand the dynamics of transcriptional response to changing environments, well defined, easily controlled, and short-term perturbation experiments were undertaken. We subjected steady-state cultures of Saccharomyces cerevisiae in chemostats growing on limiting galactose to two different size pulses of glucose, well known to be a preferred carbon source. Although these pulses were not large enough to change growth rates or cell size, approximately 25% of the genes changed their expression at least 2-fold. Using DNA microarrays to estimate mRNA abundance, we found a number of distinguishable patterns of transcriptional response among the many genes whose expression changed. Many of these genes were already known to be regulated by particular transcription factors; we estimated five potentially relevant transcription factor activities from the observed changes in gene expression (i.e., Mig1p, Gal4p, Cat8p, Rgt1p, Adr1p, and Rcs1p). With these estimates, for two regulatory circuits involving interaction among multiple regulators we could generate dynamical models that quantitatively account for the observed transcriptional responses to the transient perturbations.

Exploring methods of visualizing laboratorial data in electronic medical record systems.

Physicians in their daily practice are exposed to vast amount of laboratorial data in electronic medical record (EMR) systems, that should be taken into account in the clinical decision making process. The aim of this study is to explore the impact of different methods of visualizing laboratorial data on physicians' ability to perform common tasks related to processing laboratorial data. For this end, we developed an innovative computerized system based on a set of methods that we used.

A conserved role for a GATA transcription factor in regulating epithelial innate immune responses.

Innate immunity is an ancient and conserved defense mechanism. Although host responses toward various pathogens have been delineated, how these responses are orchestrated in a whole animal is less understood. Through an unbiased genome-wide study performed in Caenorhabditis elegans, we identified a conserved function for endodermal GATA transcription factors in regulating local epithelial innate immune responses. Gene expression and functional RNAi-based analyses identified the tissue-specific GATA transcription factor ELT-2 as a major regulator of an early intestinal protective response to infection with the human bacterial pathogen Pseudomonas aeruginosa. In the adult worm, ELT-2 is required specifically for infection responses and survival on pathogen but makes no significant contribution to gene expression associated with intestinal maintenance or to resistance to cadmium, heat, and oxidative stress. We further demonstrate that this function is conserved, because the human endodermal transcription factor GATA6 has a protective function in lung epithelial cells exposed to P. aeruginosa. These findings expand the repertoire of innate immunity mechanisms and illuminate a yet-unknown function of endodermal GATA proteins.

A comprehensive library of fluorescent transcriptional reporters for Escherichia coli.

E. coli is widely used for systems biology research; there exists a need, however, for tools that can be used to accurately and comprehensively measure expression dynamics in individual living cells. To address this we present a library of transcriptional fusions of gfp to each of about 2,000 different promoters in E. coli K12, covering the great majority of the promoters in the organism. Each promoter fusion is expressed from a low-copy plasmid. We demonstrate that this library can be used to obtain highly accurate dynamic measurements of promoter activity on a genomic scale, in a glucose-lactose diauxic shift experiment. The library allowed detection of about 80 previously uncharacterized transcription units in E. coli, including putative internal promoters within previously known operons, such as the lac operon. This library can serve as a tool for accurate, high-resolution analysis of transcription networks in living E. coli cells.

Assigning numbers to the arrows: parameterizing a gene regulation network by using accurate expression kinetics.

A basic challenge in systems biology is to understand the dynamical behavior of gene regulation networks. Current approaches aim at determining the network structure based on genomic-scale data. However, the network connectivity alone is not sufficient to define its dynamics; one needs to also specify the kinetic parameters for the regulation reactions. Here, we ask whether effective kinetic parameters can be assigned to a transcriptional network based on expression data. We present a combined experimental and theoretical approach based on accurate high temporal-resolution measurement of promoter activities from living cells by using green fluorescent protein (GFP) reporter plasmids. We present algorithms that use these data to assign effective kinetic parameters within a mathematical model of the network. To demonstrate this, we employ a well defined network, the SOS DNA repair system of Escherichia coli. We find a strikingly detailed temporal program of expression that correlates with the functional role of the SOS genes and is driven by a hierarchy of effective kinetic parameter strengths for the various promoters. The calculated parameters can be used to determine the kinetics of all SOS genes given the expression profile of just one representative, allowing a significant reduction in complexity. The concentration profile of the master SOS transcriptional repressor can be calculated, demonstrating that relative protein levels may be determined from purely transcriptional data. This finding opens the possibility of assigning kinetic parameters to transcriptional networks on a genomic scale.