A Humanized Monoclonal Antibody Potentiates Killing by Antibiotics of Diverse Biofilm-Forming Respiratory Tract Pathogens

New strategies to treat diseases wherein biofilms contribute significantly to pathogenesis are needed as biofilm-resident bacteria are highly recalcitrant to antibiotics due to physical biofilm architecture and a canonically quiescent metabolism, among many additional attributes. We, and others, have shown that when biofilms are dispersed or disrupted, bacteria released from biofilm residence are in a distinct physiologic state that, in part, renders these bacteria highly sensitive to killing by specific antibiotics. We sought to demonstrate the breadth of ability of a recently humanized monoclonal antibody against an essential biofilm structural element (DNABII protein) to disrupt biofilms formed by respiratory tract pathogens and potentiate antibiotic-mediated killing of bacteria released from biofilm residence. Biofilms formed by six respiratory tract pathogens were significantly disrupted by the humanized monoclonal antibody in a dose- and time-dependent manner, as corroborated by CLSM imaging. Bacteria newly released from the biofilms of 3 of 6 species were significantly more sensitive than their planktonic counterparts to killing by 2 of 3 antibiotics currently used clinically and were now also equally as sensitive to killing by the 3 rd antibiotic. The remaining 3 pathogens were significantly more susceptible to killing by all 3 antibiotics. A humanized monoclonal antibody directed against protective epitopes of a DNABII protein effectively released six diverse respiratory tract pathogens from biofilm residence in a phenotypic state that was now as, or significantly more, sensitive to killing by three antibiotics currently indicated for use clinically. These data support this targeted, combinatorial, species-agnostic therapy to mitigate chronic bacterial diseases.

Performance of an automated ultrasound device in identifying and tracing the heart in porcine cardiac arrest

Background While intra-arrest echocardiography can be used to guide and monitor chest compression quality, it is not currently feasible on the scene of out-of-hospital cardiac arrests. Rapid and automated sonographic localization of the heart may provide first-responders guidance to an optimal area of compression without requiring them to interpret ultrasound images. In this proof-of-concept porcine study, we sought to describe the performance of an automated ultrasound device in correctly identifying and tracing the borders of the heart in three distinct states: pre-arrest, arrest, and late arrest. Methods An automated ultrasound device (bladder scanner) was placed on the chests of 7 swine, along the left sternal border (4th–8th intercostal spaces). Scanner-generated images were recorded for each space during pre-arrest, arrest, and finally late arrest. 828 images of the LV and LV outflow tract were randomized and 150 (50/state) selected for analysis. Scanner tracings of the heart were then digitally obscured to facilitate tracing by expert reviewers who were blinded to the physiologic state. Reviewer tracings were compared to bladder scanner tracings; with concordance between these images determined via Sørensen–Dice index (SDI). Results When compared to human reviewers, the bladder scanner was able to identify and trace the borders during cardiac arrest. The bladder scanner performed best at the time of arrest (SDI 0.900 ± 0.059). As resuscitation efforts continued and time from initial arrest increased, the scanner’s performance decreased dramatically (SDI 0.597 ± 0.241 in late arrest). Conclusion An automated ultrasound device (bladder scanner) reliably traced porcine hearts during cardiac arrest. It is possible a device could be developed to indicate where compressions should be performed without requiring the operator to interpret ultrasound images. Further investigation into rapid, automated, sonographic localization of the heart to identify the area of compression in out-of-hospital cardiac arrest is warranted.

Potential Psychological and Biological Mechanisms Underlying the Effectiveness of Neonatal Music Therapy during Kangaroo Mother Care for Preterm Infants and Their Parents

Neonatal music therapy (MT) has become more accessible worldwide. Previous research suggests multiple benefits of MT for preterm infants and their caregivers; however, far too little attention has been paid to understanding the mechanisms of change in previous Neonatal Intensive Care Unit (NICU)-MT research so far. This perspective article describes potential mechanisms of MT interventions exposed during kangaroo mother care on the preterm infant’s response (behavioral and physiological outcomes) and the mother-infant relationship. The paper focuses on the hypothalamic–pituitary–adrenal axis’ role in stabilization of behavioral state, the autonomic nervous system’s role in stabilization of physiologic state, as well as co-regulation as a potential mechanism for the developing of the parent-infant relationship. Mechanisms play a pivotal role in understanding variables related to the therapy course and well as in generating new knowledge regarding treatment susceptibility and optimizing resources. Understanding of the mechanisms of how interventions may lead to specific outcomes plays an important role in addressing the issue of improvement of currently available approaches of MT used in the NICU.

Deep Learning Prediction of Biomarkers from Echocardiogram Videos

Laboratory blood testing is routinely used to assay biomarkers to provide information on physiologic state beyond what clinicians can evaluate from interpreting medical imaging. We hypothesized that deep learning interpretation of echocardiogram videos can provide additional value in understanding disease states and can predict common biomarkers results. Using 70,066 echocardiograms and associated biomarker results from 39,460 patients, we developed EchoNet-Labs, a video-based deep learning algorithm to predict anemia, elevated B-type natriuretic peptide (BNP), troponin I, and blood urea nitrogen (BUN), and abnormal levels in ten additional lab tests. On held-out test data across different healthcare systems, EchoNet-Labs achieved an area under the curve (AUC) of 0.80 in predicting anemia, 0.82 in predicting elevated BNP, 0.75 in predicting elevated troponin I, and 0.69 in predicting elevated BUN. We further demonstrate the utility of the model in predicting abnormalities in 10 additional lab tests. We investigate the features necessary for EchoNet-Labs to make successful predictions and identify potential prediction mechanisms for each biomarker using well-known and novel explainability techniques. These results show that deep learning applied to diagnostic imaging can provide additional clinical value and identify phenotypic information beyond current imaging interpretation methods.

Hemodynamic Effects of Cardiovascular Medications in a Normovolemic and Hemorrhaged Yorkshire-cross Swine Model

The Yorkshire-cross swine model is a valuable translational model commonly used to study cardiovascular physiologyand response to insult. Although the effects of vasoactive medications have been well described in healthy swine, the effects of these medications during hemorrhagic shock are less studied. In this study, we sought to expand the utility of the swine model by characterizing the hemodynamic changes that occurred after the administration of commonly available vasoactive medications during euvolemic and hypovolemic states. To this end, we anesthetized and established femoral arterial,central venous, and pulmonary arterial access in 15 juvenile Yorkshire-cross pigs. The pigs then received a series of rapidlymetabolized but highly vasoactive medications in a standard dosing sequence. After completion of this sequence, each pigunderwent a 30-mL/kg hemorrhage over 10 min, and the standard dosing sequence was repeated. We then used standard statisticaltechniques to compare the effects of these vasoactive medications on a variety of hemodynamic parameters betweenthe euvolemic and hemorrhagic states. All subjects completed the study protocol. The responses in the hemorrhagic state wereoften attenuated or even opposite of those in the euvolemic state. For example, phenylephrine decreased the mean arterialblood pressure during the euvolemic state but increased it in the hemorrhagic state. These results clarify previously poorlydefined responses to commonly used vasoactive agents during the hemorrhagic state in swine. Our findings also demonstratethe need to consider the complex and dynamic physiologic state of hemorrhage when anticipating the effects of vasoactivedrugs and planning study protocols.

Regulation of the one carbon folate cycle as a shared metabolic signature of longevity

The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in heath and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C. elegans and identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle were pervasively regulated in common. We observed similar changes in long lived mouse models of reduced insulin/IGF signaling. Genetic manipulation of pathway enzymes and supplementation with one carbon metabolites reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection.

Exaggerated Mini Puberty of Early Infancy in the Preterm Girls: A Case Report and Systematic Review

Background: Mini puberty is the important period of infancy life that has several impressions to sexual development in both sexes. In the infants born very premature and extremely low birth weight, mini puberty changes including clinical, hormonal and imaging data are severe and long lasting, especially in girls. It can be called “exaggerated mini puberty”.Methods: In this study, 6-month preterm infant with bronchopulmonary dysplasia presented with periodic vaginal bleeding, breast stage tanner 3 and pubic hairs. We followed up infant by clinical and para clinical evaluations during one year and compared this data with all of the similar articles were published.Results: During one year monitoring of the infancy puberty presentation, gradually returned to the pre pubertal state, without excessive hormonal treatment. Conclusions: Due to this systematic review, exaggerated mini puberty is the temporary physiologic state in very low birth weight preterm infants that should be prevents any extra hormonal and surgical intervention.

Dynamic network interactions among distinct brain rhythms as a hallmark of physiologic state and function

Brain rhythms are associated with a range of physiologic states, and thus, studies have traditionally focused on neuronal origin, temporal dynamics and fundamental role of individual brain rhythms, and more recently on specific pair-wise interactions. Here, we aim to understand integrated physiologic function as an emergent phenomenon of dynamic network interactions among brain rhythms. We hypothesize that brain rhythms continuously coordinate their activations to facilitate physiologic states and functions. We analyze healthy subjects during sleep, and we demonstrate the presence of stable interaction patterns among brain rhythms. Probing transient modulations in brain wave activation, we discover three classes of interaction patterns that form an ensemble representative for each sleep stage, indicating an association of each state with a specific network of brain-rhythm communications. The observations are universal across subjects and identify networks of brain-rhythm interactions as a hallmark of physiologic state and function, providing new insights on neurophysiological regulation with broad clinical implications.