Staphylococcus capitis Central-Line-Associated Bloodstream Infections in the Neonatal Intensive Care Unit: A Single-Center, Four-Year Experience in Central-Line Management during Sepsis Treatment.

Coagulase-negative staphylococci (CoNS) are reportedly responsible for 50-60% of bloodstream infections in very preterm (<1500 g) infants in neonatal intensive care units (NICUs). Staphylococcus capitis is an increasingly prevalent pathogen in the neonatal setting, frequently causing central-line-associated bloodstream infections (CLABSIs) that can be difficult to eradicate. Central venous catheter (CVC) removal versus in situ treatment with CoNS CLABSIs is a controversial treatment strategy with no clear consensus. We reviewed all S. capitis CLABSIs in our NICU between 2019 and 2022, focusing on the role of catheter removal in eradication. Among the 25 patients, 17 CVCs were removed after diagnosis, leading to a 76.5% eradication rate in this group. Three infants had a persistently positive blood culture after CVC substitution. A new catheter was then inserted after a 48 h washout period, resulting in resolution of the infection. Only two of the eight patients (25%) who retained their catheter after diagnosis achieved infection eradication with antibiotic therapy alone. When feasible, catheter removal seems to be the most effective strategy for eradicating S. capitis CLABSIs, sometimes even requiring a 48 h washout period before reinsertion. Further studies on this topic are needed to better standardize the management of this type of infection.

Preterm Infants' Airway Microbiome: A Scoping Review of the Current Evidence.

The aim of this scoping review was to investigate and synthesize existing evidence on the airway microbiome of preterm infants to outline the prognostic and therapeutic significance of these microbiomes within the preterm population and identify gaps in current knowledge, proposing avenues for future research. We performed a scoping review of the literature following the Arskey and O'Malley framework. In accordance with our inclusion criteria and the intended purpose of this scoping review, we identified a total of 21 articles. The investigation of the airway microbiome in preterm infants has revealed new insights into its unique characteristics, highlighting distinct dynamics when compared to term infants. Perinatal factors, such as the mode of delivery, chorioamnionitis, the respiratory support, and antibiotic treatment, could impact the composition of the airway microbiome. The 'gut-lung axis', examining the link between the lung and gut microbiome as well as modifications in respiratory microbiome across different sites and over time, has also been explored. Furthermore, correlations between the airway microbiome and adverse outcomes, such as bronchopulmonary dysplasia (BPD), have been established. Additional research in neonatal care is essential to understand the early colonization of infants' airways and explore methods for its optimization. The critical opportunity to shape long-term health through microbiome-mediated effects likely lies within the neonatal period.

Preterm Birth and Maternal Mood States: What Is the Impact on Bonding?

Preterm birth is a significant global health issue affecting millions of infants each year, with potential implications for their developmental outcomes. This study investigated the impact of preterm birth on maternal mood states during the early postpartum period and its subsequent effects on mother-infant bonding. Mothers of 90 preterm infants were involved in the assessment of maternal mood states, examined with the Profile of Mood States (POMS) questionnaire and the evaluation of mother-infant bonding, carried out through the Postpartum Bonding Questionnaire (PBQ). Contrary to expectations, there was no significant correlation between preterm birth characteristics and maternal mood states. On the other hand, significant correlations emerged between specific maternal mood states and the quality of mother-child bonding. More specifically, regression analyses showed that feelings of tension, anger, and confusion experienced by the mother tend to negatively affect the quality of her bond with her child. These findings emphasize the crucial role of maternal mental well-being in shaping the mother-infant relationship in the early postpartum period. The study highlights the importance of identifying and addressing maternal mood disorders to promote positive mother-infant bonding and child development, further underlining the need for comprehensive support and interventions for mothers of preterm infants.

A versatile method for the identification of senolytic compounds.

The increased burden of senescent cells is as a well-established hallmark of aging and age-related diseases. This finding sparked significant interest in the identification of molecules capable of selectively eliminating senescent cells, so-called senolytics. Here, we fine-tuned a method for the identification of senolytics that is compatible with high-content fluorescence microscopy. We used spectral detector imaging to measure the emission spectrum of unlabeled control or senescent cells. We observed that senescent cells exhibited higher levels of autofluorescence than their non-senescent counterparts, particularly in the cytoplasmic region. Building on this result, we devised a senolytic assay based on co-culturing quiescent and senescent cells, fluorescently tagged in the nuclear region through the overexpression of H2B-GFP and H2B-RFP, respectively. We validated this approach by showing that first generation senolytics were effective in reducing the number of RFP+ nuclei leaving the count of GFP+ nuclei unaffected. The result was confirmed by flow cytometry analysis of nuclei isolated from these quiescent-senescent cell co-cultures. We found that this system enables to capture cell type-specific effects of senolytics as in the case of fisetin, which kills senescent Mouse Embryonic Fibroblasts but not senescent human melanoma SK-MEL-103 cells. This approach is amenable to genetic and chemical screening for the discovery of senolytic compounds in that it overcomes the limitations of current methods, which rely upon costly chemical reagents or fluorescence microscopy using cells labeled with fluorescent cytoplasmic probes that overlap with the autofluorescence signal emitted by senescent cells.

Global and Spatial Metabolomics of Individual Cells Using a Tapered Pneumatically Assisted nano-DESI Probe.

Single-cell metabolomics has the potential to reveal unique insights into intracellular mechanisms and biological processes. However, the detection of metabolites from individual cells is challenging due to their versatile chemical properties and concentrations. Here, we demonstrate a tapered probe for pneumatically assisted nanospray desorption electrospray ionization (PA nano-DESI) mass spectrometry that enables both chemical imaging of larger cells and global metabolomics of smaller 15 µm cells. Additionally, by depositing cells in predefined arrays, we show successful metabolomics from three individual INS-1 cells per minute, which enabled the acquisition of data from 479 individual cells. Several cells were used to optimize analytical conditions, and 93 or 97 cells were used to monitor metabolome alterations in INS-1 cells after exposure to a low or high glucose concentration, respectively. Our analytical approach offers insights into cellular heterogeneity and provides valuable information about cellular processes and responses in individual cells.

Different Settings of Nonsynchronized Bilevel Nasal Continuous Positive Airway Pressure and Respiratory Function in Preterm Infants: A Pilot Study.

OBJECTIVE: With this study, we evaluated the short-term effects of different modes and settings of noninvasive respiratory support on gas exchange, breathing parameters, and thoracoabdominal synchrony in preterm infants in the acute phase of moderate respiratory distress syndrome. STUDY DESIGN: A feasibility crossover trial was conducted in neonates < 32 weeks' gestation on nasal continuous positive airway pressure (n-CPAP) or bilevel n-CPAP. Infants were delivered the following settings in consecutive order for 10 minutes each: • n-CPAP (5 cm H2O) • bilevel n-CPAP 1 (Pres low = 5 cm H2O, Pres high = 7 cm H2O, T-high = 1 second, rate = 30/min) • n-CPAP (5 cm H2O) • bilevel n-CPAP 2 (Pres low = 5 cm H2O, Pres high = 7 cm H2O, T-high = 2 second, rate = 15/min) • n-CPAP (5 cm H2O). During each phase, physiologic parameters were recorded; the thoracoabdominal synchrony expressed by the phase angle (Φ) and other respiratory patterns were monitored by noncalibrated respiratory inductance plethysmography. RESULTS: Fourteen preterm infants were analyzed. The mean CPAP level was significantly lower in the n-CPAP period compared with bilevel n-CPAP 1 and 2 (p = 0.03). Higher values were achieved with bilevel n-CPAP 2 (6.2 ± 0.6 vs. 5.7 ± 0.5 cm H2O, respectively; p < 0.05). No statistical difference in the Φ was detected, nor between the three settings. CONCLUSION: Our study did not show any superiority of bilevel n-CPAP over n-CPAP. However, nonsynchronized bilevel n-CPAP might be helpful when additional pressure is needed. KEY POINTS: · There is currently a high degree of uncertainty about the superiority of one modality and setting of noninvasive respiratory over another.. · Our study confirmed that non-synchronized bilevel n-CPAP might be helpful when additional pressure is needed for recruitment.. · A T-high of 1 second could possibly be better tolerated in this population, but further research is needed..

Spermidine rejuvenates T lymphocytes and restores anticancer immunosurveillance in aged mice.

Writing in Science, Al Habsi et al. show that spermidine boosts the efficacy of monoclonal antibodies targeting PD-L1 in aged tumor-bearing mice by enhancing fatty acid oxidation in CD8 T cells. These results open new therapeutic avenues to improve the effectiveness of anticancer immunotherapies in aged patients.

ACBP/DBI protein neutralization confers autophagy-dependent organ protection through inhibition of cell loss, inflammation, and fibrosis.

Acyl-coenzyme A (CoA)-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular feedback regulator of autophagy. Here, we report that injection of a monoclonal antibody neutralizing ACBP/DBI (α-DBI) protects the murine liver against ischemia/reperfusion damage, intoxication by acetaminophen and concanavalin A, and nonalcoholic steatohepatitis caused by methionine/choline-deficient diet as well as against liver fibrosis induced by bile duct ligation or carbon tetrachloride. α-DBI downregulated proinflammatory and profibrotic genes and upregulated antioxidant defenses and fatty acid oxidation in the liver. The hepatoprotective effects of α-DBI were mimicked by the induction of ACBP/DBI-specific autoantibodies, an inducible Acbp/Dbi knockout or a constitutive Gabrg2F77I mutation that abolishes ACBP/DBI binding to the GABAA receptor. Liver-protective α-DBI effects were lost when autophagy was pharmacologically blocked or genetically inhibited by knockout of Atg4b. Of note, α-DBI also reduced myocardium infarction and lung fibrosis, supporting the contention that it mediates broad organ-protective effects against multiple insults.

Non-syndromic bile duct paucity and non-IgE cow's milk allergy: a case report of challenging nutritional management and maltodextrin intolerance.

BACKGROUND: Cholestasis in extremely premature infants (EPI) constitutes a nutritional challenge and maltodextrins have been reported as a possible strategy for hypoglycaemia. We aim to describe the nutritional management of an EPI with non-syndromic bile duct paucity (NSBDP) and feeding intolerance. CASE PRESENTATION: A patient, born at 27 weeks of gestational age, presented cholestatic jaundice at 20 days of life with a clinical picture of NSBDP. Patient's growth was insufficient with formula rich in medium-chain triglyceride (MCT) and branched-chain amino acids (BCAA). Due to frequent fasting hypoglicemic episodes, maltodextrins supplements were provided. He subsequently presented severe abdominal distension and painful crises, which required hospital admission and withdrawal of maltodextrins. Hypercaloric extensively hydrolysed formula provided weight gain, glycemic control, and parallel improvement in cholestasis. CONCLUSIONS: Our case suggests caution with the use of maltodextrins in infants, especially if premature. Commercial preparations for hepatopatic patients contain higher concentrations of MCTs and BCAAs, but personalized strategies must be tailored to each patient.

Management of asymptomatic hypoglycemia with 40% oral dextrose gel in near term at-risk infants to reduce intensive care need and promote breastfeeding.

BACKGROUND: Neonatal hypoglycemia is a common disorder especially in at-risk infants and it can be associated with poor long-term neurological outcomes. Several therapeutic interventions are suggested, from the implementation of breastfeeding to the glucose intravenous administration. Oral dextrose gel massaged into the infant's inner cheek is a recent treatment option of asymptomatic hypoglycemia, after which oral feeding is encouraged. This approach seems to reduce the admission of infants to neonatal intensive care unit (NICU) so favouring maternal bonding and breastfeeding success at discharge. METHODS: In our ward, we prospectively compared a group of near-term neonates, (Gr2, n = 308) at risk for hypoglycemia, treated with an innovative protocol based on the addition of 40% oral dextrose gel (Destrogel, Orsana®,Italy) administered by massaging gums and cheek with historical matching newborns (Gr1, n = 389) treated with a formerly used protocol, as control group. The primary outcome was occurrence of NICU admission and the requirement of intravenous glucose administration; while discharge with full breastfeeding was the secondary outcome. RESULTS: In Gr1, 39/389 (10%) infants presented with asymptomatic hypoglycemia, 19/39 were transferred to the NICU, and 14/39 required intravenous glucose treatment. In Gr2, among the 30/308 infants with asymptomatic hypoglycemia managed according to the new protocol, 3/30 were transferred to the NICU and received intravenous glucose infusion. The mean duration of hospitalization respectively was 6.43 (± 6.36) and 3.73 ± 1.53 days (p <  0.001). At discharge, 7.7% of the infants in Gr1 and 30% of the infants in Gr2 were exclusively breastfed (p = 0.02). Considering Gr1 vs Gr2, the number of patients that were transferred to NICU was 19 (48.7%) vs 3 (10%) (p = 0.001) and the number of infants that needed intravenous glucose infusion was 14 (35.9%) vs 3 (10%) (p = 0.01), respectively. CONCLUSIONS: In our population of near term infants, the introduction of 40% oral dextrose gel to the protocol, helped in the safe management of asymptomatic hypoglycemia and, at the same time, implemented breastfeeding.

Neuroimaging and neurodevelopmental outcome after early fetal growth restriction: NEUROPROJECT-FGR.

BACKGROUND: Adverse neurodevelopmental outcomes and MRI alterations are reported in infants born after fetal growth restriction (FGR). This study evaluates the additional role of FGR over prematurity in determining brain impairment. METHODS: Retrospective observational study comparing 48 FGR and 36 appropriate for gestational age infants born between 26 and 32 weeks' gestation who underwent a cerebral MRI at term equivalent age. Exclusion criteria were twins, congenital anomalies, and findings of overt brain lesions. Main outcomes were total maturation score (TMS) and cerebral areas independently measured by two neuro-radiologists and Griffiths or Bayley scale III scores at median age of 2 years. RESULTS: TMS was not significantly different between the groups. Inner calvarium and parenchyma's areas were significantly smaller in FGR cases. There were no significant differences in the average quotient scores. A positive correlation between parenchyma area and cognitive score was found (r = 0.372, p = 0.0078) and confirmed after adjusting for sex, gestational age, and birth weight (p = 0.0014). Among FGR, the subgroup with umbilical arterial Doppler velocimetry alterations had significantly worse gross motor scores (p = 0.005). CONCLUSIONS: FGR plays additional role over prematurity in determining brain impairment. An early structural dimensional MRI evaluation may identify infants who are at higher risk. IMPACT: Fetal growth-restricted infants showed smaller cerebral parenchymal areas than preterm controls. There is a positive correlation between the parenchyma area and the cognitive score. These results highlight the already known link between structure and function and add importance to the role of a structural dimensional MRI evaluation even in the absence of overt brain lesions.

Caloric restriction mimetics for the treatment of cardiovascular diseases.

Caloric restriction mimetics (CRMs) are emerging as potential therapeutic agents for the treatment of cardiovascular diseases. CRMs include natural and synthetic compounds able to inhibit protein acetyltransferases, to interfere with acetyl coenzyme A biosynthesis, or to activate (de)acetyltransferase proteins. These modifications mimic the effects of caloric restriction, which is associated with the activation of autophagy. Previous evidence demonstrated the ability of CRMs to ameliorate cardiac function and reduce cardiac hypertrophy and maladaptive remodelling in animal models of ageing, mechanical overload, chronic myocardial ischaemia, and in genetic and metabolic cardiomyopathies. In addition, CRMs were found to reduce acute ischaemia-reperfusion injury. In many cases, these beneficial effects of CRMs appeared to be mediated by autophagy activation. In the present review, we discuss the relevant literature about the role of different CRMs in animal models of cardiac diseases, emphasizing the molecular mechanisms underlying the beneficial effects of these compounds and their potential future clinical application.

A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients. SIGNIFICANCE: The loss-of-function variant rs867228 in FPR1, harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking Fpr1, suggesting a personalized strategy for compensating for the FPR1 defect.This article is highlighted in the In This Issue feature, p. 211.

Autophagy-mediated metabolic effects of aspirin.

Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b-/- or Bcln1+/-) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.

Triethylenetetramine (trientine): a caloric restriction mimetic with a new mode of action.

Caloric restriction mimetics (CRMs) are nontoxic macroautophagy/autophagy enhancers that act through the stimulation of cytoplasmic protein deacetylation reactions. Thus far, three functional classes of CRMs have been described: inhibitors of acetyltransferases (such as spermidine), inhibitors of acetyl coenzyme (AcCoA) synthesis (such as hydroxycitrate) and activators of deacetylases/sirtuins (such as resveratrol). Triethylenetetramine (also called trientine, abbreviated TETA) is a synthetic polyamine with resemblance in its structure to spermidine, a natural polyamine reputed for its pro-autophagic, anti-obesity and anti-aging effects. TETA, which is approved for the treatment of Wilson disease, has no effects on the longevity of mice, yet does induce autophagy and reduces weight gain in mice fed a high-fat diet (HFD). Mechanistically, these effects of TETA involve an increased activity of the TETA-metabolizing enzyme, SAT1 (spermidine/spermine N1-acetyltransferase 1). SAT1 overactivation ultimately results in the depletion of intracellular AcCoA with a consequent de-acetylation of cytoplasmic proteins and induction of autophagy. Accordingly, TETA fails to induce autophagy or to control HFD-induced weight gain in SAT1-deficient mice. Altogether, these findings indicate that TETA induces autophagy through a novel mode of action, namely, by the activation of an AcCoA-depleting enzyme.

Chemical activation of SAT1 corrects diet-induced metabolic syndrome.

The pharmacological targeting of polyamine metabolism is currently under the spotlight for its potential in the prevention and treatment of several age-associated disorders. Here, we report the finding that triethylenetetramine dihydrochloride (TETA), a copper-chelator agent that can be safely administered to patients for the long-term treatment of Wilson disease, exerts therapeutic benefits in animals challenged with hypercaloric dietary regimens. TETA reduced obesity induced by high-fat diet, excessive sucrose intake, or leptin deficiency, as it reduced glucose intolerance and hepatosteatosis, but induced autophagy. Mechanistically, these effects did not involve the depletion of copper from plasma or internal organs. Rather, the TETA effects relied on the activation of an energy-consuming polyamine catabolism, secondary to the stabilization of spermidine/spermine N1-acetyltransferase-1 (SAT1) by TETA, resulting in enhanced enzymatic activity of SAT. All the positive effects of TETA on high-fat diet-induced metabolic syndrome were lost in SAT1-deficient mice. Altogether, these results suggest novel health-promoting effects of TETA that might be taken advantage of for the prevention or treatment of obesity.

Monochorionic diamniotic twin pregnancy complicated by discordant premature closure of ductus arteriosus.

Prenatal DA closure due to early maternal intake of high-dose paracetamol and selective serotonin reuptake inhibitors. MC twin pregnancy uncomplicated by TTTS with discordant prenatal DA closure.

Comprehensive autophagy evaluation in cardiac disease models.

Autophagy is a highly conserved recycling mechanism essential for maintaining cellular homeostasis. The pathophysiological role of autophagy has been explored since its discovery 50 years ago, but interest in autophagy has grown exponentially over the last years. Many researchers around the globe have found that autophagy is a critical pathway involved in the pathogenesis of cardiac diseases. Several groups have created novel and powerful tools for gaining deeper insights into the role of autophagy in the aetiology and development of pathologies affecting the heart. Here, we discuss how established and emerging methods to study autophagy can be used to unravel the precise function of this central recycling mechanism in the cardiac system.

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice.

We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8+ T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents.