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Objective: To evaluate obstetric and perinatal outcomes among small for gestational age (SGA) infants born to patients diagnosed with Gestational diabetes mellitus (GDM). Materials and methods: A multicenter retrospective cohort study between 2005 and 2021. The perinatal outcomes of SGA infants born to patients with singleton pregnancy and GDM were compared to SGA infants born to patients without GDM. The primary outcome was a composite adverse neonatal outcome. Infants with known structural/genetic abnormalities or infections were excluded. A univariate analysis was conducted followed by a multivariate analysis (adjusted odds ratio [95% confidence interval]). Results: During the study period, 11,662 patients with SGA infants met the inclusion and exclusion criteria. Of these, 417 (3.6%) SGA infants were born to patients with GDM, while 11,245 (96.4%) were born to patients without GDM. Overall, the composite adverse neonatal outcome was worse in the GDM group (53.7% vs 17.4%, p < 0.01). Specifically, adverse neonatal outcomes such as a 5 min Apgar score < 7, meconium aspiration, seizures, and hypoglycemia were independently associated with GDM among SGA infants. In addition, patients with GDM and SGA infants had higher rates of overall and spontaneous preterm birth, unplanned cesarean, and postpartum hemorrhage. In a multivariate logistic regression assessing the association between GDM and neonatal outcomes, GDM was found to be independently associated with the composite adverse neonatal outcome (aOR 4.26 [3.43–5.3]), 5 min Apgar score < 7 (aOR 2 [1.16–3.47]), meconium aspiration (aOR 4.62 [1.76–12.13]), seizures (aOR 2.85 [1.51–5.37]) and hypoglycemia (aOR 16.16 [12.79–20.41]). Conclusions: Our study demonstrates that GDM is an independent risk factor for adverse neonatal outcomes among SGA infants. This finding underscores the imperative for tailored monitoring and management strategies in those pregnancies. [ABSTRACT FROM AUTHOR]

Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRβ, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRβ as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases. [ABSTRACT FROM AUTHOR]

Background: Hepatic cancer endures a major health scourge as the consequence of a high incidence of > 1 million cases by 2025. Plant-based products are typically effective in ameliorating health conditions. Pomegranate peel extract (PE) with its high polyphenolic content has anticancer effects against different types of cancer. Herein, we aimed to maximize the PE chemotherapeutic efficacy by loading it in a suitable delivery system to overcome the limitations of PE, to control its release and to achieve liver targeting. Method: A nanoprecipitation procedure was adopted to incorporate PE into biodegradable and biocompatible natural polymeric zein (ZN)-based nanoparticles (NPs) (PE-ZN NPs). A full factorial design (22 × 31) was developed to study the effects of the formulation variables, namely pH of dispersion, PE-to-ZN ratio and surfactant concentration. Results: The optimization revealed a surfactant-free stable PE-ZN NPs formula with a small particle size of 99.5 ± 6.43 nm, high PE encapsulation efficiency % of 99.31% ± 3.64 (w/w) and controlled release of PE over 24 h. Conclusion: Moreover, the cytotoxicity of the optimum formula against hepatic cancer HepG2 cell lines was assessed and attained about a 2.5-fold reduction in the inhibitory concentration (IC50) values compared to the free PE affording a promising green platform to combat hepatic cancer. [ABSTRACT FROM AUTHOR]

Purpose: Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the alveoli lead to dysregulation of pulmonary surfactant metabolism and function. Altered surfactant synthesis, secretion, and breakdown contribute to the clinical features of decreased lung compliance and alveolar collapse. Lung function in ARDS could potentially be restored with surfactant replacement therapy, and synthetic surfactants with modified peptide analogues may better withstand inactivation in ARDS alveoli than natural surfactants. Methods: This study aimed to investigate the activity in vitro and the bolus effect (200 mg phospholipids/kg) of synthetic surfactant CHF5633 with analogues of SP‐B and SP‐C, or natural surfactant Poractant alfa (Curosurf®, both preparations Chiesi Farmaceutici S.p.A.) in a severe ARDS model (the ratio of partial pressure arterial oxygen and fraction of inspired oxygen, P/F ratio ≤ 13.3 kPa) induced by hydrochloric acid instillation followed by injurious ventilation in adult New Zealand rabbits. The animals were ventilated for 4 h after surfactant treatment and the respiratory parameters, histological appearance of lung parenchyma and levels of inflammation, oxidative stress, surfactant dysfunction, and endothelial damage were evaluated. Results: Both surfactant preparations yielded comparable improvements in lung function parameters, reductions in lung injury score, pro-inflammatory cytokines levels, and lung edema formation compared to untreated controls. Conclusions: This study indicates that surfactant replacement therapy with CHF5633 improves lung function and lung architecture, and attenuates inflammation in severe ARDS in adult rabbits similarly to Poractant alfa. Clinical trials have so far not yielded conclusive results, but exogenous surfactant may be a valid supportive treatment for patients with ARDS given its anti-inflammatory and lung-protective effects. [ABSTRACT FROM AUTHOR]

Lung ultrasound is rapidly becoming a useful tool in the care of neonates: its ease of use, reproducibility, low cost, and negligible side effects make it a very suitable tool for the respiratory care of all neonates. This technique has been extensively studied by different approaches in neonatal intensive care unit (NICU), both for diagnostic and prognostic aims and to guide respiratory treatments. However, many neonates are being born in level I/II hospitals without NICU facilities so all pediatricians, not just neonatal intensivists, should be aware of its potential. This is made possible by the increasing access to ultrasound machines in a modern hospital setting. In this review, we describe the ultrasonographic characteristics of the normal neonatal lung. We also discuss the ultrasound features of main neonatal respiratory diseases: transient tachypnea of the neonate (TTN), respiratory distress syndrome (RDS), meconium aspiration syndrome (MAS), pneumothorax (PNX), pleural effusion (PE), or pneumonia. Finally, we mention two functional approaches to lung ultrasound: The use of lung ultrasound in level I delivery centers as a mean to assess the severity of neonatal respiratory distress and request a transport to a higher degree structure in a timely fashion. The prognostic accuracy of lung ultrasound for early and targeted surfactant replacement. Conclusion: LU is still a useful tool in level I/II neonatal units, both for diagnostic and functional issues. What is Known: • Neonatal lung ultrasound has been recently introduced in the usual care in many Neonatal Intensive Care Units. What is New: • It also has many advantages in level I/II neonatal units, both for neonatologist or even pediatricians that treat neonates in those sites. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO) is an invasive life support technique that requires a blood pump, an artificial membrane lung, and vascular cannulae to drain de-oxygenated blood, remove carbon dioxide, oxygenate, and return it to the patient. ECMO is generally used to provide advanced and prolonged cardiopulmonary support in patients with refractory acute cardiac and/or respiratory failure. After its first use in 1975 to manage a severe form of meconium aspiration syndrome with resultant pulmonary hypertension, the following years were dominated by the use of ECMO to manage neonatal respiratory failure and limited to a few centers across the world. In the 1990s, evidence for neonatal respiratory ECMO support increased; however, the number of cases began to decline with the use of newer pharmacologic therapies (e.g., inhaled nitric oxide, exogenous surfactant, and high-frequency oscillatory ventilation). On the contrary, pediatric ECMO sustained steady growth. Combined advances in ECMO technology and bedside medical management have improved general outcomes, although ECMO-related complications remain challenging. Point-of-care ultrasound (POCUS) is an essential tool to monitor all phases of neonatal and pediatric ECMO: evaluation of ECMO candidacy, ultrasound-guided ECMO cannulation, daily evaluation of heart and lung function and brain perfusion, detection and management of major complications, and weaning from ECMO support. Conclusion: Based on these considerations and on the lack of specific guidelines for the use of POCUS in the neonatal and pediatric ECMO setting, the aim of this paper is to provide a systematic overview for the application of POCUS during ECMO support in these populations. What is Known: • Extracorporeal membrane oxygenation (ECMO) provides advanced cardiopulmonary support for patients with refractory acute cardiac and/or respiratory failure and requires appropriate monitoring. • Point-of-care ultrasound (POCUS) is an accessible and adaptable tool to assess neonatal and pediatric cardiac and/or respiratory failure at bedside. What is New: • In this review, we discussed the use of POCUS to monitor and manage at bedside neonatal and pediatric patients supported with ECMO. • We explored the potential use of POCUS during all phases of ECMO support: pre-ECMO assessment, ECMO candidacy evaluation, daily evaluation of heart, lung and brain function, detection and troubleshooting of major complications, and weaning from ECMO support. [ABSTRACT FROM AUTHOR]

Background: Lung biopsy remains the gold standard in the diagnosis of fibrotic interstitial lung disease (F-ILD), but there is a growing appreciation of the role of pathogenic gene variants in telomere and surfactant protein genes, especially in familial pulmonary fibrosis (FPF). Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that can coexist with different patterns of F-ILD, including FPF. It can be progressive and often leads to respiratory failure and death. This study tested the hypothesis that genetic testing goes beyond radiological and histological findings in PPFE and other F-ILD further informing clinical decision-making for patients and affected family members by identifying pathological gene variants in telomere and surfactant protein genes. Methods: This is a retrospective review of 70 patients with F-ILD in the setting of FPF or premature lung fibrosis. Six out of 70 patients were diagnosed with PPFE based on radiological or histological characteristics. All patients underwent telomere length evaluation in peripheral blood by Flow-FISH or genetic testing using a customized exome-based panel that included telomere and surfactant protein genes associated with lung fibrosis. Results: Herein, we identified six individuals where radiographic or histopathological analyses of PPFE were linked with telomere biology disorders (TBD) or variants in surfactant protein genes. Each case involved individuals with either personal early-onset lung fibrosis or a family history of the disease. Assessments of telomere length and genetic testing offered insights beyond traditional radiological and histopathological evaluations. Conclusion: Detecting anomalies in TBD-related or surfactant protein genes can significantly refine the diagnosis and treatment strategies for individuals with PPFE and other F-ILD. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) has been linked to severe, adverse child outcomes. However, little is known regarding subclinical outcomes of low/moderate PAE and its longitudinal consequences, especially regarding neurophysiological and neurocognitive development. A newborn biomarker of PAE, meconium ethyl glucuronide (EtG), has been shown to predict cognitive impairments in primary-school-aged children. The current study investigated the ongoing effects of subclinical PAE in adolescence. Methods: A sample of n = 96 mother–child dyads of the FRAMES/FRANCES cohort were classified into PAE/no PAE using EtG with a 10 ng/g cutoff. Mothers were recruited during pregnancy and children were assessed during primary-school age (M = 7.57, SD = 0.65, range: 6.00–9.92 years) and adolescence (M = 13.26, SD = 0.31, range: 12.79–14.20 years) on three levels: clinical (ADHD rating), neuropsychological (IQ score and performance in a go/nogo task), and neurophysiological (analysis of P3 event-related potentials (ERP) during said go/nogo task). Developmental outcomes and courses following PAE were assessed using rmANCOVAs, controlling for relevant confounders (socioeconomic status (SES), birth weight, and maternal psychopathology). Results: Neurophysiological impairments emerged for exposed children in the form of diminished attentional resource recruiting in childhood and adolescence (reduced go-P3 amplitudes) with no differences in performance. Neuropsychological testing showed a reduced IQ score for both time points with dose-dependent effects in childhood. Clinical ADHD symptoms were not significantly affected. Conclusion: Subclinical PAE, as determined by meconium EtG, has negative developmental consequences on cognitive function that persist from childhood to adolescence. These findings suggest that there is no safe limit for alcohol consumption during pregnancy and that more thorough screening of alcohol consumption during pregnancy is necessary for early identification and treatment of at-risk children. [ABSTRACT FROM AUTHOR]

Purposes: We previously reported an unexpected phenomenon that shaking stress could cause more protein degradation in freeze-dried monoclonal antibody (mAb) formulations than liquid ones (J Pharm Sci, 2022, 2134). The main purposes of the present study were to investigate the effects of shaking stress on protein degradation and sub-visible particle (SbVP) formation in freeze-dried mAb formulations, and to analyze the factors influencing protein degradation during production and transportation. Methods: The aggregation behavior of mAb-X formulations during production and transportation was simulated by shaking at a rate of 300 rpm at 25°C for 24 h. The contents of particles and monomers were analyzed by micro-flow imaging, dynamic light scattering, size exclusion chromatography, and ultraviolet − visible (UV–Vis) spectroscopy to compare the protective effects of excipients on the aggregation of mAb-X. Results: Shaking stress could cause protein degradation in freeze-dried mAb-X formulations, while surfactant, appropriate pH, polyol mannitol, and high protein concentration could impact SbVP generation. Water content had little effect on freeze-dried protein degradation during shaking, as far as the water content was controlled in the acceptable range as recommended by mainstream pharmacopoeias (i.e., less than 3%). Conclusions: Shaking stress can reduce the physical stability of freeze-dried mAb formulations, and the addition of surfactants, polyol mannitol, and a high protein concentration have protective effects against the degradation of model mAb formulations induced by shaking stress. The experimental results provide new insight for the development of freeze-dried mAb formulations. [ABSTRACT FROM AUTHOR]

Purpose: Zonulin has been shown to be associated with many metabolic disorders, including type 2 diabetes mellitus, metabolic syndrome, and obesity. In this study, we aimed to evaluate the association between maternal plasma zonulin levels and gestational diabetes mellitus (GDM) and its perinatal outcomes. Materials: A total of 100 pregnant women, 56 with GDM and 44 controls, were included in this prospective case–control study. Maternal plasma zonulin levels were evaluated in each trimester. The association between zonulin levels and GDM, body mass index (BMI) and adverse perinatal outcomes was evaluated. The GDM predictability of zonulin levels for each trimester was analyzed with the receiver operator curve (ROC). Results: Plasma zonulin levels were significantly higher in pregnant with GDM in all trimesters (p < 0.001; for all). Optimum cut-off values of plasma zonulin levels in predicting GDM: first trimester: 6.27 ng/mL, second trimester: 12.71 ng/mL, and third trimester: 18.38 ng/mL. BMI was significantly higher in pregnant women with GDM (30.5 vs 26.1; p < 0.001). Zonulin levels were significantly higher in pregnant women with GDM with overweight BMI [≥ 25–30 (kg/m2)] in all trimesters (p < 0.05; for all). Zonulin levels were significantly higher in pregnant women with composite adverse outcomes that included at least one of neonatal intensive care unit (NICU) admission, meconium-stained amniotic fluid, and 1st minute APGAR score < 7. Conclusion: Increased maternal plasma zonulin levels were associated with increased risk of GDM and adverse perinatal outcomes. Zonulin may be a potential marker to predict GDM risk and perinatal outcomes. [ABSTRACT FROM AUTHOR]

Neonatal respiratory failure (NRF) is an emergency which has not been examined extensively. We critically synthesized the contemporary in-hospital prevalence, mortality rate, predictors, aetiologies, diagnosis and management of NRF to better formulate measures to curb its burden. We searched MEDLINE and Google Scholar from 01/01/1992 to 31/12/2022 for relevant publications. We identified 237 papers from 58 high-income and low-and middle-income countries (LMICs). NRF prevalence ranged from 0.64 to 88.4% with some heterogeneity. The prevalence was highest in Africa, the Middle East and Asia. Globally as well as in Asia and the Americas, respiratory distress syndrome (RDS) was the leading aetiology of NRF. Neonatal sepsis was first aetiology in Africa, whereas in both Europe and the Middle East it was transient tachypnoea of the newborn. Independent predictors of NRF were prematurity, male gender, ethnicity, low/high birth weight, young/advanced maternal age, primiparity/multiparity, maternal smoking, pregestational/gestational diabetes mellitus, infectious anamneses, antepartum haemorrhage, gestational hypertensive disorders, multiple pregnancy, caesarean delivery, antenatal drugs, foetal distress, APGAR score, meconium-stained amniotic fluid and poor pregnancy follow-up. The NRF-related in-hospital mortality rate was 0.21–57.3%, highest in Africa, Asia and the Middle East. This death toll was primarily due to RDS globally and in all regions. Clinical evaluation using the Silverman-Anderson score was widely used and reliable. Initial resuscitation followed by specific management was the common clinical practice. Conclusion: NRF has a high burden globally, driven by RDS, especially in LIMCs where more aggressive treatment and innovations, preferably subsidized, are warranted to curb its alarming burden. What is Known: • Neonatal respiratory failure is a frequent emergency associated with a significant morbidity and mortality, yet there is no comprehensive research paper summarizing its global burden. • Neonatal respiratory failure needs prompt diagnosis and treatment geared at improving neonatal survival. What is New: • Neonatal respiratory failure has an alarmingly high global burden largely attributed to Respiratory distress syndrome. Low resource settings are disproportionately affected by the burden of neonatal respiratory failure. • Independent preditors of neonatal respiratory failure are several but can be classified into foetal, maternal and obstetrical factors. An illustrative pedagogical algorithm is provided to facilitate diagnosis and management of neonatal respiratory failure by healthcare providers. [ABSTRACT FROM AUTHOR]

Management of respiratory distress (RD) in the extremely preterm newborn meets recommendations. Few data are available concerning the management and the clinical course of moderate and late preterms with RD. Clinical course and management among moderate (30–33 weeks (wks) of gestation) and late preterms (34–36 wks) were assessed in the Neobs study, a French neonatal observational cohort study (2018) of preterms with RD in the first 24 h of life. Clinical course was defined as stable (use of non-invasive ventilation (NIV) only), initially severe (initial use of invasive ventilation (IV)), and worsening (switch off IV after NIV support). Surfactant therapy instillation and withdrawal of all ventilator support at 72 h were recorded. Among moderate (n = 279) and late (n = 281) preterms, the clinical course was similar (p < 0.27): stable (82.1 and 86.8%), worsening (11.8% and 9.3%), and initially severe RD (6.1% and 3.9%), respectively. Surfactant was administered more frequently in the moderate versus late preterm groups (28.3% vs 16.7%; p < 0.001). The recommended surfactant dose (200 mg/kg) was administered in 53.3–83.3% of moderate and 42.1–63.2% of late preterms according to the clinical course. Withdrawal of ventilatory support at 72 h was observed in 40.0% and 70.0% of moderate and late preterms, respectively (p < 0.05), and was significantly (p < 0.001) associated with clinical course (the minus proportion among the worsening group). Conclusion: While the proportion of clinical course pattern is similar in moderate and late preterm infants, the management of RD varies with gestational age, with late preterm infants being managed later in life and moderate premature infants weaned from ventilation at a later stage. What is Known: • There is a lack of clear guidance on the management of respiratory distress (RD) in moderate-to-late preterm infants. • Neobs was a multicentre, observational study designed to characterise the real-world management of moderate-to-late preterm infants with RD in France. What is New: • Secondary analyses of Neobs study data found that ventilatory support strategies were dependent on gestational age despite a similar clinical course. • At 30–33 weeks of gestation (wks), infants were more likely to receive non-invasive ventilation at delivery, while 34–36 wks infants were more likely to be managed using a wait-and-see approach. [ABSTRACT FROM AUTHOR]

Denial of pregnancy is a rare psychic process associated with an increased risk of infant death. Forensic examinations to determine viability at birth can heavily influence the legal proceedings in cases of clandestine deliveries that result in the death of the infant. A 32-year-old woman who experienced a denial of pregnancy up to 30 weeks of amenorrhea reported giving birth at home at an estimated term of 35 weeks of amenorrhea. No one witnessed the delivery. She claimed the infant was stillborn. Forensic examinations revealed characteristic features of a live born infant. The mother tested positive for mifepristone. Mifepristone is an anti-progestin drug used for early abortion and to induce labor in cases of in-utero fetal death in later pregnancy. Even if mifepristone crosses the placenta, it has no direct toxic effect on the fetus. Our observations suggest premature live birth caused by mifepristone, followed by asphyxia due to meconium inhalation syndrome associated with lung immaturity especially since the birth occurred at home and no medical care was provided after the birth. The tragic outcome of this clinical case calls for vigilance and global management, including the psychiatric care of parturients in the context of late discovery of pregnancy. In France, this situation showed a legal gap between the consideration of the fetus and laws concerning abortion. To our knowledge, in France, this case has allowed the court to set a legal precedent as a similar case had never been reported elsewhere. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity involving both pre- and post-natal factors. A large, prospective, longitudinal cohort study was conducted to determine whether inflammation-related factors are associated with an increased risk of BPD in preterm infants who were born at a gestational age < 32 weeks, < 72 h after birth and respiratory score > 4. The study included infants from 25 participating hospitals in China between March 1, 2020 and March 31, 2022. The primary outcomes were BPD and severity of BPD at 36 weeks post-menstrual age. A total of 1362 preterm infants were enrolled in the study. After exclusion criteria, the remaining 1088 infants were included in this analysis, of whom, 588 (54.0%) infants were in the BPD group and 500 (46.0%) were in the non-BPD group. In the BPD III model, the following six factors were identified: birth weight (OR 0.175, 95% CI 0.060–0.512; p = 0.001), surfactant treatment (OR 8.052, 95% CI 2.658–24.399; p < 0.001), mean airway pressure (MAP) ≥ 12 cm H2O (OR 3.338, 95% CI 1.656–6.728; p = 0.001), late-onset sepsis (LOS) (OR 2.911, 95% CI 1.514–5.599; p = 0.001), ventilator-associated pneumonia (VAP) (OR 18.236, 95% CI 4.700–70.756; p < 0.001) and necrotizing enterocolitis (NEC) (OR 2.725, 95% CI 1.182–6.281; p = 0.019). Premature infants remained at high risk of BPD and with regional variation. We found that post-natal inflammation-related risk factors were associated with an increased risk of severe BPD, including LOS, VAP, NEC, MAP ≥ 12 cm H2O and use of surfactant. [ABSTRACT FROM AUTHOR]

Previous studies have consistently shown a pattern of prefrontal hypoactivation in depressed patients (DP); however, it remains unclear whether this neural correlate is a consequence or concomitant feature of depression and/or whether ruminative thinking might be underlying. Using a sample comprising 65 healthy controls (HC) and 77 DP, we investigated the behavioral and neural correlates in response to stress and their association with depressive symptomatology, trait and state rumination. Fitting repeated-measurement MANOVAs including 21 fNIRS-channels covering the bilateral Inferior Frontal Gyrus (IFG), Dorsolateral Prefrontal Cortex (DLPFC) and Somatosensory Association Cortex (SAC), we investigated the predictive value of diagnostic group (HC vs. DP) and state rumination. In DP, we observed significantly lower increases in cortical oxygenation under stress in channels of the right IFG and bilateral DLPFC. Participants reporting lower state rumination and no increases in state rumination under stress showed higher increases in cortical oxygenation compared to the other groups and in more channels compared to the analysis on diagnostic group. Re-running our fNIRS-analysis while correcting for performance resulted in time-dependent changes dependent on group (DP vs. HC) no longer yielding significance, however for the differentiation of state rumination groups. [ABSTRACT FROM AUTHOR]

To the Editor Human type I interferons (IFNs) play an important role in host immunity against viruses. I IFIH1 i encodes interferon-induced helicase C domain-containing protein 1, which senses viral double-stranded RNA in the cytosol, inducing a type I IFN-mediated antiviral response. However, in the current case, CMV and I Pneumocystis jirovecii i infections may have triggered an exacerbation of the lung diseases because of an underlying condition that produces excessive type I interferon due to GOF mutation in the I IFIH1 i gene. [Extracted from the article]

Introduction: Unbiased metagenomic next-generation sequencing (mNGS) has been used for infection diagnosis. In this study, we explored the clinical diagnosis value of mNGS for pulmonary complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: From August 2019 to June 2021, a prospective study was performed to comparatively analyze the pathogenic results of mNGS and conventional tests for bronchoalveolar lavage fluid (BALF) from 134 cases involving 101 patients with pulmonary complications after allo-HSCT. Results: More pathogens were identified by mNGS than with conventional tests (226 vs 120). For bacteria, the diagnostic sensitivity (P = 0.144) and specificity (P = 0.687) were similar between the two methods. For fungus except Pneumocystis jirovecii (PJ), conventional tests had a significantly higher sensitivity (P = 0.013) with a similarly high specificity (P = 0.109). The sensitivities for bacteria and fungi could be increased with the combination of the two methods. As for PJ, both the sensitivity (100%) and specificity (99.12%) of mNGS were very high. For viruses, the sensitivity of mNGS was significantly higher (P = 0.021) and the negative predictive value (NPV) was 95.74% (84.27–99.26%). Pulmonary infection complications accounted for 90.30% and bacterium was the most common pathogen whether in single infection (63.43%) or mixed infection (81.08%). The 6-month overall survival (OS) of 88.89% in the early group (mNGS ≤ 7 days) was significantly higher than that of 65.52% (HR 0.287, 95% CI 0.101–0.819, P = 0.006) in the late group (mNGS > 7 days). Conclusions: mNGS for BALF could facilitate accurate and fast diagnosis for pulmonary complications. Early mNGS could improve the prognosis of patients with pulmonary complications after allo-HSCT. Trial Registration: ClinicalTrials.gov identifier, NCT 04051372. [ABSTRACT FROM AUTHOR]

The rapid changes in clinical maternity situations that occur in a labor and delivery unit can lead to unpredictable maternal and newborn morbidities. Cesarean section (CS) rate is a key indicator of the accessibility and quality of a labor and delivery unit. This retrospective cross-sectional study assesses the nulliparous, term, singleton, vertex (NTSV) cesarean delivery rates before and after the implementation of a smart intrapartum surveillance system. Research data were collected from the electronic medical records of a labor and delivery unit. The primary outcome was the CS rate of the NTSV population. The data of 3648 women admitted for delivery were analyzed. Of the studied deliveries, 1760 and 1888 occurred during the preimplementation and postimplementation periods, respectively. The CS rate for the NTSV population was 31.0% and 23.3% during the preimplementation and postimplementation periods, respectively, indicating a significant 24.7% (p = 0.014) reduction in CS rate after the implementation of the smart intrapartum surveillance system (relative risk, 0.75; 95% confidence interval, 0.71–0.80). In the NTSV population, the vaginal and CS birth groups, no significant difference in terms of newborn weight, neonatal Apgar scores, composite neonatal adverse outcome indicator, and the occurrence of the following: neonatal intensive care unit admission, neonatal meconium aspiration, chorioamnionitis, shoulder dystocia, perineal laceration, placental abruption, postpartum hemorrhage, maternal blood transfusion, and hysterectomy before and after the implementation of the smart intrapartum surveillance system. This study reveals that the use of the smart intrapartum surveillance system can effectively reduce the primary CS rate for low-risk NTSV pregnancies without significantly affecting perinatal outcomes. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the pain or physiological stress caused during minimally invasive surfactant therapy (MIST) to very preterm neonates. Methods: In this prospective observational study conducted in a tertiary NICU, very preterm neonates were assessed for pain using Premature Infant Pain Profile-Revised (PIPP-R) score before, during and after MIST. Changes in the heart rate and oxygen saturation were also recorded during the procedure. Results: 23 neonates who received MIST were assessed for pain using PIPP-R. Mean (SD) PIPP-R score during MIST was 3.87(1.3), before; 12.83 (1.9), during; and 6.26 (1.0), after the procedure, respectively (all P<0.001). Heart rate and oxygen saturation were also significantly reduced during MIST (P<0.001). Conclusion: The high PIPP-R scores during surfactant administration suggest that MIST can cause moderate to severe pain/discomfort and significant physiological stress in very preterm infants. [ABSTRACT FROM AUTHOR]

Background and Objective: The risk of thrombotic complications in critical patients with COVID-19 remains extremely high, and multicenter trials failed to prove a survival benefit of escalated doses of low-molecular-weight heparins (nadroparin calcium) in this group. The aim of this study was to develop a pharmacokinetic model of nadroparin according to different stages of COVID-19 severity. Methods: Blood samples were obtained from 43 patients with COVID-19 who received nadroparin and were treated with conventional oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation. We recorded clinical, biochemical, and hemodynamic variables during 72 h of treatment. The analyzed data comprised 782 serum nadroparin concentrations and 219 anti-Xa levels. We conducted population nonlinear mixed-effects modeling (NONMEM) and performed Monte Carlo simulations of the probability of target attainment for reaching 0.2–0.5 IU/mL anti-Xa levels in study groups. Results: We successfully developed a one-compartment model to describe the population pharmacokinetics of nadroparin in different stages of COVID-19. The absorption rate constant of nadroparin was 3.8 and 3.2 times lower, concentration clearance was 2.22 and 2.93 times higher, and anti-Xa clearance was 0.87 and 1.1 times higher in mechanically ventilated patients and the extracorporeal membrane oxygenation group compared with patients treated with conventional oxygen, respectively. The newly developed model indicated that 5.900 IU of nadroparin given subcutaneously twice daily in the mechanically ventilated patients led to a similar probability of target attainment of 90% as 5.900 IU of subcutaneous nadroparin given once daily in the group supplemented with conventional oxygen. Conclusions: Different nadroparin dosing is required for patients undergoing mechanical ventilation and extracorporeal membrane oxygenation to achieve the same targets as those for non-critically ill patients. Clinical Trial Registration: ClinicalTrials.gov identifier no. NCT05621915. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to determine the cause-specific hazard (CSH) and the cumulative incidence function (CIF) for umbilical cord metabolic acidemia at birth (MA; pH < 7.0 and/or BE ≤ − 12 mmol/L) at delivery in patients experiencing the 2nd stage of labor (2STG), stratified for both FIGO-2015 pathologic intrapartum cardiotocography requiring expedited delivery (CTG_RED) and duration of 2nd stage of labor. Methods: 3459 pregnancies experiencing the 2nd stage of labor and delivering at the Division of Obstetrics and Prenatal Medicine, IRCCS Sant'Orsola-Malpighi Hospital, Bologna (Italy), were identified between 2018 and 2019. Survival analysis was used to assess CSH and CIF for MA, stratified for FIGO-2015 pathologic CTG and relevant covariates. Results: FIGO-2015 pathological CTG with expedited operative delivery or urgent cesarean section within 10 or 20 min from diagnosis, respectively occurred in 282/3459 (8.20%). The rate of MA at delivery was 3.32% (115/3459). The spline of CSH for MA showed a direct correlation with the duration of 2STG always presenting higher values and greater slope in the presence of pathologic CTG, with plateau between 60 and 120 min and rapid increase after 120 min. The CIF at 180 min in the 2STG was 2.67% for nonpathological and 10.63% for pathological CTG_RED. Nulliparity, pathological CTG, and meconium-stained amniotic fluid resulted significant predictors of MA in our multivariable model. Conclusion: The risk for MA increases moderately across the 2STG with nonpathological CTG and quadruples with pathological CTG_RED. Adjustment for other predictors of MA including meconium-stained amniotic fluid and nulliparity reveals a significant hazard increase for MA associated with pathologic CTG_RED. [ABSTRACT FROM AUTHOR]

Neurological symptoms have been often reported in COVID-19 disease. In the present study, we evaluated brain damage associated with the increase of serum levels of neurological biomarkers S100B and neuron-specific enolase (NSE) induced by SARS-CoV-2 infection, in a population from Northeastern Brazil. Thirty-six healthy control (G1) individuals and 141 patients with confirmed COVID-19 were enrolled in this study. Positive-COVID-19 patients were divided into two groups according to the severity of illness by the National Institute of Health (NIH) criteria, 76 patients with mild symptoms for COVID-19 and (G2) and 65 with acute respiratory conditions requiring supplemental oxygenation via intensive care unit (ICU) admission (G3). A follow-up study was conducted with 23 patients from G2 14 (D14) and 21 (D21) days after the onset of symptoms. Serum levels of NSE and S100B were measured using the enzyme-linked immunoassay method (ELISA). Results revealed a significant positive association between G3 patients and S100B serum expression (p = 0.0403). The serum levels of NSE were also significantly enhanced in the G3 group compared to the control (p < 0.0001) and G2 group (p < 0.0001). In addition, clinical features such as symptoms and oxygenation status were not correlated with NSE or S100B serum expression. The follow-up study demonstrated a decrease over time (21 days) in NSE serum expression (p < 0.0001). These results suggest that brain damage is followed by acute virus exposure, with no long-term effects. Future work examining COVID-19 recovery will shed light on chronic neurological damage of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Congenital Diaphragmatic Hernia (CDH) is a diaphragm defect associated with lung hypoplasia and ventilation inhomogeneity (VI). The affected neonates are usually born with respiratory failure and require mechanical ventilation after birth. However, significant interindividual VI differences make ventilation difficult. So far, there are no clinical methods of VI assessment that could be applied to optimize ventilation at the bedside. A new VI index is a ratio of time constants T1/T2 of gas flows in both lungs. Pressure-controlled ventilation simulations were conducted using an infant hybrid (numerical-physical) respiratory simulator connected to a ventilator. The parameters of the respiratory system model and ventilator settings were based on retrospective clinical data taken from three neonates (2, 2.6, 3.6 kg) treated in the Paediatric Teaching Clinical Hospital of the Medical University of Warsaw. We searched for relationships between respiratory system impedance (Z) and ventilation parameters: work of breathing (WOB), peak inspiratory pressure (PIP), and mean airway pressure (MAP). The study showed the increased VI described by the T1/T2 index value highly correlated with elevated Z, WOB, PIP and MAP (0.8–0.9, the Spearman correlation coefficients were significant at P < 0.001). It indicates that the T1/T2 index may help to improve the ventilation therapy of CDH neonates. [ABSTRACT FROM AUTHOR]

There is growing evidence that less invasive surfactant administration (LISA) is a better alternative to the standard Intubate-surfactant-extubate (InSurE) procedure in spontaneously breathing preterm infants with RDS. The infant feeding tube is easily available and cost-effective in comparison to special catheters used for surfactant administration in various studies on LISA and cost-effective health care is the need of the hour for countries like ours which are Low and middle-income countries(LMICs).The present study was planned to compare the total duration of respiratory support in preterm babies between 26 to 34 weeks of gestation with RDS requiring surfactant therapy administered by LISA technique using an infant feeding tube or InSurE method. In this unblinded randomised controlled trial, 150 infants were allocated to LISA (n = 74) or InSurE group (n = 76). An 8F feeding tube was used for surfactant delivery in the LISA group. The primary outcome was the total duration of respiratory support required and secondary outcomes included the proportion of babies developing BPD, IVH, PDA, NEC, ROP, air leaks, CPAP failure, and those requiring a repeat dose of surfactant along with the duration of hospitalization, time to regain birth weight and Death. The baseline variables including birth weight and gestation age were similar in the two groups. Nearly 27% of the mothers did not receive any dose of antenatal steroids (ANS) while around 37% of the mothers received complete course of ANS. A high proportion of babies (57%) were delivered by cesarean section. Intrapharyngeal reflux was significantly more in babies who received surfactant with the LISA method in comparison to InSurE technique (32% v/s 3%, p < 0.001). There was no statistically significant difference in the primary outcome of the total duration of respiratory support in both groups with a median duration of 120 h, 95% CI (69–235), and p = 0.618. The need for invasive mechanical ventilation was significantly lower in the LISA group (p = 0.017) with RR (95% CI) 0.498 (0.259–0.958). The rate of CPAP failure was significantly lower in the LISA group (p = 0.005) with RR (95% CI) 0.55 (0.34–0.89). In this study, the total duration of hospital stay was reduced in the LISA group (19 days) compared to InSurE group (26 days), although the same was not statistically significant. LISA with an 8F feeding tube is feasible and an effective strategy for surfactant administration which resulted in a significant reduction in CPAP failure and the need for invasive mechanical ventilation. Trial registration: www.ctri.nic.in id CTRI/2020/05/025360. Trial was registered at CTRI on 26/05/2020. First case of trial was enrolled on 28/05/2020. [ABSTRACT FROM AUTHOR]

Alveolar macrophages (AM) hold lung homeostasis intact. In addition to the defense against inhaled pathogens and deleterious inflammation, AM also maintain pulmonary surfactant homeostasis, a vital lung function that prevents pulmonary alveolar proteinosis. Signals transmitted between AM and pneumocytes of the pulmonary niche coordinate these specialized functions. However, the mechanisms that guide the metabolic homeostasis of AM remain largely elusive. We show that the NK cell-associated receptor, NKR-P1B, is expressed by AM and is essential for metabolic programming. Nkrp1b−/− mice are vulnerable to pneumococcal infection due to an age-dependent collapse in the number of AM and the formation of lipid-laden AM. The AM of Nkrp1b−/− mice show increased uptake but defective metabolism of surfactant lipids. We identify a physical relay between AM and alveolar type-II pneumocytes that is dependent on pneumocyte Clr-g expression. These findings implicate the NKR-P1B:Clr-g signaling axis in AM-pneumocyte communication as being important for maintaining metabolism in AM. Alveolar macrophages (AM) in the lungs maintain surfactant during homeostasis and respond to infectious pathogens. Here the authors show that in the absence of NKR-P1B, pneumococcal infection is more severe because KO AM have increased rates of lipid surfactant uptake and reduced anti-microbial function. [ABSTRACT FROM AUTHOR]

Although lung diseases typically result from long-term exposures, even a robust, one-time exposure can result in long-lasting consequences. Endotoxin is a ubiquitous environmental/occupational inflammatory agent often used to model airway inflammation. Using a murine model, the return to lung homeostasis following high dose inhalant lipopolysaccharide (LPS, 10–100 μg) exposure were delineated over 2 weeks. LPS-induced rapid weight loss, release of proinflammatory mediators, and inflammatory cell influx with prolonged persistence of activated macrophages CD11c+CD11b+ and recruited/transitioning CD11cintCD11b+ monocyte-macrophages out to 2 weeks. Next, lung-delivered recombinant (r) interleukin (IL)-10 was intratracheally administered for 3 doses initiated 5 h following LPS (10 μg) exposure for 2 days. IL-10 therapy reduced LPS-induced weight loss and increased blood glucose levels. Whereas there was no difference in LPS-induced bronchoalveolar lavage airway fluid cellular influx, total lung cell infiltrates were reduced (37%) with rIL-10 treatment. Post-LPS exposure treatment with rIL-10 strikingly reduced lavage fluid and lung homogenate levels of tumor necrosis factor-α (88% and 93% reduction, respectively), IL-6 (98% and 94% reduction), CXCL1 (66% and 75% reduction), and CXCL2 (47% and 67% reduction). LPS-induced recruited monocyte-macrophages (CD11cintCD11b+) were reduced (68%) with rIL-10. Correspondingly, LPS-induced lung tissue CCR2+ inflammatory monocyte-macrophage were reduced with rIL-10. There were also reductions in LPS-induced lung neutrophils, lymphocyte subpopulations, collagen content, and vimentin expression. These findings support the importance of studying resolution processes for the development of treatment after unintended environmental/occupational biohazard exposures. Short-term, lung-delivered rIL-10 favorably hastened inflammatory recovery processes following acute, high dose inhalant LPS exposure. [ABSTRACT FROM AUTHOR]

Introduction: Helmet noninvasive support may provide advantages over other noninvasive oxygenation strategies in the management of acute hypoxemic respiratory failure. In this narrative review based on a systematic search of the literature, we summarize the rationale, mechanism of action and technicalities for helmet support in hypoxemic patients. Main results: In hypoxemic patients, helmet can facilitate noninvasive application of continuous positive-airway pressure or pressure-support ventilation via a hood interface that seals at the neck and is secured by straps under the arms. Helmet use requires specific settings. Continuous positive-airway pressure is delivered through a high-flow generator or a Venturi system connected to the inspiratory port of the interface, and a positive end-expiratory pressure valve place at the expiratory port of the helmet; alternatively, pressure-support ventilation is delivered by connecting the helmet to a mechanical ventilator through a bi-tube circuit. The helmet interface allows continuous treatments with high positive end-expiratory pressure with good patient comfort. Preliminary data suggest that helmet noninvasive ventilation (NIV) may provide physiological benefits compared to other noninvasive oxygenation strategies (conventional oxygen, facemask NIV, high-flow nasal oxygen) in non-hypercapnic patients with moderate-to-severe hypoxemia (PaO2/FiO2 ≤ 200 mmHg), possibly because higher positive end-expiratory pressure (10–15 cmH2O) can be applied for prolonged periods with good tolerability. This improves oxygenation, limits ventilator inhomogeneities, and may attenuate the potential harm of lung and diaphragm injury caused by vigorous inspiratory effort. The potential superiority of helmet support for reducing the risk of intubation has been hypothesized in small, pilot randomized trials and in a network metanalysis. Conclusions: Helmet noninvasive support represents a promising tool for the initial management of patients with severe hypoxemic respiratory failure. Currently, the lack of confidence with this and technique and the absence of conclusive data regarding its efficacy render helmet use limited to specific settings, with expert and trained personnel. As per other noninvasive oxygenation strategies, careful clinical and physiological monitoring during the treatment is essential to early identify treatment failure and avoid delays in intubation. [ABSTRACT FROM AUTHOR]

The effect of Ni2+, a T-type low-threshold calcium channel (T-VDCC) and Na+/Ca2+ exchanger (NCX) blocker, on cardiac and respiratory rhythm parameters was studied in newborn rats aged 3–16 days (P3–16). A distinct age dependence of the intensity of the arrhythmogenic effect evoked by calcium channel blockade was found. In 3-day-old rats injected with NiCl2 at a dose of 109 mg/kg (ED100), a transient atypical heart rhythm, representing the alternating periods of moderate bradycardia with a pathologically slow (up to 20–60 bpm) heart rhythm, occurs in 100% of animals. In parallel, a pronounced respiratory system dysfunction with burst breathing develops. This symptom complex occurs in 75% of 10–14-day-old rats and is completely absent in 15–16-day-old animals. Phenomenologically similar heart rhythm disorders are observed in newborn rats after NiCl2 injection, during poisoning with acetylcholinesterase inhibitors, and upon activation of the central N-cholinergic structures. The obtained data suggest that in the early period of rat postnatal ontogenesis, impaired mechanisms of calcium metabolism may play a certain role in the development of arrhythmogenic disorders. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) is a broad heterogeneous group of lung disorders that is characterized by inflammation of the lungs. Surfactant dysfunction disorders are a rare form of ILD diseases that result from mutations in surfactant protein C gene (SFTPC) with prevalence of approximately 1/1.7 million births. SFTPC patients are presented with clinical manifestations of ILD ranging from fatal respiratory failure of newborn to chronic respiratory problems in children. In the current study, we aimed to investigate the spectrum of SFTPC genetic variants as well as the correlation of the SFTPC gene mutations with ILD disease in twenty unrelated Egyptian children with diffuse lung disease and suspected surfactant dysfunction using Sanger sequencing. Results: Sequencing of SFTPC gene revealed five variants: c.42+35G>A (IVS1+35G>A) (rs8192340) and c.43-21T>C (IVS1-21T>C) (rs13248346) in intron 1, c.436-8C>G (IVS4-8C>G) (rs2070687) in intron 4, c.413C>A p.T138N (rs4715) in exon 4, and c.557G>Ap.S186N (rs1124) in exon 5. Conclusion: The present study confirms the association of detecting variants of SFTPC with surfactant dysfunction disorders. [ABSTRACT FROM AUTHOR]

The scarce research about the worldwide used glyphosate-based herbicide Roundup is controversial in human reproduction, especially spermatozoa. This study investigates the in vitro effect in human spermatozoa of Roundup Ultra Plus (RUP), its active ingredient glyphosate and its non-active, surfactant. Human spermatozoa were incubated (1 h, 37 °C) in presence/absence of RUP 0.01%, glyphosate, or equivalent surfactant concentration. Motility and sperm parameters were analyzed by C.A.S.A and flow cytometry, respectively. RUP significantly increases sperm plasma membrane lipid disorganization in a concentration-dependent manner while it decreases plasma membrane integrity. RUP significantly increases the death spermatozoa population after A23187-induced acrosome reaction, without affecting sperm viability, mitochondrial membrane potential, ROS content, acrosome membrane damage, phosphatidylserine exposure, A23187-induced acrosome reaction or GSK3 phosphorylation. RUP also significantly decreases motile and the a + b sperm populations. Interestingly, all sperm effects caused by RUP 0.01% are mimicked by its surfactant POEA at equivalent concentration. However, glyphosate does not affect any sperm parameter, even using 10-times higher concentration than the RUP 0.01% equivalent. RUP disturbs lipid organization and integrity of human sperm plasma membrane and reduces motility, without affecting viability or functional parameters. Importantly, RUP adverse effects in human spermatozoa are caused by the surfactant and no by glyphosate. [ABSTRACT FROM AUTHOR]

Background: Models of hypoxemic lung injury caused by lavage-induced pulmonary surfactant depletion are prone to prompt recovery of blood oxygenation following recruitment maneuvers and have limited translational validity. We hypothesized that addition of injurious ventilation following surfactant-depletion creates a model of the acute respiratory distress syndrome (ARDS) with persistently low recruitability and higher levels of titrated "best" positive end-expiratory pressure (PEEP) during protective ventilation. Methods: Two types of porcine lung injury were induced by lung lavage and 3 h of either protective or injurious ventilation, followed by 3 h of protective ventilation (N = 6 per group). Recruitment maneuvers (RM) and decremental PEEP trials comparing oxygenation versus dynamic compliance were performed after lavage and at 3 h intervals of ventilation. Pulmonary gas exchange function, respiratory mechanics, and ventilator-derived parameters were assessed after each RM to map the course of injury severity and recruitability. Results: Lung lavage impaired respiratory system compliance (Crs) and produced arterial oxygen tensions (PaO2) of 84±13 and 80±15 (FIO2 = 1.0) with prompt increase after RM to 270–395 mmHg in both groups. After subsequent 3 h of either protective or injurious ventilation, PaO2/FIO2 was 104±26 vs. 154±123 and increased to 369±132 vs. 167±87 mmHg in response to RM, respectively. After additional 3 h of protective ventilation, PaO2/FIO2 was 120±15 vs. 128±37 and increased to 470±68 vs. 185±129 mmHg in response to RM, respectively. Subsequently, decremental PEEP titration revealed that Crs peaked at 36 ± 10 vs. 25 ± 5 ml/cm H2O with PEEP of 12 vs. 16 cmH2O, and PaO2/FIO2 peaked at 563 ± 83 vs. 334 ± 148 mm Hg with PEEP of 16 vs. 22 cmH2O in the protective vs. injurious ventilation groups, respectively. The large disparity of recruitability between groups was not reflected in the Crs nor the magnitude of mechanical power present after injurious ventilation, once protective ventilation was resumed. Conclusion: Addition of transitory injurious ventilation after lung lavage causes prolonged acute lung injury with diffuse alveolar damage and low recruitability yielding high titrated PEEP levels. Mimicking lung mechanical and functional characteristics of ARDS, this porcine model rectifies the constraints of single-hit lavage models and may enhance the translation of experimental research on mechanical ventilation strategies. [ABSTRACT FROM AUTHOR]

The most classic treatment recommended in the current chronic obstructive pulmonary disease (COPD) guidelines is glucocorticoid and β2 receptor agonist combination, such as salmeterol xinafoate and fluticasone propionate (Sal/Flu), causing many adverse reactions due to hormones. Magnesium isoglycyrrhizinate (MgIG) is an anti-inflammatory glycyrrhizic acid preparation for treating chronic inflammation, contributing to its structure is similar to steroidal anti-inflammatory drugs. In this study, we successfully established COPD rat model by endotracheal-atomized lipopolysaccharide exposure and cigarette smoke induction, as characterized by lung function decline. We discovered that salmeterol xinafoate/MgIG combination could alleviated lung inflammation infiltration, airway wall thickness (AWT) and the secretion of bronchial mucin MUC5AC of COPD rats more than salmeterol xinafoate, MgIG, or salmeterol xinafoate and fluticasone propionate treatment did, as well as reduced inflammatory cells (white blood cells, neutrophils and lymphocytes) accumulation in bronchoalveolar lavage fluid and decreased TNF-α, IL-6 and IL-1β production in the serum of COPD rats. Finally, we found that Moreover, the mechanism involved might be related to the suppression of JAK/STAT signaling pathway. Overall, our studies suggested that MgIG might be a potential alternative adjuvant drug for fluticasone propionate for the clinical treatment of patients with COPD. [ABSTRACT FROM AUTHOR]

To determine whether immigrant background and socioeconomic status were associated with increased risk to develop severe Coronavirus disease 2019 (COVID-19) requiring mechanical ventilation at the intensive care unit and to study their effects on 90-day mortality. Nationwide case–control study with personal-level data from the Swedish Intensive Care register linked with socioeconomic data from Statistics Sweden and comorbidity data from the national patient register. For each case of COVID-19 treated with mechanical ventilation at the intensive care unit (outcome), 10 population controls were matched for age, sex and area of residence. Logistic and Cox regression were used to study the association between the exposure (immigrant background, income and educational level) and 90-day mortality. In total, 4 921 cases and 49 210 controls were matched. In the adjusted model, the risk of severe COVID-19 was highest in individuals born in Asia (Odds ratio [OR] = 2.44, 95% confidence interval [CI] = 2.20–2.69), South America (OR = 2.34, 95% CI = 1.82–2.98) and Africa (OR = 2.11, 95% CI = 1.76–2.50). Post-secondary education was associated with a lower risk of severe COVID-19 (OR = 0.75, CI = 0.69–0.82) as was the highest (vs. lowest) income quintile (OR = 0.87, CI = 0.77–0.97). In the fully adjusted Cox-regression analysis birth region of Africa (OR 1.38, CI = 1.03–1.86) and high income (OR 0.75, CI 0.63–0.89) were associated with 90-day mortality. Immigrant background, educational level and income were independently associated with acquiring severe COVID-19 with need for mechanical ventilation. [ABSTRACT FROM AUTHOR]

Patients supported by mechanical ventilation require frequent invasive blood gas samples to monitor and adjust the level of support. We developed a transparent and novel blood gas estimation model to provide continuous monitoring of blood pH and arterial CO2 in between gaps of blood draws, using only readily available noninvasive data sources in ventilated patients. The model was trained on a derivation dataset (1,883 patients, 12,344 samples) from a tertiary pediatric intensive care center, and tested on a validation dataset (286 patients, 4030 samples) from the same center obtained at a later time. The model uses pairwise non-linear interactions between predictors and provides point-estimates of blood gas pH and arterial CO2 along with a range of prediction uncertainty. The model predicted within Clinical Laboratory Improvement Amendments of 1988 (CLIA) acceptable blood gas machine equivalent in 74% of pH samples and 80% of PCO2 samples. Prediction uncertainty from the model improved estimation accuracy by 15% by identifying and abstaining on a minority of high-uncertainty samples. The proposed model estimates blood gas pH and CO2 accurately in a large percentage of samples. The model's abstention recommendation coupled with ranked display of top predictors for each estimation lends itself to real-time monitoring of gaps between blood draws, and the model may help users determine when a new blood draw is required and delay blood draws when not needed. [ABSTRACT FROM AUTHOR]

Background: Despite the surge in use of extracorporeal membrane oxygenation (ECMO) in the adult intensive care unit, little guidance is available on the appropriate dosing of antimicrobials in this setting. Ceftriaxone is an antimicrobial with a high affinity to plasma protein, a property identified in the literature as susceptible to sequestration into extracorporeal circuits and hypothesised to require dosage adjustments in this setting. Objective: The aim of this study was to describe the pharmacokinetics of ceftriaxone and identify the best dosing regimen for critically ill adult patients receiving ECMO. Methods: Serial blood samples were taken from patients receiving both ECMO and ceftriaxone. Total and unbound drug concentrations were measured in plasma by chromatographic assay and analysed using a population pharmacokinetic approach with Pmetrics®. Dosing simulations were performed to identify the optimal dosing strategy: 60 and 100% of time with free (unbound) drug concentration exceeding the minimum inhibitory concentration (fT>MIC). Results: In total, 14 patients were enrolled, of which three were receiving renal replacement therapy (RRT). Total and unbound ceftriaxone was best described in a two-compartment model with total body weight, serum albumin concentrations, creatinine clearance (CrCL), and the presence of RRT included as significant predictors of pharmacokinetics. Patients not on RRT generated a mean renal clearance of 0.90 L/h, non-renal clearance of 0.33 L/h, and central volume of distribution of 7.94 L. Patients on RRT exhibited a mean total clearance of 1.18 L/h. ECMO variables were not significant predictors of ceftriaxone pharmacokinetics. Steady-state dosing simulations found that dosages of 1 g every 12 h and 2 g every 24 h achieved >90% probabilities of target attainment in patients with CrCL of 0 mL/min with RRT and 30 and 100 mL/min and various serum albumin concentrations (17 and 26 g/L). Conclusions: Dosing recommendations for critically ill adult patients not on ECMO appear to be sufficient for patients on ECMO. Patients exhibiting augmented renal clearance (> 130 mL/min) or treatment of less susceptible pathogens may require higher doses, which requires further investigation. [ABSTRACT FROM AUTHOR]

Neonates born through meconium-stained amniotic fluid (MSAF) are at increased risk of altered cardiopulmonary transition at birth. There is a paucity of literature evaluating the transitional hemodynamics in these neonates. We aimed to evaluate transitional hemodynamics via echocardiography in neonates born through MSAF, compared to healthy neonates. The primary objective was to assess pulmonary vascular resistance using left pulmonary artery-velocity time integral (LPA-VTI). The secondary objectives were to assess other pulmonary vascular parameters and myocardial function. We enrolled 35 MSAF-born and 35 healthy neonates. Echocardiography was performed at 24 and 48 h of life by a pediatric cardiologist. Echocardiographic parameters were compared between MSAF-born and healthy neonates, and between MSAF-born neonates who developed meconium aspiration syndrome (MAS) and who did not (non-MAS). Among 35 MSAF-born neonates, 14 (40%) were non-vigorous, 18 (51%) required admission to neonatal intensive care unit, 8 (23%) developed MAS, 3 (9%) pulmonary hypertension and 1 (3%) air leak. On echocardiography, LPA-VTI (cm; mean ± SD) was significantly decreased at 24 and 48 h in MSAF-born neonates (14.38 ± 2.48; 15.55 ± 2.48), compared to healthy neonates (16.60 ± 2.14; 17.66 ± 2.71), respectively. Further, LPA-VTI was significantly reduced at 24 and 48 h among MAS (11.81 ± 3.0; 12.43 ± 2.5), compared to non-MAS neonates (15.15 ± 1.72; 16.48 ± 1.55), respectively. Other pulmonary vascular and myocardial function parameters were comparable between the two groups. Pulmonary adaptation was significantly delayed in neonates with MSAF, which was more pronounced in MAS neonates. Further studies should explore the utility of these parameters for early prediction of cardiorespiratory morbidities in this population. [ABSTRACT FROM AUTHOR]

The effectiveness of noninvasive respiratory support in severe COVID-19 patients is still controversial. We aimed to compare the outcome of patients with COVID-19 pneumonia and hypoxemic respiratory failure treated with high-flow oxygen administered via nasal cannula (HFNC), continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV), initiated outside the intensive care unit (ICU) in 10 university hospitals in Catalonia, Spain. We recruited 367 consecutive patients aged ≥ 18 years who were treated with HFNC (155, 42.2%), CPAP (133, 36.2%) or NIV (79, 21.5%). The main outcome was intubation or death at 28 days after respiratory support initiation. After adjusting for relevant covariates and taking patients treated with HFNC as reference, treatment with NIV showed a higher risk of intubation or death (hazard ratio 2.01; 95% confidence interval 1.32–3.08), while treatment with CPAP did not show differences (0.97; 0.63–1.50). In the context of the pandemic and outside the intensive care unit setting, noninvasive ventilation for the treatment of moderate to severe hypoxemic acute respiratory failure secondary to COVID-19 resulted in higher mortality or intubation rate at 28 days than high-flow oxygen or CPAP. This finding may help physicians to choose the best noninvasive respiratory support treatment in these patients. Clinicaltrials.gov identifier: NCT04668196. [ABSTRACT FROM AUTHOR]

Using the Toponome Imaging System (TIS), a serial immunostainer, we studied the patterns of expression of multiple markers in alveolar macrophages (AM) from female mice lacking surfactant protein A (SP-A knockouts; KO) after "rescue" with exogenous SP-A1. We also used a 7-marker subset to compare with AM from males. AM were harvested 18 h after intrapharyngeal SP-A1 or vehicle, attached to slides, and subjected to serial immunostaining for 12 markers. Expression of the markers in each pixel of the image was analyzed both in the whole image and in individual selected cells. The marker combination in each pixel is referred to as a combinatorial molecular phenotype (CMP). A subset of antibodies was used to compare AM from male mice to the females. We found: (a) extensive AM heterogeneity in females by CMP analysis and by clustering analysis of CMPs in single cells; (b) AM from female KO mice respond to exogenous SP-A1 by increasing CMP phenotypic diversity and perhaps enhancing their potential innate immune capabilities; and (c) comparison of male and female AM responses to SP-A1 revealed that males respond more vigorously than females and clustering analysis was more effective in distinguishing males from females rather than treated from control. [ABSTRACT FROM AUTHOR]

For newborns suspected having childhood interstitial lung disease (ChILD), the sequencing of genes encoding surfactant proteins is recommended. However, it is still difficult to interpret the clinical significance of those variants found. We report a full-term born female infant who presented with respiratory distress and failure to thrive at 2 months of age and both imaging and lung biopsy were consistent with ChILD. Her genetic test was initially reported as a variant of unknown significance in surfactant protein C (c.202G > T, p.V68F), which was modified later as likely pathogenic after reviewing a report of the same variant as causing ChILD. The infant was placed on noninvasive ventilation and treated with IV Methylprednisolone, Hydroxychloroquine, and Azithromycin but did not show significant clinical and radiological improvement underwent tracheostomy and is awaiting lung transplantation at 8 months of age. The challenges interpreting the genetic results are discussed. [ABSTRACT FROM AUTHOR]

Background: Given the limited treatment options for younger children with attention-deficit/hyperactivity disorder (ADHD), a clinical study for SHP465 treatment was warranted. Objectives: We aimed to evaluate the pharmacokinetics, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) 6.25 mg after multiple once-daily doses in children aged 4–5 years with ADHD. Methods: In this open-label multicenter study, SHP465 MAS 6.25 mg once daily was administered for 28 days to children aged 4–5 years with ADHD; baseline ADHD Rating Scale-5 total score ≥ 28 (boys) or ≥ 24 (girls) and Clinical Global Impression-Severity scale score ≥ 4. Blood samples were collected in the pharmacokinetic-rich group predose on day 1 week 1 and day 7 week 4 (predose, postdose at 2, 5, 8, 12, 16, 24, and 48 hours); and in the pharmacokinetic-sparse group predose on day 1 weeks 1, 2, and 3 and 24 hours postdose on day 7 week 4. Key pharmacokinetic parameters included maximum plasma drug concentration (Cmax), plasma trough drug concentration, time to Cmax during a dosing interval (tmax), area under the concentration–time curve from time 0 to time of last collected sample, area under the concentration–time curve over the dosing interval (24 h) at steady state (AUCtau,ss), first-order rate constant associated with the terminal phase of elimination, terminal half-life (t1/2), total clearance of drug from plasma after oral administration, and apparent volume of distribution at steady state. Safety endpoints included treatment-emergent adverse events and vital signs. Results: Mean ± standard deviation age and body mass index of 24 participants (66.7% male) were 4.8 ± 0.41 years and 17.2 ± 3.18 kg/m2, respectively. The most common ADHD was the combined presentation (91.7%); ratings were 50% markedly ill and 45.8% moderately ill on the Clinical Global Impression-Severity scale. Plasma d-amphetamine and l-amphetamine steady state was attained by predose on treatment day 8, consistent with the half-life. Peak steady-state plasma concentration (median tmax) for both d-amphetamine and l-amphetamine occurred at 7.92 h postdose on day 7 week 4 and thereafter declined monoexponentially, with a geometric mean t1/2 of 10.4 and 12.3 h for d-amphetamine and l-amphetamine, respectively. For both d-amphetamine and l-amphetamine, Cmax and AUCtau,ss were comparable between children aged 4 years (n = 3) and children aged 5 years (n = 8) regardless of sex. In total, 14 treatment-emergent adverse events were reported by 45.8% (11/24) of participants. Five treatment-emergent adverse events, reported for four (16.7%) participants, were considered treatment related; affect lability occurred in two (8.3%) participants, and insomnia, accidental overdose, and increased blood pressure each occurred in one (4.2%) participant. Conclusions: In children aged 4–5 years with ADHD, following multiple once-daily administrations of SHP465 MAS 6.25 mg, the pharmacokinetic profile of plasma d-amphetamine and l-amphetamine was generally consistent among participants. Between-individual variability of plasma d-amphetamine and l-amphetamine steady-state exposure was low to moderate. SHP465 MAS was generally well tolerated in this study. Trial Registration: ClinicalTrials.gov, NCT03327402 (31 October, 2017). [ABSTRACT FROM AUTHOR]

Background: Perforated peptic ulcer is a life-threatening condition. Traditional treatment is surgery. Esophageal perforations and anastomotic leakages can be treated with endoscopically placed covered stents and drainage. We have treated selected patients with a perforated duodenal ulcer with a partially covered stent. The aim of this study was to compare surgery with stent treatment for perforated duodenal ulcers in a multicenter randomized controlled trial. Methods: All patients presenting at the ER with abdominal pain, clinical signs of an upper G-I perforation, and free air on CT were approached for inclusion and randomized between surgical closure and stent treatment. Age, ASA score, operation time, complications, and hospital stay were recorded. Laparoscopy was performed in all patients to establish diagnosis. Surgical closure was performed using open or laparoscopic techniques. For stent treatment, a per-operative gastroscopy was performed and a partially covered stent was placed through the scope. Abdominal lavage was performed in all patients, and a drain was placed. All patients received antibiotics and intravenous PPI. Stents were endoscopically removed after 2–3 weeks. Complications were recorded and classified according to Clavien-Dindo (C-D). Results: 43 patients were included, 28 had a verified perforated duodenal ulcer, 15 were randomized to surgery, and 13 to stent. Median age was 77.5 years (23–91) with no difference between groups. ASA score was unevenly distributed between the groups (p = 0.069). Operation time was significantly shorter in the stent group, 68 min (48–107) versus 92 min (68–154) (p = 0.001). Stents were removed after a median of 21 days (11–37 days) without complications. Six patients in the surgical group had a complication and seven patients in the stent group (C-D 2–5) (n.s.). Conclusions: Stent treatment together with laparoscopic lavage and drainage offers a safe alternative to traditional surgical closure in perforated duodenal ulcer. A larger sample size would be necessary to show non-inferiority regarding stent treatment. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to describe the efficacy and safety of furosemide and chlorothiazide combination continuous infusion (FCCCI) in children in a pediatric intensive care unit (ICU), including postoperative cardiac patients. Methods: This was a retrospective cohort study in a pediatric ICU within a tertiary care teaching hospital. Children aged < 18 years admitted from 1 January 2010 to 31 December 2019 were included if they received a furosemide infusion for at least 6 h and then transitioned to FCCCI. Each patient acted as their own control. Results: A total of 203 patients (107 [53%] postoperative cardiac) met the study inclusion criteria. The study population was 55% male and 74% Caucasian, with a median age of 4.9 months. Of the total patients, 143 (70.4%) required mechanical ventilation and 39 (19.2%) required dialysis. The median duration of furosemide and FCCCI was 24.6 h (interquartile range [IQR] 12.4–54) and 41 h (IQR 15–162), respectively. Urine output increased by 52% with FCCCI (mean increase of 2.2 mL/kg/h [95% confidence interval {CI} 1.8–2.5]; p < 0.01). The change to FCCCI led to a net negative daily fluid balance (mean difference − 301.9 mL/day [95% CI − 390.9 to − 212.9]; p < 0.01). FCCCI resulted in a greater requirement for potassium bolus supplementation (mean increase of 12.8 boluses [95% CI 8.5–17.2]; p < 0.01) and a small but statistically significant increase in serum creatinine (mean difference 0.1 mg/dL [95% CI 0.06–0.14]; p < 0.01) with a resultant decrease in estimated glomerular filtration rate (mean difference − 13.5 [95% CI 9.7–17.4]; p < 0.01). Of the furosemide-refractory patients, 78.9% were responsive to FCCCI. Younger patients and patients who underwent cardiothoracic surgery were more likely to be responsive. Nonresponders to FCCCI had slightly higher mortality (21 vs. 6.6%, p = 0.05). Conclusions: FCCCI resulted in a significant improvement in diuresis with achievement of negative fluid balance in pediatric ICU patients. FCCCI is a reasonable approach to aggressive diuresis in the pediatric patient, particularly in patients with limited access. Serum potassium should be routinely monitored during such therapy. [ABSTRACT FROM AUTHOR]

For instance, some clinicians initially believed that reducing labor pain by LNA increased cesarean delivery rate [[1]]; LNA induced maternal fever, well known as "epidural fever", which was thought to result from intrauterine infection [[3]]; prolonged labor by LNA increased incidence of postpartum hemorrhage [[4]]. Classical LNA consumed semi-surgical concentrated local anesthetics (bupivacaine 0.25% or ropivacaine 0.3%) for maintaining labor analgesia and produced motor blockade during labor, which interfered pushing in the second stage of labor, resulting in failure to progress and cesarean section. LNA in the early days did increase the cesarean delivery rate. Labor neuraxial analgesia (LNA) is a gold standard for managing labor pain in the modern world. [Extracted from the article]

Refractory cardiogenic shock (CS) often requires veno-arterial extracorporeal membrane oxygenation (VA-ECMO) to sustain end-organ perfusion. Current animal models result in heterogenous cardiac injury and frequent episodes of refractory ventricular fibrillation. Thus, we aimed to develop an innovative, clinically relevant, and titratable model of severe cardiopulmonary failure. Six sheep (60 ± 6 kg) were anaesthetized and mechanically ventilated. VA-ECMO was commenced and CS was induced through intramyocardial injections of ethanol. Then, hypoxemic/hypercapnic pulmonary failure was achieved, through substantial decrease in ventilatory support. Echocardiography was used to compute left ventricular fractional area change (LVFAC) and cardiac Troponin I (cTnI) was quantified. After 5 h, the animals were euthanised and the heart was retrieved for histological evaluations. Ethanol (58 ± 23 mL) successfully induced CS in all animals. cTnI levels increased near 5000-fold. CS was confirmed by a drop in systolic blood pressure to 67 ± 14 mmHg, while lactate increased to 4.7 ± 0.9 mmol/L and LVFAC decreased to 16 ± 7%. Myocardial samples corroborated extensive cellular necrosis and inflammatory infiltrates. In conclusion, we present an innovative ovine model of severe cardiopulmonary failure in animals on VA-ECMO. This model could be essential to further characterize CS and develop future treatments. [ABSTRACT FROM AUTHOR]

Background: The role of gastric lavage in neonates delivered through meconium-stained amniotic fluid remains unclear. Objective: This study evaluated the effects of gastric lavage, compared to no gastric lavage, on the incidences of feeding intolerance, respiratory distress, meconium aspiration syndrome, time to establish breastfeeding, hospitalization and procedure-related complications in late-preterm and term neonates delivered through meconium-stained amniotic fluid. Design: Systematic review and meta-analysis. Data sources and selection criteria: MEDLINE, EMBASE, CENTRAL, and other databases were searched for randomized controlled trials and quasi-randomized controlled trials using search terms: neonate OR newborn infant, meconium OR meconium-stained amniotic fluid, and lavage OR gastric lavage from inception to May 2020. Data were pooled in RevMan and analyzed in GRADE. Results: Pooled effects (9 randomized controlled trials, number=3668), showed a significant reduction in the incidence of feeding intolerance (relative risk 0.70; 95% confidence interval 0.58,0.85, I2=0) after gastric lavage. No difference was observed for the incidence of meconium aspiration syndrome (4 studies) or procedure-related complications (7 studies). Only one study, reporting the proportion of neonates with low oxygenation (SpO2<85%), did not find any significant difference. No study evaluated the effects of gastric lavage on respiratory distress, breastfeeding, and hospitalization. Conclusions: Low-quality evidence supported the role of gastric lavage for the prevention of feeding intolerance in late-preterm and term neonates born through meconium-stained amniotic fluid. Applicability of results was limited by the high risk of bias. Well-conducted randomized controlled trials with impor-tant patient outcomes are needed before recommending the practice of gastric lavage. [ABSTRACT FROM AUTHOR]

We recently documented that cardiopulmonary resuscitation (CPR) generates the same level of cardiac output (CO) and mean arterial pressure (MAP) during both normothermia (38 °C) and hypothermia (27 °C). Furthermore, continuous CPR at 27 °C provides O2 delivery (ḊO2) to support aerobic metabolism throughout a 3-h period. The aim of the present study was to investigate the effects of extracorporeal membrane oxygenation (ECMO) rewarming to restore ḊO2 and organ blood flow after prolonged hypothermic cardiac arrest. Eight male pigs were anesthetized and immersion cooled to 27 °C. After induction of hypothermic cardiac arrest, CPR was started and continued for a 3-h period. Thereafter, the animals were rewarmed with ECMO. Organ blood flow was measured using microspheres. After cooling with spontaneous circulation to 27 °C, MAP and CO were initially reduced to 66 and 44% of baseline, respectively. By 15 min after the onset of CPR, there was a further reduction in MAP and CO to 42 and 25% of baseline, respectively, which remained unchanged throughout the rest of 3-h CPR. During CPR, ḊO2 and O2 uptake (V̇O2) fell to critical low levels, but the simultaneous small increase in lactate and a modest reduction in pH, indicated the presence of maintained aerobic metabolism. Rewarming with ECMO restored MAP, CO, ḊO2, and blood flow to the heart and to parts of the brain, whereas flow to kidneys, stomach, liver and spleen remained significantly reduced. CPR for 3-h at 27 °C with sustained lower levels of CO and MAP maintained aerobic metabolism sufficient to support ḊO2. Rewarming with ECMO restores blood flow to the heart and brain, and creates a "shockable" cardiac rhythm. Thus, like continuous CPR, ECMO rewarming plays a crucial role in "the chain of survival" when resuscitating victims of hypothermic cardiac arrest. [ABSTRACT FROM AUTHOR]

Less invasive surfactant administration (LISA) has become increasingly popular in neonatal intensive care units (NICUs), but there are currently no guidelines for the premedication prior to this procedure. The aim of this observational study was to compare the efficacy and tolerance of intravenous administrations of ketamine and propofol before LISA in neonates born before 30 weeks of gestational age (GA). The primary outcome was requirement of intubation within 2 h of the procedure. One hundred and fourteen infants, with respective GA and birthweight of 27.6 (26.4, 28.7) weeks and 940 (805, 1140) g, were prospectively included from January 2016 to December 2019. Drug doses were 1 (0.5, 1) mg/kg for ketamine and 1 (1, 1.9) mg/kg for propofol, providing comparable comfort during LISA (p = 0.61). Rates of intubation within 2 h were 5/52 after ketamine, and 5/62 after propofol [aOR 0.54 (0.11–2.68)]. No difference was observed for rates of intubation at 24 h and 72 h following LISA, mortality, or severe morbidity. Conclusion: Pending results from prospective trials, these findings suggest that ketamine or propofol can be used for premedication before LISA, as they show comparable efficacy and tolerance. Trial registration: This study was recorded on the National Library of Medicine registry (https:// clinicaltrials.gov/ Identifier: NCT03705468). What is Known? • Less invasive surfactant administration (LISA) is increasingly used in spontaneously breathing premature infants supported with continuous positive airway pressure, but few data are available to guide adequate premedication for this procedure. What is New? • This observational study of 114 neonates, all less than 30-week gestational age and requiring surfactant without endotracheal tube in the delivery room, suggested that ketamine or propofol can be used for premedication before LISA with comparable efficacy and tolerance. [ABSTRACT FROM AUTHOR]

Foetal hypoxia–ischaemia is a key trigger of meconium aspiration syndrome (MAS). However, many neonates develop MAS without evidence of hypoxia–ischaemia, suggesting the presence of covert but important risk variables. We evaluated the association of MAS with clinical variables, placental histopathologic findings, and inflammatory biomarkers at birth. Of 1336 symptomatic and asymptomatic term singleton neonates with meconium-stained amniotic fluid, 88 neonates (6.6%) developed MAS. Univariate analysis showed that MAS development was associated with low 1- and 5-min Apgar scores, low cord blood pH, funisitis, higher α1-acid glycoprotein levels, and higher haptoglobin levels (all p < 0.001 except for p = 0.001 for haptoglobin). Associations of MAS with caesarean delivery (p = 0.004), premature rupture of the membranes (p = 0.006), chorioamnionitis (p = 0.007), and higher C-reactive protein levels (p = 0.008) were lost when adjusted for multiple comparisons. The final multivariate model to explain MAS development comprised lower cord blood pH (odds ratio [OR] 0.58; 95% confidence interval [CI] 0.47–0.73; p < 0.001), funisitis (OR 2.45; 95% Cl 1.41–4.26; p = 0.002), and higher α1-acid glycoprotein levels (OR 1.02; 95% Cl 1.01–1.03; p = 0.001). Our data from a large cohort of neonates suggested that intrauterine inflammation is one of the key independent variables of MAS development, together with foetal hypoxia–ischaemia. [ABSTRACT FROM AUTHOR]