The mother-child interface: A neurobiological metamorphosis.

From the start of pregnancy, mother and child induce reciprocal neurobiological changes in the brain that will prove critical for neurodevelopment and survival of both. Molecular communication between mother and fetus is constantly active and persists even after the fetus starts to synthesize its hormones in late gestation. Intriguingly, some mother and fetus exchange cells remain in the other's brain and body with long-lasting effects and memories that do not follow the laws of classical genetics but involve complex epigenetic mechanisms. After childbirth, mother and child go through a transitional phase, a sort of limbo in which both will have a peculiar functioning profile, which is adaptive for contingencies but also renders them vulnerable. The interplay between these two "limbo" states allows for an easier transition to the subsequent phases of development. In this review, we will trace mother's and child's path from pregnancy to the months following birth and, in particular, unravel i) the key features of pregnancy and brain development and the reciprocal influences; ii) how a transitory pattern of functioning characterize mother and child, moving them toward more flexible and evolved forms; and iii) how mother and fetus act during childbirth to promote neuroprotection, pain reduction, and neurophysiological changes. Therefore, this review covers a wide range of topics, integrating neuroanatomical, neurological, biochemical, neurophysiological, and psychological studies in a meaningful way, trying to integrate them in a holistic view of the mother-child interface that is usually neglected.

Postoperative Outcomes of Fontan Operation in a Multicenter Italian Study. How Far Have We Gone? Early Outcomes After Fontan Operation.

Despite the clinical results of the Fontan operation have certainly improved, it still presents with an inherent surgical risk of death and early morbidities. This is a retrospective clinical study of children undergoing Fontan operation in 9 congenital cardiac centers in Italy between 1990 and 2023. Clinical and surgical data were collected via a dedicated RedCap database. Primary outcome was cohort's mortality, also considering different decades, while secondary outcomes were postoperative complications and reintervention. In the last 3 decades, there were 897 patients undergoing Fontan operation, M/F 512/384, median age: 4.5 years (IQR 3.3-6.4), median weight 16 kg (IQR 14-22). A first palliation was deemed necessary in 710 patients (80%), and most patients underwent a staged Fontan (93%); an extracardiac conduit was used in 790 patients (88%). Postoperative complications (mild to severe) occurred in 410 patients (46%), and early reinterventions were required in 66 patients (7.5%). Overall operative mortality was 1.7% (15 patients). Age at Fontan greater than 4 years was associated with an early need for transcatheter reintervention (adj p value = 0.037) and a higher incidence of postoperative complications (adj p value = 0.017). The Fontan operation has seen significant improvements in immediate outcomes, notably a remarkable reduction in overall mortality to just 1.35% in the last decade. While minor complications have remained steady, there has been a substantial decrease in major early complications, deaths, and the need for reinterventions. Notably, patients aged over 4 years seem to face a higher risk of postoperative morbidity, underscoring the critical role of age in preoperative assessment and management strategies for Fontan patients.

Is There a Link between Chronic Obstructive Pulmonary Disease and Lung Adenocarcinoma? A Clinico-Pathological and Molecular Study.

Chronic Obstructive Pulmonary Disease (COPD) and lung cancer are strictly related. To date, it is unknown if COPD-associated cancers are different from the tumors of non-COPD patients. The main goal of the study was to compare the morphological/molecular profiles of lung adenocarcinoma (LUAD) samples of COPD, non-COPD/smokers and non-COPD/non-smokers, and to investigate if a genetic instability also characterized non-pathological areas. This study included 110 patients undergoing surgery for a LUAD, divided into three groups: COPD/smoker LUAD (38), non-COPD/smoker LUAD (54) and non-COPD/non-smoker LUAD (18). The tissue samples were systemically evaluated by pathologists and analyzed using a 30-gene Next Generation Sequencing (NGS) panel. In a subset of patients, tissues taken far from the neoplasia were also included. The non-COPD/smoker LUAD were characterized by a higher proliferative index (p = 0.001), while the non-COPD/non-smoker LUAD showed higher percentages of lepidic pattern (p = 0.008), lower necrosis, higher fibrosis, and a significantly lower mutation rate in the KRAS and PIK3CA genes. Interestingly, the same gene mutations were found in pathological and normal areas exclusively in the COPD/smokers and non-COPD/smokers. COPD/smoker LUAD seem to be similar to non-COPD/smoker LUAD, particularly for the genetic background. A less aggressive cancer phenotype was confirmed in non-COPD/non-smokers. The genetic alterations detected in normal lungs from smokers with and without COPD reinforce the importance of screening to detect early neoplastic lesions.

Global and Regional Heterogeneity of Lung Aeration in Neonates with Different Respiratory Disorders: A Physiologic Observational Study.

BACKGROUND: Aeration heterogeneity affects lung stress and influences outcomes in adults with acute respiratory distress syndrome (ARDS). The authors hypothesize that aeration heterogeneity may differ between neonatal respiratory disorders and is associated with oxygenation, so its evaluation may be relevant in managing respiratory support. METHODS: This was an observational prospective study. Neonates with respiratory distress syndrome, transient tachypnea of the neonate, evolving bronchopulmonary dysplasia, and neonatal ARDS were enrolled. Quantitative lung ultrasound and transcutaneous blood gas measurements were simultaneously performed. Global aeration heterogeneity (with its intra- and interpatient components) and regional aeration heterogeneity were primary outcomes; oxygenation metrics were the secondary outcomes. RESULTS: A total of 230 (50 respiratory distress syndrome, transient tachypnea of the neonate or evolving bronchopulmonary dysplasia, and 80 neonatal ARDS) patients were studied. Intrapatient aeration heterogeneity was higher in transient tachypnea of the neonate (mean ± SD, 61 ± 33%) and evolving bronchopulmonary dysplasia (mean ± SD, 57 ± 20%; P < 0.001), with distinctive aeration distributions. Interpatient aeration heterogeneity was high for all disorders (Gini-Simpson index, between 0.6 and 0.72) except respiratory distress syndrome (Gini-Simpson index, 0.5), whose heterogeneity was significantly lower than all others (P < 0.001). Neonatal ARDS and evolving bronchopulmonary dysplasia had the most diffuse injury and worst gas exchange metrics. Regional aeration heterogeneity was mostly localized in the upper anterior and posterior zones. Aeration heterogeneity and total lung aeration had an exponential relationship (P < 0.001; adj-R2 = 0.62). Aeration heterogeneity is associated with greater total lung aeration (i.e., higher heterogeneity means a relatively higher proportion of normally aerated lung zones, thus greater aeration; P < 0.001; adj-R2 = 0.83) and better oxygenation metrics upon multivariable analyses. CONCLUSIONS: Global aeration heterogeneity and regional aeration heterogeneity differ among neonatal respiratory disorders. Transient tachypnea of the neonate and evolving bronchopulmonary dysplasia have the highest intrapatient aeration heterogeneity. Transient tachypnea of the neonate, evolving bronchopulmonary dysplasia, and neonatal ARDS have the highest interpatient aeration heterogeneity, but the latter two have the most diffuse injury and worst gas exchange. Higher aeration heterogeneity is associated with better total lung aeration and oxygenation.

New Insights into Pediatric Kidney Transplant Rejection Biomarkers: Tissue, Plasma and Urine MicroRNAs Compared to Protocol Biopsy Histology.

The early identification of a subclinical rejection (SCR) can improve the long-term outcome of the transplanted kidney through intensified immunosuppression. However, the only approved diagnostic method is the protocol biopsy, which remains an invasive method and not without minor and/or major complications. The protocol biopsy is defined as the sampling of allograft tissue at pre-established times even in the absence of an impaired renal function; however, it does not avoid histological damage. Therefore, the discovery of new possible biomarkers useful in the prevention of SCR has gained great interest. Among all the possible candidates, there are microRNAs (miRNAs), which are short, noncoding RNA sequences, that are involved in mediating numerous post-transcriptional pathways. They can be found not only in tissues, but also in different biological fluids, both as free particles and contained in extracellular vesicles (EVs) released by different cell types. In this study, we firstly performed a retrospective miRNA screening analysis on biopsies and serum EV samples of 20 pediatric transplanted patients, followed by a second screening on another 10 pediatric transplanted patients' urine samples at one year post-transplant. In both cohorts, we divided the patients into two groups: patients with histological SCR and patients without histological SCR at one year post-transplantation. The isolated miRNAs were analyzed in an NGS platform to identify different expressions in the two allograft states. Although no statistical data were found in sera, in the tissue and urinary EVs, we highlighted signatures of miRNAs associated with the histological SCR state.

Assessing the role of phosphorylated S6 ribosomal protein in the pathological diagnosis of pulmonary antibody-mediated rejection.

BACKGROUND: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients. METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed. RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%. CONCLUSIONS: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.

Prospective assessment of early developmental markers and their association with neuropsychological impairment.

Children who experience adversities in the pre-perinatal period are at increased risk of developing impairment later in life, despite the absence of overt brain and neurological abnormalities. However, many of these children exhibit sequelae several years after a period of normal appearance. As a result, the need for reliable developmental assessments for the early detection of infants at high risk of adverse neurodevelopmental outcomes has emerged. The Griffiths Mental Developmental Scales have a promising but poorly explored prognostic ability. This longitudinal study evaluated the predictive power of the Griffiths Mental Developmental Scales at 12 and 24 months on the cognitive and neuropsychological profile at 6 years of age in a sample of 70 children with a history of prematurity or perinatal asphyxia but without brain and neurological abnormalities. We found that the Griffiths Mental Developmental Scales at 24 months had good predictive ability on the intelligence quotient at 6 years and the capacity to predict some neuropsychological performances. On the other hand, the Griffiths Mental Developmental Scale at 12 months was not associated with the performance at 6 years or 24 months.   Conclusion: Data on brain development converge to indicate that the first two years of age represent a critical stage of development, particularly for children experiencing mild pre-perinatal adversities who are thought to exhibit white matter dysmaturity. For this reason, this age is crucial for identifying which children are at major risk, leaving enough time to intervene before overt deficits become apparent. Brain development in the first 2 years could explain the limited reliability of early neurodevelopmental testing. What is Known: • Pre-perinatal adversities increase the risk of developing neurodevelopmental disorders. • The predictive ability of the Griffith scale is poorly explored in low-grade conditions. What is New: • The predictive ability of the Griffith scale has been investigated in low-risk children. • A complete neuropsychological profile could offer a more accurate prediction than the intellectual quotient.

Tricuspid Valve Repair Can Restore the Prognosis of Patients with Hypoplastic Left Heart Syndrome and Tricuspid Valve Regurgitation: A Meta-analysis.

To date, evidence supporting the efficacy of tricuspid valve (TV) repair in interrupting the progression of systemic right ventricular (RV) adverse remodeling in hypoplastic left heart syndrome (HLHS) is conflicting. We conducted a systematic review and meta-analysis of scientific literature to assess the impact of TV repair in effectively modifying the prognosis of patients with HLHS. We conducted a systematic review of PubMed, Web of Science, and Scopus databases. A random-effect meta-analysis was performed and transplant-free survival, freedom from TV regurgitation, and TV reoperation data were reconstructed using the published Kaplan-Meier curves. Nine studies were included, comprising 203 HLHS patients undergoing TV repair and 323 HLHS controls. The estimated transplant-free survival at 1, 5, and 10 years of follow-up was 75.5% [95% confidence interval (CI) = 67.6-84.3%], 63.6% [95% CI = 54.6-73.9%], and 61.9% [95% CI = 52.7-72.6%], respectively. Transplant-free survival was comparable to HLHS peers without TV regurgitation (p = 0.59). Five-year freedom from recurrence of TV regurgitation and freedom from TV reoperation was 57% [95% CI = 46.7-69.7%] and 63.6% [95% CI = 54.5-74.3%], respectively. Younger age and TV repair at the time of Norwood operation increased the risk of TV regurgitation recurrence and the need for TV reoperation. Our meta-analysis supports the efficacy of TV repair in favorably modifying the prognosis of patients with HLHS and TV regurgitation, reestablishing a medium-term transplant-free survival which is comparable to HLHS peers. However, durability of surgery and long-term fate of TV and RV performance are still unclear.

Chest pain in cardiac amyloidosis: occurrence, causes and prognostic significance.

BACKGROUND: Chest pain is experienced by patients with cardiac amyloidosis (CA), but a systematic investigation of its frequency, underlying etiologies and clinical significance is lacking. METHODS: Clinical, echocardiographic, laboratory characteristics, available coronary arteries imaging and endomyocardial biopsy (EMB) findings of 174 patients with CA (n = 104 with transthyretin, ATTR; n = 70 with light chains, AL) were analyzed. RESULTS: Chest pain was reported in 66 (38%) CA patients. Compared to those without, patients with chest pain had more frequently a history of coronary artery disease (CAD) (27% vs 15%, p = 0.048) and heart failure (HF) symptoms (62% vs 43%, p = 0.015), higher high sensitivity troponin I (hs-cTnI, 101 vs 65 ng/L, p = 0.032) and higher brain natriuretic peptide (597 vs 407 ng/L, p = 0.024). Among CA patients with chest pain undergoing coronary arteries imaging (n = 37), obstructive CAD was detected in 14 (38%), 13 of whom with ATTR-CA. Of these 37 patients, EMB was available in 10 and vascular/perivascular amyloid deposition was detected in 4/5 (80%) of AL-CA patients and 1/5 ATTR-CA. Among patients with suspected acute coronary syndrome (n = 22), obstructive CAD was detected in 9/17 (53%) ATTR-CA and 0/5 AL-CA; hs-cTnI levels were similar between those with and without obstructive CAD. During a follow-up of 17 (8-34) months, chest pain was a significant predictor of HF hospitalization (HR1.86, 95% CI 1.02-3.39, p = 0.042), even after adjustment for CA subtype and CAD. CONCLUSION: Chest pain is a common symptom in patients with CA, reflects a more advanced cardiac impairment and predicts future HF hospitalization. The etiology of chest pain seems to differ, with obstructive CAD more frequent in ATTR-CA whilst amyloid vascular/perivascular involvement more common in AL-CA.

Comprehensive bronchoalveolar lavage characterization in COVID-19 associated acute respiratory distress syndrome patients: a prospective cohort study.

COVID-19-related acute respiratory distress syndrome (CARDS) is associated with high mortality rates. We still have limited knowledge of the complex alterations developing in the lung microenvironment. The goal of the present study was to comprehensively analyze the cellular components, inflammatory signature, and respiratory pathogens in bronchoalveolar lavage (BAL) of CARDS patients (16) in comparison to those of other invasively mechanically ventilated patients (24). In CARDS patients, BAL analysis revealed: SARS-CoV-2 infection frequently associated with other respiratory pathogens, significantly higher neutrophil granulocyte percentage, remarkably low interferon-gamma expression, and high levels of interleukins (IL)-1ß and IL-9. The most important predictive variables for worse outcomes were age, IL-18 expression, and BAL neutrophilia. To the best of our knowledge, this is the first study that was able to identify, through a comprehensive analysis of BAL, several aspects relevant to the complex pathophysiology of CARDS.

Vascular/epithelial changes as late sequelae after recovery from SARS-COV-2 infection: an in-vivo comparative study.

AIMS: While there is partial evidence of lung lesions in patients suffering from long COVID there are substantial concerns about lung remodelling sequelae after COVID-19 pneumonia. The aim of the present retrospective comparative study was to ascertain morphological features in lung samples from patients undergoing tumour resection several months after SARS-CoV-2 infection. METHODS AND RESULTS: The severity of several lesions with a major focus on the vascular bed was analysed in 2 tumour-distant lung fragments of 41 cases: 21 SARS-CoV-2 (+) lung tumour (LT) patients and 20 SARS-CoV-2 (-) LT patients. A systematic evaluation of several lesions was carried out by combining their scores into a grade of I-III. Tissue SARS-CoV-2 genomic/subgenomic transcripts were also investigated. Morphological findings were compared with clinical, laboratory and radiological data. SARS-CoV-2 (+) LT patients with previous pneumonia showed more severe parenchymal and vascular lesions than those found in SARS-CoV-2 (+) LT patients without pneumonia and SARS-CoV-2 (-) LT patients, mainly when combined scores were used. SARS-CoV-2 viral transcripts were not detected in any sample. SARS-CoV-2 (+) LT patients with pneumonia showed a significantly higher radiological global injury score. No other associations were found between morphological lesions and clinical data. CONCLUSIONS: To our knowledge, this is the first study that, after a granular evaluation of tissue parameters, detected several changes in lungs from patients undergoing tumour resection after SARS-CoV-2 infection. These lesions, in particular vascular remodelling, could have an important impact overall on the future management of these frail patients.

Nasopharyngeal SARS-CoV-2 load and perinatal outcomes after maternal infection diagnosed close to delivery.

BACKGROUND: The occurrence of COVID-19 during the pregnancy can cause several negative maternal and neonatal outcomes. Nasopharyngeal viral load is associated with inflammatory markers and might influence the disease severity in non-pregnant patients, but there are no data about the relationship between viral load and perinatal outcomes in pregnant patients. OBJECTIVE: To investigate the hypothesis that nasopharyngeal SARS-CoV-2 load (estimated with real-time polymerase chain reaction delta cycle (ΔCt), measured in hospital clinical laboratories) is associated with perinatal outcomes, when COVID-19 is diagnosed in the third trimester of pregnancy. STUDY DESIGN: International, retrospective, observational, multi-center, cohort study enrolling 390 women (393 neonates, three pairs of twins), analyzed with multivariate generalized linear models with skewed distributions (gamma) and identity link. The analyses were conducted for the whole population and then followed by a subgroup analysis according to the clinical severity of maternal COVID-19. RESULTS: The estimated viral load in maternal nasopharynx is not significantly associated with gestational age at birth (adjusted B: -0.008 (95%CI: -0.04; 0.02); p = 0.889), birth weight (adjusted B: 4.29 (95%CI: -25; 35); p = 0.889), weight Z-score (adjusted B: -0.01 (95%CI: -0.03; 1); p = 0.336), 5' Apgar scores (adjusted B: -0. -9.8e-4 (95%CI: -0.01; 0.01); p = 0.889), prematurity (adjusted OR: -0.97 (95%CI: 0.93; 1.03); p = 0.766) and the small for gestational age status (adjusted OR: 1.03 (95%CI: 0.99; 1.07); p = 0.351). Similar results were obtained in subgroup analyses according to COVID-19 clinical severity. CONCLUSIONS: The estimated maternal nasopharyngeal viral load in pregnant women affected by COVID-19 during the third trimester is not associated with main perinatal outcomes.

Voice Parameters in Children With Cochlear Implants: A Systematic Review and Meta-Analysis.

INTRODUCTION: An intact auditory system is essential for the development and maintenance of voice quality and speech prosody. On the contrary hearing loss affects the adjustments and appropriate use of organs involved in speech and voice production. Spectro-acoustic voice parameters have been evaluated in Cochlear Implant (CI) users, and the authors of previous systematic reviews on the topic concluded that fundamental frequency (F0) seemed preliminarily the most reliable parameter to evaluate voice alterations in adult CI users. The main aim of this systematic review and meta-analysis was to clarify the vocal parameters and prosodic alterations of speech in pediatric CI users. MATERIALS AND METHODS: The protocol of the systematic review was registered on the PROSPERO database, International prospective register of systematic reviews. We conducted a search of the English literature published in the period between January 1, 2005 and April 1, 2022 on the Pubmed and Scopus databases. A meta-analysis was conducted to compare the values of voice acoustic parameters in CI users and non-hearing-impaired controls. The analysis was conducted using the standardized mean difference as the outcome measure. A random-effects model was fitted to the data. RESULTS: A total of 1334 articles were initially evaluated using title and abstract screening. After applying inclusion/exclusion criteria, 20 articles were considered suitable for this review. The age of the cases ranged between 25 and 132 months at examination. The most studied parameters were F0, Jitter, Shimmer and Harmonics-to-Noise Ratio (HNR); other parameters were seldom reported. A total of 11 studies were included in the meta-analysis of F0, with the majority of estimates being positive (75%); the estimated average standardized mean difference based on the random-effects model was 0.3033 (95% CI: 0.0605 to 0.5462; P = 0.0144). For Jitter (0.2229; 95% CI: -0.1862 to 0.7986; P = 0.2229) and shimmer (0.2540; 95% CI: -0.1404 to 0.6485; P = 0.2068) there was a trend toward positive values without reaching statistical significance. DISCUSSION AND CONCLUSIONS: This meta-analysis confirmed that higher F0 values have been observed in the pediatric population of CI users compared to age-matched normal hearing volunteers, whereas the parameters of voice noise were not significantly different between cases and controls. Prosodic aspects of language need further investigations. In longitudinal contexts, prolonged auditory experience with CI has brought voice parameters closer to the norm. Following the available evidence, we stress the utility of inclusion of vocal acoustic analysis in the clinical evaluation and follow-up of CI patients to optimize the rehabilitation process of pediatric patients with hearing loss.

Effect of preoperative pulmonary hemodynamic and cardiopulmonary bypass on lung function in children with congenital heart disease.

In children with congenital heart disease (CHD), pulmonary blood flow (Qp) contributes to alterations of pulmonary mechanics and gas exchange, while cardiopulmonary bypass (CPB) induces lung edema. We aimed to determine the effect of hemodynamics on lung function and lung epithelial lining fluid (ELF) biomarkers in biventricular CHD children undergoing CPB. CHD children were classified as high Qp (n = 43) and low Qp (n = 17), according to preoperative cardiac morphology and arterial oxygen saturation. We measured ELF surfactant protein B (SP-B) and myeloperoxidase activity (MPO) as indexes of lung inflammation and ELF albumin as index of alveolar capillary leak in tracheal aspirate (TA) samples collected before surgery and in 6 hourly intervals within 24 h after surgery. At the same time points, we recorded dynamic compliance and oxygenation index (OI). The same biomarkers were measured in TA samples collected from 16 infants with no cardiorespiratory diseases at the time of endotracheal intubation for elective surgery. Preoperative ELF biomarkers in CHD children were significantly increased than those found in controls. In the high Qp, ELF MPO and SP-B peaked 6 h after surgery and tended to decrease afterward, while they tended to increase within the first 24 h in the low Qp. ELF albumin peaked 6 h after surgery and decreased afterwards in both CHD groups. Dynamic compliance/kg and OI significantly improved after surgery only in the High Qp.  Conclusion: In CHD children, lung mechanics, OI, and ELF biomarkers were significantly affected by CPB, according to the preoperative pulmonary hemodynamics. What is Known: • Congenital heart disease children, before cardiopulmonary run, exhibit changes in respiratory mechanics, gas exchange, and lung inflammatory biomarkers that are related to the preoperative pulmonary hemodynamics. • Cardiopulmonary bypass induces alteration of lung function and epithelial lining fluid biomarkers according to preoperative hemodynamics. What is New: • Our findings can help to identify children with congenital heart disease at high risk of postoperative lung injury who may benefit of tailored intensive care strategies, such as non-invasive ventilation techniques, fluid management, and anti-inflammatory drugs that can improve cardiopulmonary interaction in the perioperative period.

Molecular Profiling of Tissue Samples with Chronic Rejection from Patients with Chronic Lung Allograft Dysfunction: A Pilot Study in Cystic Fibrosis Patients.

Chronic rejection (CR) is the main culprit for reduced survival and quality of life in patients undergoing lung transplantation (Ltx). High-throughput approaches have been used to unveil the molecular pathways of CR, mainly in the blood and/or in bronchoalveolar lavage. We hypothesized that a distinct molecular signature characterizes the biopsies of recipients with clinically confirmed histological signs of CR. Eighteen cystic fibrosis patients were included in the study and RNA sequencing was performed in 35 scheduled transbronchial biopsies (TBBs): 5 with acute cellular rejection, 9 with CR, and 13 without any sign of post-LTx complication at the time of biopsy; 8 donor lung samples were used as controls. Three networks with 33, 26, and 36 differentially expressed genes (DEGs) were found in TBBs with CR. Among these, seven genes were common to the identified pathways and possibly linked to CR and five of them (LCN2, CCL11, CX3CL1, CXCL12, MUC4) were confirmed by real-time PCR. Immunohistochemistry was significant for LCN2 and MUC4. This study identified a typical gene expression pattern in TBBs with histological signs of CR and the LCN2 gene appeared to play a central role. Thus, it could be crucial in CR pathophysiology.

Respiratory and haemodynamic effects of 6h-pronation in neonates recovering from respiratory distress syndrome, or affected by acute respiratory distress syndrome or evolving bronchopulmonary dysplasia: a prospective, physiological, crossover, controlled cohort study.

Background: Pronation ameliorates oxygenation in adults with acute respiratory distress syndrome (ARDS); the effect in neonates with ARDS or other types of respiratory failure is unknown. We aimed to verify if pronation has similar respiratory and haemodynamic effects in three common types of neonatal respiratory failure. Methods: Prospective, physiologic, crossover, quasi-randomised, controlled cohort study performed in a tertiary academic neonatal intensive care unit. We enrolled neonates with: 1) recovering respiratory distress syndrome (RDS, mild restrictive pattern); 2) neonatal ARDS (NARDS, severe restrictive pattern); or 3) evolving bronchopulmonary dysplasia (BPD), that is chronic pulmonary insufficiency of prematurity (mixed restrictive/obstructive pattern). Neonates with other lung disorders, malformations or haemodynamic impairment were excluded. Patients were started prone or supine and then shifted to the alternate position for 6h; measurements were performed after 30' of "wash out" from the positioning and at the end of 6h period. Primary outcomes were respiratory (PtcCO2, modified ventilatory index, PtcO2/FiO2, SpO2/FiO2, oxygenation index, ultrasound-assessed lung aeration) and haemodynamic (perfusion index, heart rate, arterial pressure, cardiac output) parameters. Findings: Between May 1st, 2019, and May 31st, 2021, 161 participants were enrolled in this study, and included in the final analysis. Pronation improved gas exchange and lung aeration (p always <0.01) and these effects were overturned in the alternate position, except for lung aeration in NARDS where the improvement persisted. The effects were greater in patients recovering from RDS than in those with evolving BPD than in those with NARDS, in this order (p always <0.01). Pronation produced a net recruitment as lung ultrasound score decreased in patients shifted from supine (16.9 (standard deviation: 5.8)) to prone (14.1 (standard deviation: 3.3), p < 0.01) and this reduction correlated with oxygenation improvement. Haemodynamic parameters remained within normal ranges. Interpretation: 6h-pronation can be used to improve gas exchange and lung aeration in neonates with recovering RDS, evolving BPD or NARDS without relevant haemodynamic effects. Funding: None.

EEG correlates of developmental dyslexia: a systematic review.

Dyslexia is one of the most studied learning disorders. Despite this, its biological basis and main causes are still not fully understood. Electroencephalography (EEG) could be a powerful tool in identifying the underlying mechanisms, but knowledge of the EEG correlates of developmental dyslexia (DD) remains elusive. We aimed to systematically review the evidence on EEG correlates of DD and establish their quality. In July 2021, we carried out an online search of the PubMed and Scopus databases to identify published articles on EEG correlates in children with dyslexia aged 6 to 12 years without comorbidities. We follow the PRISMA guidelines and assess the quality using the Appraisal Tool questionnaire. Our final analysis included 49 studies (14% high quality, 63% medium, 20% low, and 2% very low). Studies differed greatly in methodology, making a summary of their results challenging. However, some points came to light. Even at rest, children with dyslexia and children in the control group exhibited differences in several EEG measures, particularly in theta and alpha frequencies; these frequencies appear to be associated with learning performance. During reading-related tasks, the differences between dyslexic and control children seem more localized in the left temporoparietal sites. The EEG activity of children with dyslexia and children in the control group differed in many aspects, both at rest and during reading-related tasks. Our data are compatible with neuroimaging studies in the same diagnostic group and expand the literature by offering new insights into functional significance.

Application of Patient Reported Outcome Measures in Cochlear Implant Patients: Implications for the Design of Specific Rehabilitation Programs.

INTRODUCTION: Cochlear implants (CI) have been developed to enable satisfying verbal communication, while music perception has remained in the background in both the research and technological development, thus making CI users dissatisfied by the experience of listening to music. Indications for clinicians to test and train music abilities are at a preliminary stage compared to the existing and well-established hearing and speech rehabilitation programs. The main aim of the present study was to test the utility of the application of two different patient reporting outcome (PRO) measures in a group of CI users. A secondary objective was to identify items capable of driving the indication and design specific music rehabilitation programs for CI patients. MATERIALS AND METHODS: A consecutive series of 73 CI patients referred to the Audiology Unit, University of Padova, was enrolled from November 2021 to May 2022 and evaluated with the audiological battery test and PRO measures: Musica e Qualità della Vita (MUSQUAV) and Nijmegen Cochlear Implant Questionnaire (NCIQ) Italian version. RESULTS: The reliability analysis showed good consistency between the different PRO measures (Cronbach's alpha = 0.873). After accounting for the epidemiological and clinical variables, the PRO measures showed a correlation with audiological outcomes in only one case (rho = -0.304; adj. p = 0.039) for NCIQ-T with the CI-pure tone average. A willingness for musical rehabilitation was present in 63% of patients (Rehab Factor, mean value of 0.791 ± 0.675). CONCLUSIONS: We support the role of the application of MUSQUAV and NCIQ to improve the clinical and audiological evaluation of CI patients. Moreover, we proposed a derivative item, called the rehab factor, which could be used in clinical practice and future studies to clarify the indication and priority of specific music rehabilitation programs.

Ventricular morphology of single-ventricle hearts has a significant impact on outcomes after Fontan palliation: a meta-analysis.

OBJECTIVES: A conclusive interpretation of the role of ventricular dominance in outcomes after Fontan palliation has not been formulated yet. We conducted a systematic review and meta-analysis of scientific literature to give an insight into the impact of ventricular morphology in single-ventricle palliation, focusing on its influence on survival, morbidities, ventricular performance and functional capacity. METHODS: A systematic review of PubMed, Web of Science and Scopus databases was performed. A random-effect meta-analysis was conducted, and survival data were reconstructed using the published Kaplan-Meier survival curves. RESULTS: Twenty-seven studies were selected, for a total of 4529 left-dominant versus 4844 right-dominant patients. Estimated survival at 1, 5, 10, 20 and 30 years of follow-up was 0.99 [95% confidence interval (CI) = 0.98-0.99], 0.95 [95% CI = 0.94-0.96], 0.92 [95% CI = 0.91-0.93], 0.86 [95% CI = 0.84-0.88] and 0.68 [95% CI = 0.65-0.83] for left-dominant patients and 0.94 [95% CI = 0.93-0.95], 0.89 [95% CI = 0.88-0.9], 0.85 [95% CI = 0.83-0.87], 0.69 [95% CI = 0.63-0.75] and 0.59 [95% CI = 0.5-0.69] for right-dominant patients, respectively. Survival was statistically lower for right-dominant patients (P < 0.001), with an hazard ratio for the mortality of 2.38 (2.03-2.80); also, they displayed significantly longer hospital stay, worse ventricular function, larger ventricular volumes and a higher incidence of moderate or severe atrioventricular valve regurgitation when compared to left-dominant patients. CONCLUSIONS: According to our meta-analysis, the morphology of the dominant ventricle has a significant impact on outcomes after Fontan palliation. Right-dominant patients experience an inferior long-term survival when the anatomical right ventricle is included in the systemic circulation.

Embrace the Complexity: Agnostic Evaluation of Children's Neuropsychological Performances Reveals Hidden Neurodevelopment Patterns.

The most common adverse pre/perinatal events have a great impact on neurodevelopment, with avalanche effects on academic performance, occupational status, and quality of life. Although the injury process starts early, the effects may become evident much later, when life starts to pose more challenging demands. In the present work, we want to address the impact of early insults from an evolutionary perspective by performing unsupervised cluster analysis. We fed all available data, but not the group identification, into the algorithm for 114 children aged 5-10 years, with different adverse medical conditions: healthy (n = 30), premature (n = 28), neonatal hypoxic-ischemic encephalopathy (n = 28), and congenital heart disease (n = 28). We measured general intelligence and many neuropsychological domains (language, attention, memory, executive functions, and social skills). We found three emerging groups that identify children with multiple impairments (cluster 3), children with variable neuropsychological profiles but in the normal range (cluster 2), and children with adequate profiles and good performance in IQ and executive functions (cluster 1). Our analysis divided our patients by severity levels rather than by identifying specific neuropsychological phenotypes, suggesting different developmental trajectories that are characterized by good resilience to early stressful events with adequate development or by pervasive vulnerability to neurodevelopmental disorders.