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.

Increasing market opportunities for renewable energy technologies with innovations in aquifer thermal energy storage.

Heating and cooling using aquifer thermal energy storage (ATES) has hardly been applied outside the Netherlands, even though it could make a valuable contribution to the energy transition. The Climate-KIC project "Europe-wide Use of Energy from aquifers" - E-USE(aq) - aimed to pave the way for Europe-wide application of ATES, through the realization and monitoring of six ATES pilot plants across five different EU countries. In a preceding paper, based on preliminary results of E-USE(aq), conclusions were already drawn, demonstrating how the barriers for this form of shallow geothermal energy can be overcome, and sometimes even leveraged as opportunities. Based on final pilot project results, key economic and environmental outcomes are now presented. This paper starts with the analysis of specific technological barriers: unfamiliarity with the subsurface, presumed limited compatibility with existing energy provision systems (especially district heating), energy imbalances and groundwater contamination. The paper then shows how these barriers have been tackled, using improved site investigation and monitoring technologies to map heterogeneous subsoils. In this way ATES can cost-efficiently be included in smart grids and combined with other sources of renewable (especially solar) energy, while at the same time achieving groundwater remediation. A comparative assessment of economic and environmental impacts of the pilots is included, to demonstrate the sustainability of ATES system with different renewables and renewable-based technologies. The paper concludes with an assessment of the market application potential of ATES, including in areas with water scarcity, and a review of climate beneficial impact.

A solution based on melatonin, tryptophan, and vitamin B6 (Melamil Tripto©) for sedation in newborns during brain MRI.

INTRODUCTION: Melatonin has been studied and used for several years as a sleep-wake cycle modulator in patients with sleep disorders. Experimental evidence has demonstrated the multiple neuroprotective benefits of this indoleamine secreted by the pineal gland. Melatonin is also used in neurological investigations, for its ability to induce sleep in children. In fact, it favors falling asleep during electroencephalogram, Magnetic Resonance Imaging (MRI), and during brainstem auditory evoked potentials. Previous studies are focused on infants and children. No investigation have been performed in neonates, before or during instrumental assessments. MATERIAL AND METHODS: One hundred ten newborns (term and preterm) undergoing brain MRI were enrolled in the study. Thirty minutes before the planned time for the examination, we administered a single dose solution of melatonin- tryptophan-vitamin B6. Twenty minutes after the initial administration of 2 mg, a second dose of 1 mg was administered, if the baby was still awake. If after further 15 min the baby was still not sleeping, an additional dose of 1 mg was administered. RESULTS: In 106 patients we obtained adequate sedation without adverse events, allowing us to perform an adequate quality MRI, with a median time of 25 min to reach sleeping. Only in three patients MRI could not be performed. In patients having a large weight, higher doses of melatonin were necessary to reach sleeping. Considering the pro kg dose of melatonin, the average dose that induced sleepiness in neonates was 0,64 ± 0.16 mg/Kg. CONCLUSION: A solution based on Melatonin- tryptophan-vitamin B6 can be a helpful sedative to administer to neonates undergoing brain MRI, avoiding the use of anesthetics and achieving adequate assessments.

Low carbon heating and cooling by combining various technologies with Aquifer Thermal Energy Storage.

A transition to a low carbon energy system is needed to respond to global challenge of climate change mitigation. Aquifer Thermal Energy Storage (ATES) is a technology with worldwide potential to provide sustainable space heating and cooling by (seasonal) storage and recovery of heat in the subsurface. However, adoption of ATES varies strongly across Europe, because of both technical as well as organizational barriers, e.g. differences in climatic and subsurface conditions and legislation respectively. After identification of all these barriers in a Climate-KIC research project, six ATES pilot systems have been installed in five different EU-countries aiming to show how such barriers can be overcome. This paper presents the results of the barrier analysis and of the pilot plants. The barriers are categorized in general barriers, and barriers for mature and immature markets. Two pilots show how ATES can be successfully used to re-develop contaminated sites by combining ATES with soil remediation. Two other pilots show the added value of ATES because its storage capacity enables the utilization of solar heat in combination with solar power production. Finally, two pilots are realized in countries with legal barriers where ATES systems have not previously been applied at all.

Early manifestation of arm-leg coordination during stepping on a surface in human neonates.

The accomplishment of mature locomotor movements relies upon the integrated coordination of the lower and upper limbs and the trunk. Human adults normally swing their arms and a quadrupedal limb coordination persists during bipedal walking despite a strong corticospinal control of the upper extremities that allows to uncouple this connection during voluntary activities. Here we investigated arm-leg coordination during stepping responses on a surface in human neonates. In eight neonates, we found the overt presence of alternating arm-leg oscillations, the arms moving up and down in alternation with ipsilateral lower limb movements. These neonates moved the diagonal limbs together, and the peak of the arm-to-trunk angle (i.e., maximum vertical excursion of the arm) occurred around the end of the ipsilateral stance phase, as it occurs during typical adult walking. Although episodes of arm-leg coordination were sporadic in our sample of neonates, their presence provides significant evidence for a neural coupling between the upper and lower limbs during early ontogenesis of locomotion in humans.

Corrigendum: Foot Placement Characteristics and Plantar Pressure Distribution Patterns during Stepping on Ground in Neonates.

[This corrects the article on p. 784 in vol. 8, PMID: 29066982.].

Foot Placement Characteristics and Plantar Pressure Distribution Patterns during Stepping on Ground in Neonates.

Stepping on ground can be evoked in human neonates, though it is rather irregular and stereotyped heel-to-toe roll-over pattern is lacking. Such investigations can provide insights into the role of contact- or load-related proprioceptive feedback during early development of locomotion. However, the detailed characteristics of foot placements and their association with motor patterns are still incompletely documented. We elicited stepping in 33 neonates supported on a table. Unilateral limb kinematics, bilateral plantar pressure distribution and EMG activity from up to 11 ipsilateral leg muscles were recorded. Foot placement characteristics in neonates showed a wide variation. In ~25% of steps, the swinging foot stepped onto the contralateral foot due to generally small step width. In the remaining steps with separate foot placements, the stance phase could start with forefoot (28%), midfoot (47%), or heel (25%) touchdowns. Despite forefoot or heel initial contacts, the kinematic and loading patterns markedly differed relatively to toe-walking or adult-like two-peaked vertical force profile. Furthermore, while the general stepping parameters (cycle duration, step length, range of motion of proximal joints) were similar, the initial foot contact was consistently associated with specific center-of-pressure excursion, range of motion in the ankle joint, and the center-of-activity of extensor muscles (being shifted by ~5% of cycle toward the end of stance in the "heel" relative to "forefoot" condition). In sum, we found a variety of footfall patterns in conjunction with associated changes in motor patterns. These findings suggest the potential contribution of load-related proprioceptive feedback and/or the expression of variations in the locomotor program already during early manifestations of stepping on ground in human babies.

Caffeine citrate: when and for how long. A literature review.

The efficacy of caffeine in an episode of Apnoea of Prematurity (AOP) has been known for over thirty years. Its use over long periods of time has not only found it to be manageable within the field of neonatology, but it has also been found to have other favourable actions, such as reducing the incidence of extubation failure, preventing Bronchopulmonary Dysplasia (BPD), reducing the need for Patent Ductus Arteriosus treatment and the beneficial effect it has on Retinopathy of Prematurity. Recent in vitro trials have highlighted the neuroprotective role that caffeine plays, which has already partly been observed from in vivo trials. Just recently, caffeine citrate has become a "label" drug and it would be beneficial if more studies could confirm the more significant effects it has on the more severe conditions of prematurity.

Neonatal outcomes in a population of late-preterm infants.

The late-preterm infants are a group of premature steadily increasing, different from term infants as immature in terms of respiratory, metabolic, neurological, and immunological features. They may present at birth and during the first week of life various diseases and brain lesions echographically evident. We analyzed the neonatal outcomes of 417 late-preterm infants, born in our Department of Neonatology in a period of two and a half years, evaluating respiratory problems (RDS, transient tachypnea, pneumonia, pneumothorax, and apnea), metabolic problems (hypoglycemia, hypomagnesemia, hypo-hypernatremia, dehydration, hypocalcemia, and hyperbilirubinemia), infections, neurological symptoms associated with electrolyte disturbances, the disease patterns observed by ultrasound examination of the brain, the kidney ultrasound images, genital malformations.

Sequence comparison of the EcoHK31I and EaeI restriction-modification systems suggests an intergenic transfer of genetic material.

The genes coding for the EcoHK31I and EaeI restriction-modification (R-M) systems from Escherichia coli strain HK31 and Enterobacter aerogenes, respectively, have been cloned and sequenced. Both ENases recognize and cleave Y/GGCCR leaving 4 nucleotide 5'-protruding ends, while the MTases modify the internal cytosine. The systems were isolated on a 2.3kb AseI fragment for EcoHK31I, and a 4.6 kb HindIII fragment for EaeI. The R and M genes of both systems converge and overlap by 14 nucleotides. Previously, we found that M.EcoHK31I consisted of two subunits, (alpha and beta), with the beta subunit being translated from an alternative open reading frame within the gene encoding the alpha subunit. Sequence comparison between the EcoHK31I and EaeI systems reveals striking similarity. The eaeIM gene also encodes alpha and beta polypeptides of 309 and 176 amino acids which share 96% and 97% identity, respectively, with those of ecoHK31IM. ecoHK31IR and eaeIR encode proteins of 318 and 315 aa, respectively, which share 92% identity but are otherwise unique in the GenBank database. The EaeI and the EcoHK31I R-M systems were found to be flanked by genes coding for integrases. It is possible that these integrases have facilitated the transfer of this system among different bacterial species.

Effects of long-term growth hormone therapy on adrenal steroidogenesis in Turner syndrome.

It has been shown that growth hormone (GH) and insulin-like growth factor-1 (IGF1) enhance steroidogenesis responsiveness to ACTH in cultured adrenal cells. To investigate the GH effect on adrenal steroidogenesis in non-GH-deficient subjects, we studied 9 girls with Turner syndrome (chronological age 5.5-7.2 years; bone age 5-7 years). In all subjects an ACTH test (Synacthen depot, 0.25 mg i.v. with blood samples at 0 and 60 min) was performed basally at 8-9 a.m. and 6 months after GH therapy (1 IU/kg/week). 17-Hydroxypregnenolone (17PGN), 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHA), its sulfate (DHA-S), androstenedione and cortisol were evaluated by radioimmunoassay. Two groups of normal girls were selected as controls: group A age-matched the patients at the start of the study, and group B age-matched the patients at the end of the study. The responsiveness of each hormone to ACTH was expressed as the difference between stimulated and basal values. A p value of < 0.01 was considered to indicate significance. There were no significant differences between pre- and posttreatment basal values of 17PGN, 17OHP, DHA, androstenedione and cortisol in the Turner syndrome patients, whereas a significant increase was observed for basal DHA-S (1.57+/-0.31; 1.89+/-0.43 micromol/l, p < 0.01). Comparison of increments before and after GH treatment showed a significant increase in responsiveness to ACTH after GH therapy DHA (p < 0.01). The increase in 17PGN was evident (p < 0.02), but the established significant p value was not reached. No differences for 17OHP, androstenedione and cortisol were found. The stimulated 17PGN/17OHP ratio was significantly higher (p < 0.01) after GH, whereas the 17OHP/androstenedione ratio was considerably lower, but the p value was < 0.02. No differences between pretreatment values with the control group androstenedione was found, whereas basal and stimulated posttreatment values of DHA and stimulated values of 17PGN were higher in patients after GH therapy than in control group B. No differences between the 2 control groups were found. In conclusion our study showed that adrenal steroid responsiveness to ACTH increases in Turner syndrome after long-term treatment with high GH doses. An increase in the number of ACTH adrenal receptors and/or a modulation of enzyme activities may be suggested. The positive or negative pharmacological implications of these data remain to be determined especially when taking into consideration the wide use of GH therapy in non-GH-deficient subjects.

Adult height in short normal adolescent girls treated with gonadotropin-releasing hormone analog and growth hormone.

GnRH analog associated with GH therapy has potential importance for treatment of short stature in subjects without GH deficiency and with a normal onset of puberty. We treated 10 girls with familial short stature with the GnRH analog leuprolide (3.75 mg, im, every 25 days) and GH (0.1 IU/kg.day, sc, 6 days/week). The combined therapies were started simultaneously, and the patients were treated for 28.1 +/- 5.4 (range, 24-36) months. At the onset of treatment, chronological age was 11.6 +/- 1.4 yr, bone age was 10.6 +/- 0.9 yr, height was -2.7 +/- 0.7 SD, predicted height (PH; Bayley-Pinneau score) was 143.2 +/- 3 cm. Target height was 147.6 +/- 5.6 cm. Tanner stage was II-III for breast and genitalia. During treatment, puberty was completely suppressed in all patients. Statistical analysis was performed using Student's t test for paired data. After 12 months of treatment, we observed a significant (P < 0.02) improvement of predicted height (146.2 +/- 3.4 cm). This improvement remained significant (147.6 +/- 3.5; P < 0.001) when treatment was withdrawn. At that time, chronological age was 13.9 +/- 1.2 yr, and bone age was 12.4 +/- 0.7 yr. At the present time (3 +/- 0.97 yr after discontinuation), all of the girls have reached a final height of 144.6 +/- 3 cm (range, 140-149.3 cm). The final height is not significantly different compared with the PH at the beginning of treatment or with target height. These data show that in our patients, combined treatment with GnRH analog and GH, despite a significant improvement in PH during therapy and upon its withdrawal, does not result in a significant increase in adult stature. Larger and perhaps more prolonged studies in patients of both sexes are required to reach definitive conclusions. Nevertheless, the cost of this treatment in terms of both subject compliance and economic cost should be weighed against the small height gain, if any, that may be achieved.

Primary carcinoma of the vagina. Case report.

An unusual case of Primary Carcinoma of the vagina was recently observed. The patient was treated surgically in 1981 for squamous cervical carcinoma in situ (CIN 3); eight years later the same patient was treated for squamous carcinoma of the vagina that involved the upper, median and lower tract. She was treated with radical colpectomy and VBP chemotherapy for three courses. The pathology, natural history and treatment are discussed.

Ultrasound with graded compression in the evaluation of acute appendicitis.

Acute appendicitis is the most common diagnosis made (in the Western world) in patients with an "acute abdomen." Although the mortality rate has been vastly reduced, the diagnostic inaccuracy rate of 15% to 20% has remained unchanged in the past 100 years. In this article, the authors report the ultrasonographic findings in 80 patients examined using a small linear-array transducer, which enables direct visualization of the inflamed appendix. During 22 months, 80 patients (28 males and 52 females; age range, 3 to 81 years; mean, 32.3 years) with equivocal clinical signs and symptoms of acute appendicitis were examined sonographically. Of the 29 patients whose appendicitis was verified at surgery, ultrasonography was positive in 26, with an overall sensitivity of 90%. Of the 51 patients who did not have appendicitis, ultrasonography was negative in all, with a specificity of 100%. The authors concur with reports in the literature that ultrasonography is helpful in diagnosing appendicitis.

Abdominal colectomy for chronic encephalopathy due to portal-systemic shunt.

Chronic portal-systemic encephalopathy (CPSE) following portal-systemic shunts may be incapacitating and non-responsive to intensive medical management. Between 1960 and 1980, 12 patients with cirrhosis who were institutionalized with CPSE underwent colonic exclusion. Cirrhosis was due to alcohol in ten patients and to cryptogenic liver disease in two. Nine patients had previously undergone end-to-side portacaval shunts and two patients had had mesocaval shunts. One patient had a spontaneous shunt between splenic and renal veins. Ten patients underwent colectomy and ileosigmoidostomy; one had colectomy, ileostomy, and mucous fistula; and one had colonic bypass and ileosigmoidostomy. Four patients died postoperatively. Survivors were clinically improved and able to leave a closed institutional environment. Colectomy may be considered in disabling cases of CPSE unresponsive to medical therapy; it is a final effort at functional rehabilitation. Although mortality is high, improvement in functional status can be expected among survivors of the operation.