Exploring pulmonary distribution of intratracheally instilled liquid foams in excised porcine lungs.

The applicability of inhalation therapy to some severe pulmonary conditions is often compromised by limited delivery rates (i.e. total dose) and low deposition efficiencies in the respiratory tract, most notably in the deep pulmonary acinar airways. To circumvent such limitations, alternative therapeutic techniques have relied for instance on intratracheal liquid instillations for the delivery of high-dose therapies. Yet, a longstanding mechanistic challenge with such latter methods lies in delivering solutions homogeneously across the whole lungs, despite an inherent tendency of non-uniform spreading driven mainly by gravitational effects. Here, we hypothesize that the pulmonary distribution of instilled liquid solutions can be meaningfully improved by foaming the solution prior to its instillation, owing to the increased volume and the reduced gravitational bias of foams. As a proof-of-concept, we show in excised adult porcine lungs that liquid foams can lead to significant improvement in homogenous pulmonary distributions compared with traditional liquid instillations. Our ex-vivo results suggest that liquid foams can potentially offer an attractive novel pulmonary delivery modality with applications for high-dose regimens of respiratory therapeutics.

Ventilation-induced epithelial injury drives biological onset of lung trauma in vitro and is mitigated with prophylactic anti-inflammatory therapeutics.

Mortality rates among patients suffering from acute respiratory failure remain perplexingly high despite the maintenance of blood oxygen homeostasis during ventilatory support. The biotrauma hypothesis advocates that mechanical forces from invasive ventilation trigger immunological mediators that spread systemically. Yet, how these forces elicit an immune response remains unclear. Here, a biomimetic in vitro three-dimensional (3D) upper airways model allows to recapitulate lung injury and immune responses induced during invasive mechanical ventilation in neonates. Under such ventilatory support, flow-induced stresses injure the bronchial epithelium of the intubated airways model and directly modulate epithelial cell inflammatory cytokine secretion associated with pulmonary injury. Fluorescence microscopy and biochemical analyses reveal site-specific susceptibility to epithelial erosion in airways from jet-flow impaction and are linked to increases in cell apoptosis and modulated secretions of cytokines IL-6, -8, and -10. In an effort to mitigate the onset of biotrauma, prophylactic pharmacological treatment with Montelukast, a leukotriene receptor antagonist, reduces apoptosis and pro-inflammatory signaling during invasive ventilation of the in vitro model. This 3D airway platform points to a previously overlooked origin of lung injury and showcases translational opportunities in preclinical pulmonary research toward protective therapies and improved protocols for patient care.

Group B Streptococcus real-time PCR may potentially reduce intrapartum maternal antibiotic treatment.

BACKGROUND: Protocols for preventing early-onset group B streptococcal (GBS) neonatal infection may result in unnecessary antibiotics administration. Real-time polymerase chain reaction (PCR) can provide a result within 30-60 min and has been found to be specific and sensitive for defining intrapartum GBS status. OBJECTIVE: To evaluate whether implementation of GBS fast real-time PCR to all women who require GBS prophylaxis may reduce the use of maternal prophylactic antibiotics. METHODS: This prospective cohort study included women admitted to a single delivery ward who required prophylactic antibiotics either due to a positive antepartum GBS culture screening performed at 35-37 weeks or due to an unknown GBS status with an intrapartum risk factor. All the women were tested by a double vaginal swab (real-time PCR and culture) as soon as it became apparent, they required antibiotic prophylaxis and prior to its administration. RESULTS: Between May 2019 and August 2020, 303 women met eligibility criteria and were enrolled, but four were excluded from the analysis due to failed culture or PCR tests. Of 299 women included in the study, 208 (69.5%) and 180 (60.2%) women, showed no evidence of GBS on intrapartum culture or PCR, respectively. Of 89 GBS antepartum carriers, 43 (48.3%) and 32 (35.9%) had negative intrapartum culture and PCR results, respectively. Of the 210 women with risk factors, 165 (78.5%) were culture negative and 148 (70.4%) had a negative PCR. Using intrapartum culture as the gold standard, intrapartum GBS real-time PCR was found to have a sensitivity of 97.8% (95% confidence interval [CI] 92.3, 99.7) and a specificity of 85.6% (95% CI 80.1, 90.1). CONCLUSIONS: Compared with antepartum universal culture screening or intrapartum risk-factor assessment, the need for maternal antibiotic treatment may be substantially reduced by implementation of intrapartum GBS real-time PCR, without compromising the sensitivity of GBS detection.

Expect the Unexpected-First Case of Congenital Rubella Syndrome in Israel in 20 Years: A Case Report.

Congenital rubella syndrome (CRS) is a devastating condition associated with significant morbidity. Due to universal vaccination programs, it is currently a rare condition, especially in developed countries. We report an infant born in Israel to a foreign worker from the Philippines who presented with a blueberry muffin rash immediately after birth. Initial workup revealed sonographic brain anomalies, abnormal hearing tests, and a patent ductus arteriosus. CRS was subsequently confirmed by laboratory diagnosis. Rubella virus genotype 1E was detected in the infant's nasopharyngeal swab and urine samples. This was the first case of CRS in Israel in 20 years, emphasizing the need to "think outside the box" when dealing with infants of mothers who are foreign workers, refugees, or visitors of foreign relatives, in which rubella immune status is unknown. Additionally, public health authorities should consider the routine assessment of rubella immunity status of foreign workers in order to avoid such tragic, preventable diseases. We present a case of congenital rubella syndrome - rarely seen in developed countries. This emphasis the need to "think out of the box" when dealing with infants of mothers who come from countries in which the vaccination program is not well established.

Teaching During the COVID-19 Pandemic: The Experience of the Faculty of Medicine at the Technion-Israel Institute of Technology.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic forced drastic changes in all layers of life. Social distancing and lockdown drove the educational system to uncharted territories at an accelerated pace, leaving educators little time to adjust. OBJECTIVES: To describe changes in teaching during the first phase of the COVID-19 pandemic. METHODS: We described the steps implemented at the Technion-Israel Institute of Technology Faculty of Medicine during the initial 4 months of the COVID-19 pandemic to preserve teaching and the academic ecosystem. RESULTS: Several established methodologies, such as the flipped classroom and active learning, demonstrated effectiveness. In addition, we used creative methods to teach clinical medicine during the ban on bedside teaching and modified community engagement activities to meet COVID-19 induced community needs. CONCLUSIONS: The challenges and the lessons learned from teaching during the COVID-19 pandemic prompted us to adjust our teaching methods and curriculum using multiple online teaching methods and promoting self-learning. It also provided invaluable insights on our pedagogy and the teaching of medicine in the future with emphasis on students and faculty being part of the changes and adjustments in curriculum and teaching methods. However, personal interactions are essential to medical school education, as are laboratories, group simulations, and bedside teaching.

Towards homogenization of liquid plug distribution in reconstructed 3D upper airways of the preterm infant.

Liquid plug therapies are commonly instilled in premature babies suffering from infant respiratory distress syndrome (IRDS) by a procedure called surfactant replacement therapy (SRT) in which a surfactant-laden bolus is instilled endotracheally in the neonatal lungs, dramatically reducing mortality and morbidity in neonatal populations. Since data are frequently limited, the optimal method for surfactant delivery has yet to be established towards more standardized guidelines. Here, we explore the dynamics of liquid plug transport using an anatomically-relevant, true-scale in vitro 3D model of the upper airways of a premature infant. We quantify the initial plug's distribution as a function of two underlying parameters that can be clinically controlled; namely, the injection flow rate and the viscosity of the administered fluid. By extracting a homogeneity index (HI), our in vitro results underline how the combination of both high fluid viscosity and injection flow rates may be advantageous in improving homogeneous dispersion. Such outcomes are anticipated to help refine future SRT administration guidelines towards more uniform distribution using more anatomically-realistic 3D in vitro models at true scale of the preterm neonate.

Neonatal SARS-CoV-2 Infections in Breastfeeding Mothers.

OBJECTIVES: To assess infection rates predischarge and postdischarge in breast milk-fed newborns with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive mothers who were separated postdelivery from their mothers and discharged from the hospital. Also, we aim to evaluate breastfeeding rates predischarge and postdischarge. METHODS: Nasopharyngeal swabs for SARS-CoV-2 were obtained from symptomatic and high-risk women in the delivery room. Mothers with positive SARS-CoV-2 test results were separated from the newborns. Newborns were screened within 48 hours of delivery, and anti-infectious guidelines were imparted to the mothers before discharge. Rescreening took place ≥14 days postdischarge. Data regarding SARS-CoV-2-positive household members and breastfeeding were obtained by follow-up phone calls. RESULTS: A total of 73 newborns of SARS-CoV-2-positive mothers were born in Israel during the ∼3-month period under study. Overall, 55 participated in this study. All neonates tested negative for the virus postdelivery. A total 74.5% of the neonates were fed unpasteurized expressed breast milk during the postpartum separation until discharge. Eighty-nine percent of the neonates were discharged from the hospital after their mothers were instructed in anti-infection measures. In 40% of the households, there were additional SARS-CoV-2-positive residents. A total of 85% of the newborns were breastfed postdischarge. Results for all 60% of the newborns retested for SARS-CoV-2 postdischarge were negative. CONCLUSIONS: No viral infection was identified in neonates born to and separated from their SARS-CoV-2-positive mothers at birth and subsequently fed unpasteurized breast milk. All infants breastfed at home remained SARS-CoV-2 negative. These findings may provide insights regarding the redundancy of postpartum mother-newborn separation in SARS-CoV-2-positive women and, assuming precautions are adhered to, support the safety of breast milk.

Using heated humidified high-flow nasal cannulas for premature infants may result in an underestimated amount of water reaching the airways.

AIM: Condensation often occurs when providing humidified respiratory support. We examined conditions conducive to excess water formation in heated humified high-flow nasal cannula (HHHFNC). METHODS: An HHHFNC device, at 35 or 37°C, was attached with a nasal cannula to a reservoir and tested in five ambient conditions and flows. For Group A, tubing and collection bottle remained at room temperature (23°C). Group B, tubing and reservoir remained inside an incubator (31°C). Group C, tubing and reservoir remained at 33°C. In Group D, the HHHFNC was set to 35°C, the reservoir remained at 33°C, and the nasal cannula and tubing remained at 23°C. Group E, same as D, with HHHFNC at 37°C. RESULTS: The largest amounts of collected water were in groups A and E. Both had highest temperature differences. Median (range) was 4.9°C (4.1-6.9) and 4.0°C, collecting 38.4 (26.4-50.4) and 26.4 (19.2-50.4) ml/24 h, respectively. Smallest amounts of water were seen with lower temperature differences as in groups B, C, and D with 2.7 (1.9-4.7), 1.6 (1.2-2.1), and 2.0°C with 8.4 (0.0-33.6), 2.4 (0.0-14.4), and 9.6 (4.8-16.8) ml/24 h, respectively. CONCLUSION: HHHFNC devices may produce clinically significant amounts of water reaching the upper airways. This may be prevented with appropriate device set-up.

[GETTING READY FOR THE FIRST MINUTE OF LIFE - THE DEVELOPMENT AND ORGANIZATION OF NEONATAL RESUSCITATION IN ISRAEL].

INTRODUCTION: The recognition of the newborn as a separate patient with special unique needs and rights began relatively late compared to other medical disciplines. This process occurred concomitantly with the development of modern neonatology in the country and the establishment of special care nurseries. The process included organization of skilled teams, standardization of treatment methods, introduction of standardized language and practices, and teamwork optimization. The importance of providing support to a newborn in distress after birth - in the first minute, and as needed for the first hour of his life, coined as "The Golden Hour", is highlighted in the training sessions in the program. These principles are conveyed today in multiple simulation-based training courses of multidisciplinary teams taking place in most Israeli hospitals, based on the recommendations of the leading organizations in the field and following the consensus statements outlined by the International Liaison Committee for Resuscitation (ILCOR). This article describes the processes that enabled present achievements, and the goals for further future improvements in the outcomes of newborn resuscitation in Israel.

Ventilation-induced jet suggests biotrauma in reconstructed airways of the intubated neonate.

We investigate respiratory flow phenomena in a reconstructed upper airway model of an intubated neonate undergoing invasive mechanical ventilation, spanning conventional to high-frequency ventilation (HFV) modes. Using high-speed tomographic particle image velocimetry, we resolve transient, three-dimensional flow fields and observe a persistent jet flow exiting the endotracheal tube whose strength is directly modulated according to the ventilation protocol. We identify this synthetic jet as the dominating signature of convective flow under intubated ventilation. Concurrently, our in silico wall shear stress analysis reveals a hitherto overlooked source of ventilator-induced lung injury as a result of jet impingement on the tracheal carina, suggesting damage to the bronchial epithelium; this type of injury is known as biotrauma. We find HFV advantageous in mitigating the intensity of such impingement, which may contribute to its role as a lung protective method. Our findings may encourage the adoption of less invasive ventilation procedures currently used in neonatal intensive care units.

While waiting for a vaccine: opportunities for optimization of neonatal group B streptococcal (GBS) disease prevention in Israel.

OBJECTIVE: To quantify effects of different strategies for decreasing neonatal early onset GBS sepsis (EOGBS) in Israel. STUDY DESIGN: A risk allocation model for EOGBS among infants ≥ 35w was adapted to Israeli data. Effects of strategies for antepartum (APS) and intrapartum (IPS) screening, and intrapartum (IAP) and/or postpartum antibiotic prophylaxis (PAP) were calculated. RESULTS: Estimated EOGBS attack rates (AR) with APS in 90%, IAP in 90%, may reduce AR to 0.18/1000. A rapid intrapartum test would further decrease AR to 0.16/1000, while reducing IAP from 21.3 to 12.5% of women. For babies with risk factors and GBS+ who do not receive IAP, further risk reduction could be achieved by PAP. CONCLUSION: IAP remains the main intervention to decrease EOGBS. IAP and PAP together may reduce EOGBS present incidence by 40%. Combining rapid intrapartum screening with selective IAP and selective PAP for remaining gaps, would be the most efficient strategy.

Red blood cell (RBC) suspensions in confined microflows: Pressure-flow relationship.

Microfluidic-based assays have become increasingly popular to explore microcirculation in vitro. In these experiments, blood is resuspended to a desired haematocrit level in a buffer solution, where frequent choices for preparing RBC suspensions comprise notably Dextran and physiological buffer. Yet, the rational for selecting one buffer versus another is often ill-defined and lacks detailed quantification, including ensuing changes in RBC flow characteristics. Here, we revisit RBC suspensions in microflows and attempt to quantify systematically some of the differences emanating between buffers. We measure bulk flow rate (Q) of RBC suspensions, using PBS- and Dextran-40, as a function of the applied pressure drop (ΔP) for two hematocrits (∼0% and 23%). Two distinct microfluidic designs of varying dimensions are employed: a straight channel larger than and a network array similar to the size of individual RBCs. Using the resulting pressure-flow curves, we extract the equivalent hydrodynamic resistances and estimate the relative viscosities. These efforts are a first step in rigorously quantifying the influence of the 'background' buffer on RBC flows within microfluidic devices and thereby underline the importance of purposefully selecting buffer suspensions for microfluidic in vitro assays.

Red blood cell dynamics in biomimetic microfluidic networks of pulmonary alveolar capillaries.

The pulmonary capillary networks (PCNs) embody organ-specific microvasculatures, where blood vessels form dense meshes that maximize the surface area available for gas exchange in the lungs. With characteristic capillary lengths and diameters similar to the size of red blood cells (RBCs), seminal descriptions coined the term "sheet flow" nearly half a century ago to differentiate PCNs from the usual notion of Poiseuille flow in long straight tubes. Here, we revisit in true-scale experiments the original "sheet flow" model and devise for the first time biomimetic microfluidic platforms of organ-specific PCN structures perfused with RBC suspensions at near-physiological hematocrit levels. By implementing RBC tracking velocimetry, our measurements reveal a wide range of heterogonous RBC pathways that coexist synchronously within the PCN; a phenomenon that persists across the broad range of pressure drops and capillary segment sizes investigated. Interestingly, in spite of the intrinsic complexity of the PCN structure and the heterogeneity in RBC dynamics observed at the microscale, the macroscale bulk flow rate versus pressure drop relationship retains its linearity, where the hydrodynamic resistance of the PCN is to a first order captured by the characteristic capillary segment size. To the best of our knowledge, our in vitro efforts constitute a first, yet significant, step in exploring systematically the transport dynamics of blood in morphologically inspired capillary networks.

Does Haptoglobin Phenotype Influence Postnatal Morbidity in Preterm Neonates?

BACKGROUND: Haptoglobin (Hp) is an acute phase protein with antioxidant, bacteriostatic, and anti-inflammatory activities. Hp proteins associated with the three major phenotypes differ in their proinflammatory and anti-inflammatory action. Inflammation and oxidative stress are both involved in most pathophysiological processes in premature infants. The objective of this study was to determine whether Hp phenotype influences clinical manifestations and sepsis incidence in the premature infants. OBJECTIVE: Infants born before 35 weeks gestational age were prospectively evaluated for Hp phenotype and clinical events, including sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, intraventricular hemorrhage, and retinopathy of prematurity. The participants were observed until discharge. METHODS: A total of 122 preterm infants were enrolled in the study. Clinical events were not affected by the Hp phenotype. The expression of Hp protein was extremely low in the study population. More septic episodes were found in infants with a birth weight greater than 1,500 g, although, the difference was not statistically significant. RESULTS: Extremely low expression of Hp may explain the lack of a correlation between Hp phenotype and sepsis in preterm infants. Further research involving a larger neonatal population is required to better understand the role of the Hp phenotype in morbidity of premature infants.

Real-time detection, classification, and quantification of apneic episodes using miniature surface motion sensors in rats.

BACKGROUND: Real-time detection and classification of apneic episodes remain significant challenges. This study explores the applicability of a novel method of monitoring the respiratory effort and dynamics for rapid detection and classification of apneic episodes. METHODS: Obstructive apnea (OA) and hypopnea/central apnea (CA) were induced in nine tracheostomized rats, by short-lived airway obstruction and administration of succinylcholine, respectively. Esophageal pressure (EP), EtCO2, arterial O2 saturation (SpO2), heart rate, and blood pressure were monitored. Respiratory dynamics were monitored utilizing three miniature motion sensors placed on the chest and epigastrium. Three indices were derived from these sensors: amplitude of the tidal chest wall displacement (TDi), breath time length (BTL), that included inspiration and rapid expiration phases, and amplitude time integral (ATI), the integral of breath amplitude over time. RESULTS: OA induced a progressive 6.42 ± 3.48-fold increase in EP from baseline, which paralleled a 3.04 ± 1.19-fold increase in TDi (P < 0.0012), a 1.39 ± 0.22-fold increase in BTL (P < 0.0002), and a 3.32 ± 1.40-fold rise in the ATI (P < 0.024). During central hypopneic/apneic episodes, each sensor revealed a gradual decrease in TDi, which culminated in absence of breathing attempts. CONCLUSION: Noninvasive monitoring of chest wall dynamics enables detection and classification of central and obstructive apneic episodes, which tightly correlates with the EP.

Prophylactic treatment of asthma by an ozone scavenger in a mouse model.

Our hypothesis that inflammation in asthma involves production of ozone by white blood cells and that ozone could be an inflammatory mediator suggests that scavengers of reactive oxygen species (ROS), for example, electron-rich olefins, could serve for prophylactic treatment of asthma. Olefins could provide chemical protection against either exogenous or endogenous ozone and other ROS. BALB/c mice pretreated by inhalation of d-limonene before an ovalbumin challenge exhibited significant attenuation of the allergic asthma symptoms. Diminution of the inflammatory process was evident by reduced levels of aldehydes, reduced counts of neutrophils in the BAL fluid and by histological tests. A surprising systemic effect was observed by decreased levels of aldehydes in the spleen, suggesting that the examination of tissues and organs that are remote from the inflammation foci could provide valuable information on the distribution of the oxidative stress and may serve as guide for targeted treatment.

[Why perform routine brain sonography in late preterm infants?].

We present a case of a late preterm baby with respiratory distress syndrome (RDS), prolonged jaundice and congenital hypothyroidism. The infant developed late lenticulostriate vasculopathy (LSV). LSV was previously described in association with various neurodevelopmental abnormalities and in this case would have been missed by the current US brain screening recommendations for newborns.

Zn/Ga-DFO iron-chelating complex attenuates the inflammatory process in a mouse model of asthma.

BACKGROUND: Redox-active iron, a catalyst in the production of hydroxyl radicals via the Fenton reaction, is one of the key participants in ROS-induced tissue injury and general inflammation. According to our recent findings, an excess of tissue iron is involved in several airway-related pathologies such as nasal polyposis and asthma. OBJECTIVE: To examine the anti-inflammatory properties of a newly developed specific iron-chelating complex, Zn/Ga-DFO, in a mouse model of asthma. MATERIALS AND METHODS: Asthma was induced in BALBc mice by ovalbumin, using aluminum hydroxide as an adjuvant. Mice were divided into four groups: (i) control, (ii) asthmatic and sham-treated, (iii) asthmatic treated with Zn/Ga-DFO [intra-peritoneally (i/p) and intra-nasally (i/n)], and (iv) asthmatic treated with Zn/Ga-DFO, i/n only. Lung histology and cytology were examined. Biochemical analysis of pulmonary levels of ferritin and iron-saturated ferritin was conducted. RESULTS: The amount of neutrophils and eosinophils in bronchoalveolar lavage fluid, goblet cell hyperplasia, mucus secretion, and peri-bronchial edema, showed markedly better values in both asthmatic-treated groups compared to the asthmatic non-treated group. The non-treated asthmatic group showed elevated ferritin levels, while in the two treated groups it returned to baseline levels. Interestingly, i/n-treatment demonstrated a more profound effect alone than in a combination with i/p injections. CONCLUSION: In this mouse model of allergic asthma, Zn/Ga-DFO attenuated allergic airway inflammation. The beneficial effects of treatment were in accord with iron overload abatement in asthmatic lungs by Zn/Ga-DFO. The findings in both cellular and tissue levels supported the existence of a significant anti-inflammatory effect of Zn/Ga-DFO.