Comparison of "IN-REC-SUR-E" and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN-REC-LISA trial).

BACKGROUND: Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. METHODS: In this study, 382 infants born at 24+0-27+6 weeks' gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks' postmenstrual age. The secondary outcomes are BPD at 36 weeks' postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24+0 to 25+6 weeks or 26+0 to 27+6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). DISCUSSION: This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24+0-27+6 weeks' gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks' postmenstrual age of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

Prognostic value of brain proton MR spectroscopy and diffusion tensor imaging in newborns with hypoxic-ischemic encephalopathy treated by brain cooling.

INTRODUCTION: MRI, proton magnetic resonance spectroscopy (¹H-MRS), and diffusion tensor imaging (DTI) have been shown to be of great prognostic value in term newborns with moderate-severe hypoxic-ischemic encephalopathy (HIE). Currently, no data are available on ¹H-MRS and DTI performed in the subacute phase after hypothermic treatment. The aim of the present study was to assess their prognostic value in newborns affected by moderate-severe HIE and treated with selective brain cooling (BC). METHODS: Twenty infants treated with BC underwent conventional MRI and (1)H-MRS at a mean (SD) age of 8.3 (2.8) days; 15 also underwent DTI. Peak area ratios of metabolites and DTI variables, namely mean diffusivity (MD), axial and radial diffusivity, and fractional anisotropy (FA), were calculated. Clinical outcome was monitored until 2 years of age. RESULTS: Adverse outcome was observed in 6/20 newborns. Both ¹H-MRS and DTI variables showed higher prognostic accuracy than conventional MRI. N-acetylaspartate/creatine at a basal ganglia localisation showed 100% PPV and 93% NPV for outcome. MD showed significantly decreased values in many regions of white and gray matter, axial diffusivity showed the best predictive value (PPV and NPV) in the genu of corpus callosum (100 and 91%, respectively), and radial diffusivity was significantly decreased in fronto white matter (FWM) and fronto parietal (FP) WM. The decrement of FA showed the best AUC (0.94) in the FPWM. CONCLUSION: Selective BC in HIE neonates does not affect the early and accurate prognostic value of ¹H-MRS and DTI, which outperform conventional MRI.

[Italian guidelines and recommendations for prevention and treatment of pain in the newborn]. / Linee-guida e raccomandazioni per la prevenzione ed il trattamento del dolore nel neonato.

OBJECTIVE: Despite accumulating evidence that procedural pain experienced by preterm infants may have acute detrimental and even long-term effects on an infant's subsequent behavior and neurological outcome, neonates admitted to Neonatal Intensive Care Units still frequently experience acute and prolonged uncontrolled pain. Many invasive and surgical procedures are routinely performed at the bedside in the NICU without adequate pain management. AIM: To develop evidence-based guidelines and recommendations for pain control and prevention in Italian i.e. heel lancing, venipuncture and percutaneous venous line positioning, tracheal intubation, mechanical ventilation, lumbar puncture, chest tube positioning, for certain surgical procedures performed at the NICU, e.g. central venous cutdown, surgical PDA ligation, and cryotherapy, laser therapy for ROP, and for postoperative pain management. CONCLUSION: Adequate pain prevention and management should be an essential part of standard health care at the NICU, and recognizing and assessing sources of pain should be routine in the day-to-day practice of physicians and nurses taking care of the newborn. We hope these guidelines will contribute towards increasing the NICU caregiver's awareness and understanding of the importance of adequate pain control and prevention.

Evaluation of genotoxic effects of the herbicide dicamba using in vivo and in vitro test systems.

The genotoxic effects of the herbicide dicamba have been studied by measuring 1) the unwinding rate of liver DNA from intraperitoneally (i.p.) treated rats (fluorimetric assay); 2) DNA repair as unscheduled DNA synthesis (UDS) induced in cultured human peripheral blood lymphocytes (HPBL); and 3) sister chromatid exchanges (SCE) in HPBL. Results show that dicamba is capable of inducing DNA damage since it significantly increases the unwinding rate of rat liver DNA in vivo and also induces UDS in HPBL in vitro in the presence of exogenous metabolic activation (S-9 mix). Furthermore, dicamba causes a very slight increase in SCE frequency in HPBL in vitro.

Prophylactic nasal continuous positive airways pressure in newborns of 28-31 weeks gestation: multicentre randomised controlled clinical trial.

BACKGROUND: The role of nasal continuous positive airways pressure (nCPAP) in the management of respiratory distress syndrome in preterm infants is not completely defined. OBJECTIVE: To evaluate the benefits and risks of prophylactic nCPAP in infants of 28-31 weeks gestation. DESIGN: Multicentre randomised controlled clinical trial. SETTING: Seventeen Italian neonatal intensive care units. PATIENTS: A total of 230 newborns of 28-31 weeks gestation, not intubated in the delivery room and without major malformations, were randomly assigned to prophylactic or rescue nCPAP. INTERVENTIONS: Prophylactic nCPAP was started within 30 minutes of birth, irrespective of oxygen requirement and clinical status. Rescue nCPAP was started when Fio2 requirement was > 0.4, for more than 30 minutes, to maintain transcutaneous oxygen saturation between 93% and 96%. Exogenous surfactant was given when Fio2 requirement was > 0.4 in nCPAP in the presence of radiological signs of respiratory distress syndrome. MAIN OUTCOME MEASURES: Primary end point: need for exogenous surfactant. Secondary end points: need for mechanical ventilation and incidence of air leaks. RESULTS: Surfactant was needed by 22.6% in the prophylaxis group and 21.7% in the rescue group. Mechanical ventilation was required by 12.2% in both the prophylaxis and rescue group. The incidence of air leaks was 2.6% in both groups. More than 80% of both groups had received prenatal steroids. CONCLUSIONS: In newborns of 28-31 weeks gestation, there is no greater benefit in giving prophylactic nCPAP than in starting nCPAP when the oxygen requirement increases to a Fio2 > 0.4.

Pain management during invasive procedures at Italian NICUs: has anything changed in the last five years?

OBJECTIVE: To ascertain the extent to which neonatal analgesia for invasive procedures has changed in the last 5 years since the publication of Italian guidelines. METHODS: We compared survey data for the years 2004 and 2010 on analgesia policy and practices for common invasive procedures at Italian Neonatal Intensive Care Units (NICUs); 75 NICUs answered questionnaires for both years and formed the object of this analysis. RESULTS: By 2010 analgesia practices for procedural pain had improved significantly for almost all invasive procedures (p < 0.05), both non-pharmacological and pharmacological methods being adopted by the majority of NICUs (unlike the situation in 2004). The routine use of medication for major invasive procedures was still limited, however (35% of lumbar punctures, 40% of tracheal intubations, 46% during mechanical ventilation). Postoperative pain treatment was still inadequate, and 41% of facilities caring for patients after surgery did not treat pain routinely. Pain monitoring had definitely improved since 2004 (p < 0.05), but not enough: only 21% and 17% of NICUs routinely assess pain during mechanical ventilation and after surgery, respectively. CONCLUSION: There have been improvements in neonatal analgesia practices in Italy since national guidelines were published, but pain is still undertreated and underscored, especially during major invasive procedures. It is mandatory to address the gap between the recommendations in the guidelines and clinical practice must be addressed through with effective quality improvement initiatives.

Systematic review of nonpharmacological analgesic interventions for common needle­related procedure in newborn infants and development of evidence­based clinical guidelines

The aim of this literature review was to develop clinical guidelines for the prevention and control of needle­related pain in newborn infants. The guidelines were developed by the Italian Society of Neonatology, using the Grading of Recommendations, Assessment, Development and Evaluation approach, based on the assessment of 232 papers published between 1986 and 2015. The quality of the evidence was high or moderate for some behavioural and nonpharmacological interventions.

Systematic review of nonpharmacological analgesic interventions for common needle­related procedure in newborn infants and development of evidence­based clinical guidelines

The aim of this literature review was to develop clinical guidelines for the prevention and control of needle-related pain in newborn infants. The guidelines were developed by the Italian Society of Neonatology, using the Grading of Recommendations, Assessment, Development and Evaluation approach, based on the assessment of 232 papers published between 1986 and 2015. The quality of the evidence was high or moderate for some behavioural and nonpharmacological interventions. CONCLUSION: There was sufficient evidence to strongly support the use of nonpharmacological interventions for common needle-related procedures in newborn infants. Combined interventions seemed to be more effective in relieving procedural pain

[The well-being of the newborn infant in neonatal intensive care]. / Il benessere del neonato in Terapia Intensiva Neonatale.

Patients referred to Neonatal Intensive Care Units are particularly vulnerable because they are in a critical or sensitive period of development. When physicians were first able to really save preemies 40 years ago, not much thought was given to their brain development. The babies we care for are so early that the brain cells are still migrating to where they will finally rest in developed brain. We are shaped, to an extent, by our environment. In early life, the environment takes on a particularly important role. So treatments may over-stimulate areas of the brain with unknown consequences. For this reason minimally invasive treatments together with attention to the environment will favour a care developmentally appropriate for pre-term babies. Use of nasalCPAP, early rescue surfactant, synchronized mechanical ventilation, together with temperature, light and noise control could help to obtain these results. Pain control, music therapy, massage, kangaroo care and a family centred care are essential to optimize results obtained from the intensive care.

Combined oesophageal impedance-pH monitoring in preterm newborn: comparison of two options for layout analysis.

Gastro-oesophageal reflux (GOR) is common in preterm infants. Combined multichannel intraluminal impedance and pH monitoring (pH-MII) is emerging as an useful tool to study both acid and non-acid GOR in this population. We aimed to highlight main advantages and limits of pH-MII in preterm infants and to test whether the inclusion of GOR episodes detected only by pH monitoring details better the features of GOR. Fifty-two symptomatic preterm infants underwent a 24-hour, continuous and simultaneous measurement of pH-MII. Each layout was analyzed using two different options: option 1 included GOR episodes detected by MII and then classified as acid or non-acid according to the associated pH change; option 2 included GOR episodes detected by MII and also GOR episodes detected only by pH sensor. By adopting option 1, a total number of 2834 GOR episodes was detected by MII: 2162 of them were characterized as non-acid and 672 were characterized as acid. The median (range) number of acid MII-GOR episodes was 10 (1-52); the median (range) number of non-acid MII-GOR episodes was 36.5 (2-119). Median (range) acid MII-GOR-bolus exposure index was 0.28% (0.02-2.73%); median (range) non-acid MII-GOR-bolus exposure index was 1.03% (0.06-38.15%). By adopting option 2, an average of 53.2 acid GOR episodes and an average of 11% oesophageal exposure to acid GOR more than by option 1 was detected. An accurate and detailed description of GOR in preterm infants can be obtained only by including in the analysis all acid GOR episodes detected by pH sensor.

Influence of gestational age on the EDIN score: an observational study.

BACKGROUND AND AIM: Hospitalised neonates, particularly if preterm, may be exposed to prolonged pain. At present the only validated scale to assess prolonged pain in preterms is the EDIN (Echelle Douleur Inconfort Nouveau-Né) scale. Gestational age has been shown to influence the response of infants to acute pain but its potential effect in the setting of prolonged pain has not been investigated. The aim of the present study was to evaluate whether neonatal maturity as expressed by gestational age and/or postnatal age influences their expression of prolonged pain. METHODS: In a 1 year period, 84 neonates (gestational age 25-41 weeks), referred to the authors' neonatal intensive care unit were evaluated using the EDIN scale two to three times a day (1571 scores). The EDIN scores were categorised as indicative (>6) or not indicative (< or =6) of pain. Gestational age and postnatal age were included in a logistic regression analysis along with some painful situations and analgesic treatment to identify the impact on the EDIN scores. RESULTS: Logistic regression analysis showed that the EDIN scores were positively associated with gestational age (odds ratio 1.166; 95% CI 1.123 to 1.211). Postnatal age, sepsis and presence of respiratory support also influenced the EDIN score. CONCLUSIONS: Gestational age influences expression of prolonged pain. Content validity of the EDIN scale could be improved by adding categories for gestational age and attributing higher basal scores to less mature newborns.

Is the ABC pain scale reliable for premature babies?

AIM: We recently developed the ABC scale to assess pain in term newborns. The aim of the present study was to assess the reliability of the scale in preterm babies. MATERIAL AND METHODS: The scale consists of three cry parameters: (a) pitch of the first cry, (b) rhythmicity of the bout of crying and (c) cry constancy. Changes in these parameters were previously found to distinguish medium and high levels of pain as evaluated by spectral analysis of crying. We enrolled 72 babies to perform the steps usually requested to validate a scale, namely the study of the concurrent validity, specificity and sensibility. Moreover, we assessed the interjudge reliability and the clinical utility and ease of the scale. RESULTS: A good correlation (r = 0.68; r(2)= 0.45; p < 0.0001) was found between scores obtained with the ABC scale and the premature infant pain profile (PIPP) scale, demonstrating a good concurrent validity. The scale also showed good sensitivity and specificity (we found statistically significant differences between mean values of scores obtained in babies who underwent pain and babies who underwent non-painful stimulus.) Interobserver reliability was good: Cohen's kappa = 0.7. CONCLUSION: The good correlation between the two scales shows that the ABC scale is also reliable for premature babies.

Accurate neurosonographic prediction of brain injury in the surviving fetus after the death of a monochorionic cotwin.

OBJECTIVE: To assess the feasibility of the prenatal diagnosis using fetal neurosonography of brain injuries in the surviving fetus after the demise of a monochorionic cotwin. METHODS: This was a retrospective observational study in the period 1990-2004 of monochorionic twin pregnancies with a single fetal demise. A detailed sonographic evaluation of the intracranial anatomy of the surviving twin had been performed whenever possible using a multiplanar approach and from 1999, fetal magnetic resonance imaging was offered as well. Postnatal follow-up was obtained in all cases. RESULTS: In six of nine cases, abnormal neurosonographic findings were identified including intracranial hemorrhage, brain atrophy, porencephaly and periventricular echogenicities evolving into polymicrogyria. Prenatal diagnosis of brain lesions was confirmed postnatally and all affected infants who survived had severe neurological sequelae. Two fetuses had normal cerebral structures both on the prenatal neurosonogram and on postnatal imaging and were following normal developmental milestones, one at 1 and the other at 5 years of age. In one case the neurosonographic examination was suboptimal and the infant was found at birth to have a porencephalic cyst. Fetal magnetic resonance imaging was performed in two cases and confirmed the ultrasound diagnosis. CONCLUSIONS: Prenatal neurosonography is a valuable tool for the prediction of neurological outcome in fetuses surviving after the intrauterine death of a monochorionic cotwin. Although our experience is limited, we suggest that magnetic resonance imaging should also be offered.

Plant regeneration from mesophyll protoplasts in commercial potato cultivars (Primura, Kennebec, Spunta, Desirée).

In view of an evaluation of the relative efficiency of different in vitro systems for mutant induction and isolation in potato, a procedure of plant regeneration from protoplasts of some potato (Solanum tuberosum L.) cultivars was developed. Four cultivars (Primura, Kennebec, Spunta, Desirée) were used for isolation, culture and regeneration of leaf mesophyll protoplasts.These lines were chosen because of their economic importance in Italy and in the case of cv. Desirée for the presence of markers useful in the morphological characterization of regenerants.

cDNA cloning of artichoke mottled crinkle virus RNA and localization and sequencing of the coat protein gene.

We report the cDNA cloning of the genomic RNA of artichoke mottled crinkle virus (AMCV), which is a member of Tombusvirus group. AMCV has a monopartite positive sense RNA genome, which is not polyadenylated at the 3' end. The genome size is 4.8 kb. We have localized and sequenced the open reading frame (ORF) encoding the coat protein. Unlike most monopartite positive-strand RNA plant viruses, the ORF is not located near the 3' end, but like other members of the Tombusvirus group, CyRSV (cymbidium ringspot virus), TBSV-cherry (tomato bushy stunt virus cherry strain) and CNV (cucumber necrosis virus) it starts ca. 2.7 kb downstream of the 5' end and stops ca. 1 kb upstream of the 3' end. This ORF predicts a polypeptide chain of 387 amino acids. Comparison of the coat proteins of AMCV, TBSV-BS3, TBSV-cherry and CNV confirms that, within the Tombusvirus group, there exists a high degree of similarity among coat proteins but that this similarity is not uniformly distributed among domains. In particular, the N-terminal region, thought to make contact with the phosphate groups of the viral RNA, and the C-terminal region, considered the most immunogenic portion of the capsid, are found to be the least homologous.

Protein accumulation, RNA and soluble amino nitrogen content in developing endosperm of two varieties of Triticum aestivum with high and low protein seed.

The kinetics of protein accumulation, the variation in RNA, the soluble amino nitrogen content of developing endosperm of two varieties of Triticum aestivum, with high and low protein content in the mature seed, suggest a possible relation between maintenance of the RNA content and the ability to synthesize protein. A sudden halt in protein accumulation is observed as the RNA starts to decrease. The hypothesis is also advanced that maintenance of the RNA content might, in turn, be dependent on the presence, in the endosperm of developing wheat seed, of a certain level of soluble amino nitrogen which could then play the role of limiting factor for protein synthesis.

In vivo unwinding fluorimetric assay as evidence of the damage induced by fenarimol and DNOC in rat liver DNA.

Five pesticides [amitraz, cyanazine, cyhexatin, dinitro-o-cresol (DNOC), and fenarimol] were tested as pure active ingredients for in vivo induction of DNA strand breaks on rat hepatocytes after intraperitoneal (ip) treatment. Two pesticides, fenarimol and DNOC, were capable of inducing DNA damage because they significantly increased the DNA unwinding rate. On the contrary, amitraz, cyanazine, and cyhexatin were not DNA-damaging agents.

The T-DNA of Agrobacterium rhizogenes is transmitted through meiosis to the progeny of hairy root plants.

Plants regenerated from tobacco hairy root callus cultures were fertilized by self-pollination, and healthy, morphologically normal R1 offspring were obtained. Three of these R1 seedlings were analyzed for the presence of T-DNA and synthesis of the T-DNA-specific compound agropine. All three R1 plants analyzed contained the same full-length T-DNA as the parental regenerant, while only two showed agropine synthesis.