Comparison between available early antiviral treatments in outpatients with SARS-CoV-2 infection: a real-life study.

PURPOSE: To investigate the clinical impact of three available antivirals for early COVID-19 treatment in a large real-life cohort. METHODS: Between January and October 2022 all outpatients tested positive for SARS-CoV-2 referring to IRCCS S. Orsola hospital treated with an early antiviral therapy were enrolled. A comparison between patients treated with nirmatrelvir/ritonavir (NTV/r), molnupiravir (MPV) and remdesivir (RDV) was conducted in term of indications and outcome. To account for differences between treatment groups a propensity score analysis was performed. After estimating the weights, we fitted a survey-weighted Cox regression model with inverse-probability weighting with hospital admission/death versus clinical recovery as the primary outcome. RESULTS: Overall 1342 patients were enrolled, 775 (57.8%), 360 (26.8%) and 207 (15.4%) in MPV, NTV/r and RDV group, respectively. Median age was 73 (59-82) years, male sex was 53.4%. Primary indication was immunosuppression (438, 32.6%), the median time from symptom onset to drug administration was 3 [2-4] days. Overall, clinical recovery was reached in 96.9% of patients, with hospital admission rate of 2.6%. No significant differences were found in clinical recovery nor hospitalization. Cox regression showed a decreased probability of hospital admission/ death among prior vaccinated patients compared with unvaccinated (HR 0.31 [95%CI 0.14-0.70], p = 0.005]). No difference in hospitalization rates in early treatment compared to late treatment were found. CONCLUSIONS: No differences among MPV, NTV/r and RDV in terms of clinical recovery or hospitalization were found. Patients not vaccinated had a significant increased risk of hospitalization.

Biodegradable Mulching Film vs. Traditional Polyethylene: Effects on Yield and Quality of San Marzano Tomato Fruits.

Mulching is a common practice for improving crop yield and obtaining an out-of-season production, but when made using plastic materials it can bring environmental problems due to the management and the disposal of films at the end of the cropping seasons. To increase the sustainability of this practice, recently, mulching films made with biodegradable organic materials have become more widely used. Our aim was to evaluate the effect of a biodegradable mulching film on yield and qualitative traits of the San Marzano tomato fruits over two years (2014 and 2015). Two different types of mulching were tested: (i) black biodegradable film (MB12) and (ii) black low-density polyethylene (LDPE) were compared to bare soil (BS). Both mulching films elicited a 25% increase in yield, mainly due to the significantly higher number of fruits per square meter, compared to BS. Both mulching films also elicited a 9.9% increase in total soluble solids and a 57% increase in carotenoid content, while firmness showed the highest value in BS fruits. MB12 determined the highest value of the Hunter color ratio a/b of tomato fruits, followed by LDPE, while the lowest value was recorded in BS fruits. Both mulching films elicited an increase of 9.6%, 26.0%, and 11.7% for flavonoids, polyphenols, and AsA, respectively. In 2014, the MB12 degradation started at 71 days after transplant (DAT); in 2015, at 104 DAT. Therefore, replacing polyethylene with biodegradable film would seem to be an agronomically efficient and environmentally sustainable practice.

The future of neonatal lung ultrasound: Validation of an artificial intelligence model for interpreting lung scans. A multicentre prospective diagnostic study.

BACKGROUND: Artificial intelligence (AI) is a promising field in the neonatal field. We focused on lung ultrasound (LU), a useful tool for the neonatologist. Our aim was to train a neural network to create a model able to interpret LU. METHODS: Our multicentric, prospective study included newborns with gestational age (GA) ≥ 33 + 0 weeks with early tachypnea/dyspnea/oxygen requirements. For each baby, three LU were performed: within 3 h of life (T0), at 4-6 h of life (T1), and in the absence of respiratory support (T2). Each scan was processed to extract the region of interest used to train a neural network to classify it according to the LU score (LUS). We assessed sensitivity, specificity, positive and negative predictive value of the AI model's scores in predicting the need for respiratory assistance with nasal continuous positive airway pressure and for surfactant, compared to an already studied and established LUS. RESULTS: We enrolled 62 newborns (GA = 36 ± 2 weeks). In the prediction of the need for CPAP, we found a cutoff of 6 (at T0) and 5 (at T1) for both the neonatal lung ultrasound score (nLUS) and AI score (AUROC 0.88 for T0 AI model, 0.80 for T1 AI model). For the outcome "need for surfactant therapy", results in terms of area under receiver operator characteristic (AUROC) are 0.84 for T0 AI model and 0.89 for T1 AI model. In the prediction of surfactant therapy, we found a cutoff of 9 for both scores at T0, at T1 the nLUS cutoff was 6, while the AI's one was 5. Classification accuracy was good both at the image and class levels. CONCLUSIONS: This is, to our knowledge, the first attempt to use an AI model to interpret early neonatal LUS and can be extremely useful for neonatologists in the clinical setting.

Normal values for superior vena cava flow in preterm neonates using a new echocardiographic approach.

OBJECTIVE: Recently, a novel approach to imaging Superior Vena Cava (SVC) flow has been presented, showing better repeatability and better agreement with MRI-derived SVC flow measures. The objective was to establish normal values of SVC flow with the novel approach in the first 48 h of life. STUDY DESIGN: This was a prospective, observational study. All infants with gestational age (GA) less than 31 weeks were eligible. Echocardiographic evaluation was performed at 5, 12, 24, 48 h of postnatal life. A subgroup of uncomplicated infants was studied to define a normal range for SVC flow. RESULTS: Forty-five infants were enrolled. We estimated normative values in a subgroup of 31 uncomplicated infants. The median SVC flow significantly increases from 83 ml/kg/min at 5 h of life to 153 ml/kg/min at 48 h (p < .001). CONCLUSION: Using the novel approach we derived normal values of SVC flow in a cohort of uncomplicated preterm population at high risk for developing IVH.

Lowering of the Neonatal Lung Ultrasonography Score after nCPAP Positioning in Neonates over 32 Weeks of Gestational Age with Neonatal Respiratory Distress.

Respiratory distress (RD) is one of the most common causes of admission to the neonatal intensive care unit. Correct diagnosis and timely intervention are crucial. Lung ultrasonography (LU) is a useful diagnostic tool for the neonatologist in the diagnosis of RD; the neonatal lung ultrasonography score (nLUS) can be used in the diagnostic process, but some authors hypothesise that it is also useful for the management of some neonatal RD. The aim of this study is to analyse the changes in nLUS score before (T0) and after (T1) the start of respiratory support with nasal CPAP in neonates over 32 weeks of age with RD. Thirty-three newborns were enrolled in this retrospective study. LU was performed before and after the start of CPAP. The median nLUS scores at T0 and T1 were 9 (IQR 7−12) and 7 (IQR 4−10), respectively, and showed a significant difference (p < 0.001). The magnitude of reduction in nLUS score, expressed as a percentage, was inversely related to the need for subsequent administration of exogenous surfactant. The study suggests the usefulness of the nLUS score in assessing the response to CPAP in neonates over 32 weeks gestational age.

Early lung ultrasound score to predict noninvasive ventilation needing in neonates from 33 weeks of gestational age: A multicentric study.

OBJECTIVE: To propose an early lung ultrasound (LUS) score for the prediction of the need for respiratory assistance in newborns of gestational age (GA) ≥ 33 weeks presenting respiratory distress. STUDY DESIGN AND SETTING: Multicenter, prospective observational study in third-level neonatal intensive care units. PATIENT SELECTION: Infants with GA ≥ 33 + 0 weeks with respiratory distress within 3 h of life. METHODS: Three LUS for each patient were collected: within 3 h of life (T0), at 4-6 h of life (T1), and at the resolution of symptoms (T2). The primary aim was to assess the validity of the early LUS score in predicting the need for continuous positive airway pressure (CPAP). We also evaluated the validity of the score in predicting the need for surfactant, the scores' trend in our population, and any correlation with the duration of ventilation and oxygen therapy. RESULTS: Sixty-two patients were enrolled in the study. The mean GA was 36 weeks. The receiver operating characteristic analysis for the LUS T0 and T1 yielded area under the curves of 0.91 and 0.82 in predicting the need for CPAP, respectively. LUS score cut off of 6 (sensitivity 84.8%, specificity 86.2%) and 5 (sensitivity 66.7%, specificity 100%) were calculated at T0 and T1, respectively. We found significant correlations between LUS score and respiratory assistance, surfactant administration, and SpO2 /FiO2 ratio. CONCLUSION: An early LUS score is a good noninvasive predictor of the need for respiratory assistance with CPAP and surfactant administration in newborns with GA ≥ 33 weeks.

Biochemical Characterization of Some Varieties of Apricot Present in the Vesuvius Area, Southern Italy.

The witnesses of the millenary history of Campania felix in southern Italy highlighted that several fruit and vegetables cultivated in such territory could potentially be a treasure trove of important health elements. Our work evaluated the content of ß-carotene, ascorbic acid, and total phenolics and the antioxidant activity of ten typical varieties of apricots cultivated in the Vesuvius area in the Campania region. The total polyphenols varied between 10.24 and 34.04 mg/100 g of a fresh sample. The amount of ascorbic acid also varied greatly, ranging from 2.65 to 10.65 mg/100 g of a fresh product. B-Carotene reached values up to 0.522 mg/100 g of the fresh sample. The correlation analysis performed, accounting for these parameters, showed that the antioxidant activity, calculated by 2,2-diphenyl-1-picrylhydrazyl (DPPH assay) and azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) tests, was influenced mainly by the content of total polyphenols, with ρ = -0.762 and ρ = 0.875 when we considered DPPH and ABTS tests, respectively, slightly less by the content of ascorbic acid, and not by ß-carotene. The dendrogram clustered eight varieties into two main groups; on the other hand, two varieties ("Vitillo" and "Preveta bella") seemed hierarchically distant. The gas chromatography-mass spectrometry (GC-MS) analysis of volatile organic compounds (VOCs), herein performed for the first time, demonstrated the influence of the varieties on the VOC profiles, both from a qualitative and semiquantitative perspective, discriminating the varieties in different clusters, each of which was characterized by specific notes. α-Terpinolene was the only terpene identified by GC-MS that appeared to affect the antioxidant activity.

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma.

Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy.

hTERT Transduction Extends the Lifespan of Primary Pediatric Low-Grade Glioma Cells While Preserving the Biological Response to NGF.

The neurotrophin nerve growth factor (NGF) modulates the growth of human gliomas and is able to induce cell differentiation through the engagement of tropomyosin receptor kinase A (TrkA) receptor, although the role played in controlling glioma survival has proved controversial. Unfortunately, the slow growth rate of low-grade gliomas (LGG) has made it difficult to investigate NGF effects on these tumors in preclinical models. In fact, patient-derived low-grade human astrocytoma cells duplicate only a limited number of times in culture before undergoing senescence. Nevertheless, replicative senescence can be counteracted by overexpression of hTERT, the catalytic subunit of telomerase, which potentially increases the proliferative potential of human cells without inducing cancer-associated changes. We have extended, by hTERT transduction, the proliferative in vitro potential of a human LGG cell line derived from a pediatric pilocytic astrocytoma (PA) surgical sample. Remarkably, the hTERT-transduced LGG cells showed a behavior similar to that of the parental line in terms of biological responses to NGF treatment, including molecular events associated with induction of NGF-related differentiation. Therefore, transduction of LGG cells with hTERT can provide a valid approach to increase the in vitro life-span of patient-derived astrocytoma primary cultures, characterized by a finite proliferative potential.

The BET Inhibitor OTX015 Exhibits In Vitro and In Vivo Antitumor Activity in Pediatric Ependymoma Stem Cell Models.

Childhood ependymomas are heterogenous chemoresistant neoplasms arising from aberrant stem-like cells. Epigenome deregulation plays a pivotal role in ependymoma pathogenesis, suggesting that epigenetic modifiers hold therapeutic promise against this disease. Bromodomain and extraterminal domain (BET) proteins are epigenome readers of acetylated signals in histones and coactivators for oncogenic and stemness-related transcriptional networks, including MYC/MYCN (Proto-Oncogene, BHLH Transcritpion Factor)-regulated genes. We explored BET inhibition as an anticancer strategy in a panel of pediatric patient-derived ependymoma stem cell models by OTX015-mediated suppression of BET/acetylated histone binding. We found that ependymoma tissues and lines express BET proteins and their targets MYC and MYCN. In vitro, OTX015 reduced cell proliferation by inducing G0/G1-phase accumulation and apoptosis at clinically tolerable doses. Mechanistically, inhibitory p21 and p27 increased in a p53-independent manner, whereas the proliferative driver, phospho-signal transducer and activator of transcription 3 (STAT3), decreased. Upregulation of apoptosis-related proteins and survivin downregulation were correlated with cell line drug sensitivity. Minor alterations of MYC/MYCN expression were reported. In vivo, OTX015 significantly improved survival in 2/3 orthotopic ependymoma models. BET proteins represent promising targets for pharmaceutical intervention with OTX015 against ependymoma. The identification of predictive determinants of sensitivity may help identify ependymoma molecular subsets more likely to benefit from BET inhibitor therapies.

Targeting the mitogen­activated protein kinase kinase and protein kinase A pathways overcomes acquired resistance to Selumetinib in low­grade glioma cells.

The Ras/Raf/MEK/MAPK signaling cascade is frequently activated in human cancer and serves a crucial role in the oncogenesis of pediatric low­grade gliomas (PLGGs). Therefore, drugs targeting kinases among the mitogen­activated protein kinase (MAPK) effectors of receptor tyrosine kinase signaling may represent promising candidates for the treatment of PLGGs. The aim of the present study was to elucidate the anticancer effects of the MEK inhibitor Selumetinib on two low­grade glioma cell lines and the possible underlying effects on intracellular signal transduction. The two cancer cell lines displayed different levels of sensitivity to Selumetinib, as Res186 cells were resistant (IC50>1 µM), whereas Res259 cells were sensitive (IC50≤1 µM) to MEK inhibition. Despite the different levels of sensitivity, Selumetinib mediated the phosphorylation of AKT and MEK in both cell lines and suppressed the phosphorylated MAPK cascades. In addition, Selumetinib induced cell cycle arrest at the G0/G1 phase by downregulating the expression levels of cyclin D1 and p21 and upregulating those of p27 compared with those in the control cells. A Res259 cell line with acquired resistance to Selumetinib (Res259/R) was next established and biologically and molecularly characterized, and it was demonstrated that addition of a selective cAMP­dependent protein kinase A inhibitor to Selumetinib overcame drug resistance in Res 259/R cells. In conclusion, the results of the present study provided three low­grade glioma cell line models characterized by sensitivity, intrinsic and acquired resistance to Selumetinib, which may be usuful tools to study new mechanisms of chemoresistance to MEK inhibitors and to explore alternative therapeutic strategies in low­grade gliomas for personalization of treatment.

[I thought it was right... Late diagnosis of accidental lead misplacement in the left ventricle across patent foramen ovale]. / Pensavo fosse a destra Diagnosi tardiva di malposizionamento accidentale di elettrocatetere in ventricolo sinistro attraverso forame ovale pervio.

Accidental lead misplacement in the left ventricle is a rare complication, which should be diagnosed early and treated with lead removal. In case of late diagnosis, chronic anticoagulant therapy or, if the patient needs cardiac surgery for other reasons, surgical lead removal are recommended. In the present case, lead misplacement occurred at the time of a traditional pacemaker implantation due to bradycardia.

Biochemical Characterization of Traditional Varieties of Sweet Pepper (Capsicum annuum L.) of the Campania Region, Southern Italy.

Bioactive compounds of different Campania native sweet pepper varieties were evaluated. Polyphenols ranged between 1.37 mmol g-1 and 3.42 mmol g-1, ß-carotene was abundant in the red variety "Cazzone" (7.05 µg g-1). Yellow and red varieties showed a content of ascorbic acid not inferior to 0.82 mg g-1, while in some green varieties the presence of ascorbic acid was almost inconsistent. Interrelationships between the parameters analyzed and the varieties showed that ascorbic acid could represent the factor mostly influencing the antioxidant activity. Polyphenol profile was different among the varieties, with a general prevalence of acidic phenols in yellow varieties and of flavonoids in red varieties. Principal Component Analysis, applied to ascorbic acid, total polyphenols and ß-carotene, revealed that two of the green varieties ("Friariello napoletano" and "Friariello Sigaretta") were well clustered and that the yellow variety "Corno di capra" showed similarity with the green varieties, in particular with "Friariello Nocerese". This was confirmed by the interrelationships applied to polyphenol composition, which let us to light on a clustering of several red and yellow varieties, and that mainly the yellow "Corno di capra" was closer to the green varieties of "Friariello".

Qualitative Aspects of Some of Some Traditional Landraces of the Tomato "Piennolo" (Solanum lycopersicum L.) of the Campania Region, Southern Italy.

Our study aimed to analyze some qualitative aspects of five landraces of the tomato "Piennolo," typical of the Vesuvian area, Italy, and determine the in vitro antioxidant activity. All samples showed a high °Brix value and acidity, as well as a discrete amount of reducing sugars, indicating their good quality as fresh products. They showed a high content of lycopene (up to 218 mg g-1 of fresh product) and ascorbic acid (up to 238 mg g-1 of fresh product). The content of total polyphenols was never less than 278 mg g-1 of fresh product. Hyperoside, chlorogenic and gallic acids were the most abundant polyphenols. The interrelationships between the parameters analyzed and the different landraces showed that total polyphenols could have mostly affected (r = 0.76) the antioxidant activity more than lycopene (r = -0.96). The interrelationships between the most abundant polyphenols and antioxidant activity showed that hyperoside, although the most abundant, negatively affected (r = -0.93) the antioxidant activity. Due to the high content of lycopene, ascorbic acid, and hyperoside, the five landraces of the tomato "Piennolo" could be considered promising in terms of their potential healthy characteristics.

CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models.

Pediatric ependymoma (EPN) is a highly aggressive tumor of the central nervous system that remains incurable in 40% of cases. In children, the majority of cases develop in the posterior fossa and can be classified into two distinct molecular entities: EPN posterior fossa A (PF-EPN-A) and EPN posterior fossa B (PF-EPN-B). Patients with PF-EPN-A have poor outcome and are in demand of new therapies. In general, PF-EPN-A tumors show a balanced chromosome copy number profile and have no recurrent somatic nucleotide variants. However, these tumors present abundant epigenetic deregulations, thereby suggesting that epigenetic therapies could provide new opportunities for PF-EPN-A patients. In vitro epigenetic drug screening of 11 compounds showed that histone deacetylase inhibitors (HDACi) had the highest anti-proliferative activity in two PF-EPN-A patient-derived cell lines. Further screening of 5 new brain-penetrating HDACi showed that CN133 induced apoptosis in vitro, reduced tumor growth in vivo and significantly extended the survival of mice with orthotopically-implanted EPN tumors by modulation of the unfolded protein response, PI3K/Akt/mTOR signaling, and apoptotic pathways among others. In summary, our results provide solid preclinical evidence for the use of CN133 as a new therapeutic agent against PF-EPN-A tumors.

Neonatal lung ultrasonography score after surfactant in preterm infants: A prospective observational study.

OBJECTIVE: To assess changes in neonatal lung ultrasonography score (nLUS) after surfactant administration in preterm infants with respiratory distress syndrome (RDS). WORKING HYPOTHESIS: The reduction of nLUS score before (nLUSpre), 2 hours (nLUS2h), and 12 hours (nLUS12h) after surfactant administration to identify patients who will not need a second treatment. STUDY DESIGN AND SETTING: Prospective observational study in the tertiary neonatal intensive care unit. PATIENTS SELECTION: Forty-six preterm neonates with RDS of 32 weeks median gestational age (IQR 30-33) and mean birth weight of 1650 ± 715 g. METHODOLOGY: Lung ultrasonography was performed before, 2 hours, and 12 hours after surfactant administration in preterm infants with RDS needing surfactant treatment. Resulting nLUS was analyzed. RESULTS: The Wilcoxon signed-rank test demonstrated an nLUS lowering after 2 hours (P < .001) and 12 hours (P < .001) from surfactant administration. Sixteen newborns required surfactant retreatment with median gestational age of 32 weeks (IQR 29-33) and mean birth weight of 1519 ± 506 g.The receiver operating characteristic analysis for the nLUS2h yielded an area under the curve of 0.80 (95% confidence interval, 0.76-0.85; P < .001). A nLUS2h ≥7 showed a sensitivity of 94% and a specificity of 60% for needing a second treatment with surfactant. CONCLUSIONS: In preterm infants with RDS requiring surfactant treatment, nLUS evaluated 2 hours after surfactant administration can be used to identify patients who will not need a second treatment.

Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study.

AIM: To assess objective response after two cycles of temozolomide and topotecan (TOTEM) in children with refractory or relapsed miscellaneous extracranial solid and central nervous system (CNS) tumors, including medulloblastoma and primitive neuroectodermal tumors (PNET). PROCEDURE: Multicenter, nonrandomized, phase 2 basket trial including children with solid tumors, completed by a one-stage design confirmatory cohort for medulloblastoma, and an exploratory cohort for PNET. Main eligibility criteria were refractory/relapsed measurable disease and no more than two prior treatment lines. Temozolomide was administered orally at 150 mg/m2 /day followed by topotecan at 0.75 mg/m2 /day intravenously for five consecutive days every 28 days. Tumor response was assessed every two cycles according to WHO criteria and reviewed independently. RESULTS: Thirty-two patients were enrolled and treated in the miscellaneous solid tumor and 33 in the CNS strata; 20 patients with medulloblastoma and six with PNET were included in the expansion cohorts. The median age at inclusion was 10.0 years (range, 0.9-20.9). In the basket cohorts, confirmed complete and partial responses were observed in one glioma, four medulloblastoma, and one PNET, leading to the extension. The overall objective response rate (ORR) in medulloblastoma was 28% (95% CI, 12.7-47.2) with 1/29 complete and 7/29 partial responses, those for PNET 10% (95% CI, 0.3-44.5). Post hoc Bayesian analysis estimates that the true ORR in medulloblastoma is probably between 20% and 30% and below 20% in PNET. The most common treatment-related toxicities of the combination therapy were hematologic. CONCLUSIONS: Temozolomide-topotecan results in significant ORR in children with recurrent and refractory medulloblastoma with a favorable toxicity profile.

Mother-to-child transmission of hepatitis C virus.

This review reinforces the lack of a single maternal risk factor that is highly associated with vertical transmission (VT) of the infection with hepatitis C virus (HCV): indeed HCV RNA levels, mode of delivery, breast feeding, viral genotype or maternal IL28B status were not associated with HCV VT.