The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking. METHODS AND ANALYSIS: In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses. ETHICS AND DISSEMINATION: Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained. TRIAL REGISTRATION NUMBER: NTR6982; Pre-results

A pilot study analysing the composition of human milk and assessing the effects of fortification with MIRIS Human Milk Analyzer

Muttermilch (MM) ist einzigartig und stellt den Goldstandard für die Ernährung von Neugeborenen dar. Allerdings enthält MM für extremely low birth weight (ELBW) Säuglinge unzureichende Mengen an Protein. Nährstoffsupplemente zur Anreicherung von MM (human milk fortifier, HMF) wurden entwickelt, um den Nährstoffbedarf von Frühgeborenen zu decken. Durch Einsatz von HMF kann die empfohlene Proteinzufuhr von 4.0- 4.5g/kg/d für Säuglinge unter 1kg Körpergewicht dennoch nicht erreicht werden. Ein neues Supplement (das Aptamil Protein+®-Milupa/Danone) wurde entwickelt. MIRIS (Muttermilch-Analysator) ist ein Gerät, welches zur Messung der MM-Zusammensetzung entwickelt wurde. MIRIS Hersteller haben angegeben, dass es für destilliertes Wasser und MM-Messung vorgesehen ist. Klinisch ist MM-Messung nach Fortifizierung mit HMF und/oder P+® von großem Interesse. Ziel der Compo-HMA Studie: MIRIS auf die Messbarkeit der MM-Zusammensetzung, vor allem des Proteingehalts, nach Gabe von HMF, bovinem Protein Pulvers (P+®) und weiteren Zusatzstoffen (therapeutische Zusatzstoffe=TA) zu evaluieren. Resultate sollen Basis für weitere in vivo MIRIS-Studien sein. Dies war die Pilotstudie zur geplanten klinischen Studie bei Frühgeborenen, der Additional Protein Supplement Study (APSS). Pre-analytische Untersuchungen aller Studienprodukte wurden mit MIRIS im destillierten Wasser durchgeführt und danach in Kombination mit frühgeborenen MM. Zur Validierung wurde MIRIS mit einer Methode, der Elemental Analyse (EA), verglichen. Zusammensetzung wurde in MM, nach Fortifizierung mit HMF (Aptamil 4.3%FMS®-Milupa/Danone und BEBA 5%FM85®-Nestlé) und nach zusätzlicher Proteingabe (P+®-Milupa/Danone) in 0.5g Schritten bis zu 4.0g/100ml (0.5gP+® Pulver enthält 0.4g Protein) evaluiert. Veränderungen unter TA- Beigabe wurde untersucht. Unterschiedliche Prozessierungen und Einfluss auf MIRIS wurde evaluiert. MIRIS lieferte bei pre-analytischen Untersuchungen exakte Ergebnisse von bovinem Protein in Wasser (H20+0.5gP+®=0.4g, H20+4.3%FMS®=0.8g, H20+5%FM85®=1.0g pro 100ml). Abweichung zwischen erwartetem und gemessenem Proteingehalt begann nach Zugabe von 0.5gP+® zu den HM-Fortifier Mischungen und nach 4.0gP+® Beigabe wurde eine Differenz von bis zu 20% beobachtet. Native MM (FMS Gruppe, n=67) setzte sich im Mittelwert aus 1.10.3g Protein, 3.10.8g Fett, 6.60.3g Lactose, 11.70.8g Trockenmasse und 5910kcal Energie/100ml MM zusammen. Nach Fortifizierung von MM mit HMF und 4.0g P+® wurde ein Unterschied im Proteingehalt von 1.0g Protein/100ml in der FMS Gruppe (MIRIS: 4.1g vs. Ziel: 5.1g) und in der FM85 Gruppe (MIRIS: 4.4g vs. Ziel: 5.4g) beobachtet, übereinstimmend mit pre-analytischen Untersuchungen. Im Gegensatz zu MIRIS hat EA den erwarteten Proteingehalt der fortifizierten MM-Mischungen exakt gemessen. Signifikante Unterschiede zwischen beiden Methoden bestätigten, MIRIS lieferte ein zu niedriges Proteingehalt-Ergebnis von fortifizierter MM mit HMF und P+® Mischungen (p<0.05). MIRIS unterschätzte Kohlenhydrate und den Energie-Gehalt. Prozessierungsarten hatten keinen Einfluss auf den Proteingehalt. Laktationstag korrelierte signifikant mit dem Proteingehalt (p<0.0001; r=-,4243). Zugabe von TA beeinflusste MIRIS. MIRIS ist ein geeignetes Instrument, um die Zusammensetzung unfortifizierter MM zu ermitteln. MIRIS ist imstande einzeln bovines (in Wasser) und humanes Protein in MM zu messen. Eine Kombination aus beiden Proteinarten scheint MIRIS in Bezug auf Präzision der Proteinmessung zu beeinflussen. Obwohl Kuh- als auch Frauenmilch ähnlichen Spektralbereich in der IR Spektroskopie aufweisen, aber sich im Profil der Wellenlänge unterscheiden, könnte dies die Erklärung unserer Resultate sein. Prozessierungsarten haben keinen Einfluss auf den Proteingehalt. Von Mutter zu Mutter gibt es große Unterschiede, insbesondere bei Protein. Proteinanteil frühgeborener MM nimmt mit der Lactationsperiode signifikant ab.Human milk (HM) is unique and the gold standard for feeding neonates. However, HM contains insufficient quantity of protein for extremely low birth weight (ELBW) infants. Human milk fortifiers (HMF) have been developed to achieve the nutritional needs of preterm infants. By using these HMF the recommended protein intake of 4.0-4.5g protein/kg/day for infants under 1kg bodyweight can still not be achieved. A new supplement (the Aptamil Protein+®-Milupa/Danone) was developed. The MIRIS (Human Milk Analyzer) is a device designed for the measurement of the nutritional content of HM. Manufacturers of MIRIS device stated that it can be used for distilled water and measurements of the nutritional content of HM. For clinical practice, it would be of high interest to measure HM after fortification with HMF and/or Aptamil Protein+®. Aim of Compo-HMA study was to learn about the capability of MIRIS to measure the composition, particular of the protein content, in HM after addition of HMF, a bovine protein powder (P+®) and further additives (therapeutic additives=TA). These findings can form the basis for other in vivo studies using MIRIS device. This was a pilot study for a subsequent clinical trial in preterm infants named Additional Protein Supplement Study (APSS). Preanalytic testing of all study products in sterile water was performed with MIRIS. Then, study products dissolved in preterm HM were analyzed. For validation, protein measurements were compared between MIRIS and a validated method-the Elemental Analysis (EA). Nutrient composition of HM was measured baseline, after fortification with commercial HMF (Aptamil 4.3%FMS®-Milupa/Danone and BEBA 5%FM85®-Nestlé), and after addition of further protein (Aptamil Protein+®-Milupa/Danone) in 0.5g steps up to 4.0g/100ml (0.5g P+® powder contains 0.4g protein). Nutritional content was determined after adding therapeutic additives. Different milk processing types and the influence on MIRIS measurements was evaluated. Preanalytic testing of study products demonstrated that MIRIS was capable to measure bovine protein dissolved in water accurately (H20+0.5gP+®=0.4g, H20+4.3%FMS®=0.8g, H20+5%FM85®=1.0g per 100ml). Impreciseness between anticipated and measured protein content started after adding 0.5g P+® to HM-fortifier mixtures and revealed up to 20% difference after addition of 4.0g P+®. Native HM (FMS group, n=67) contained in mean 1.10.3g protein, 3.10.8g fat, 6.60.3g lactose, 11.70.8g of dry mass and 5910kcal per 100ml HM. After fortification of HM with HMF and 4.0g Protein+® a deviation in protein content of 1.0g protein/100ml in FMS® group (actual 4.1g vs. target 5.1g) and in FM85® group (actual 4.4g vs. target 5.4g) was observed which is consistent with the findings of preanalytic testing. In contrast to MIRIS, EA measured anticipated protein content of HM fortifier mixtures accurately. Significant differences between the two methods confirmed that MIRIS underestimated the results in protein content of HM fortified with HMF and P+® mixtures (p<0.05). MIRIS underevaluated carbohydrates and energy content. Processing of HM had no effects on protein level. Lactationday correlated significantly with protein content (p<0.0001; r=-,4243). Addition of TA influenced MIRIS measurements of HM. MIRIS is an adjuvant tool to provide the actual nutrient composition of unfortified HM. MIRIS has the ability to measure solely bovine protein (in water) and human protein in HM. A combination of both types of protein generated imprecise results of protein content altogether. Although, cow`s milk and breast milk have a similar spectral region, the wavelength profile is different and this might explain our findings. Processing had no effect on the measured protein content. Variations from mother to mother according to macronutrients are high, particularly in protein. Protein significantly decreased with lactation period in preterm milk.submitted by Alexandra KreißlAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. SpracheWien, Med. Univ., Diss., 2014OeBB(VLID)171605

Correction: Does Visceral Osteopathic Treatment Accelerate Meconium Passage in Very Low Birth Weight Infants?- A Prospective Randomized Controlled Trial.

[This corrects the article DOI: 10.1371/journal.pone.0123530.]

Clinical Oral Investigations / The anti-inflammatory effect of milk and dairy products on periodontal cells : an in vitro approach

Objective Milk can reduce intestinal tissue damage in colitis models, and protects infants against necrotizing enterocolitis. However, whether milk can decrease inflammation related to peri-implantitis and oral mucosal dehiscence remains unclear. We therefore investigated whether or not milk and fermented by-products have any anti-inflammatory effects on the cells of the oral cavity. Material and methods Human gingival fibroblasts and the human oral epithelial cell line HSC2 were exposed to pasteurized human milk, pasteurized cows milk, dairy products, and powdered milk. An inflammatory response was then provoked with IL1 and TNF. The expression changes of IL1, IL6, and IL8 were detected by reverse transcriptase PCR and immunoassay. Results We can report that pasteurized human milk and pasteurized cows milk as well as yoghurt, buttermilk, sour milk, whey, and powdered milk can lower the expression of inflammatory cytokines in gingival fibroblasts being stimulated by IL1 and TNF. A similar anti-inflammatory response to pasteurized milk and dairy products was observed with the human oral epithelial cell line HSC2. Conclusion These data suggest that pasteurized and powdered milk, as well as fermented dairy products, display an anti-inflammatory effect on oral fibroblasts and oral epithelial cells. Clinical relevance Our in vitro findings provide the scientific basis to extend this research towards testing the anti-inflammatory effects of milk in a pre-clinical periodontitis and peri-implantitis model.(VLID)366404

BMC Pediatrics / Clinically relevant body composition methods for obese pediatric patients

Background There is no gold standard in body composition measurement in pediatric patients with obesity. Therefore, the aim of this study was to investigate if there are any differences between two bioelectrical impedance analysis techniques performed in children and adolescents with obesity. Methods Data were collected at the Department of Pediatrics and Adolescent Medicine in Vienna from September 2015 to May 2017. Body composition measurement was performed with TANITA scale and BIA-BIACORPUS. Results In total, 38 children and adolescents (age: 1018years, BMI: 2554kg/m) were included. Boys had significantly increased fat free mass (TANITA p=0.019, BIA p=0.003), total body water (TANITA p=0.020, BIA p=0.005), and basal metabolic rate (TANITA p=0.002, BIA p=0.029). Girls had significantly increased body fat percentage with BIA (BIA p=0.001). No significant gender differences of core abdominal area have been determined. TANITA overestimated body fat percentage (p<0.001), fat mass (p=0.002), and basal metabolic rate (p<0.001) compared to BIA. TANITA underestimated fat free mass (p=0.002) in comparison to BIA. The Bland Altman plot demonstrated a low agreement between the body composition methods. Conclusions Low agreement between TANITA scale and BIA-BIACORPUS has been observed. Body composition measurement should always be performed by the same devices to obtain comparable results. At clinical routine due to its feasibility, safety, and efficiency, bioelectrical impedance analysis is appropriate for obese pediatric patients.(VLID)489645

Does Visceral Osteopathic Treatment Accelerate Meconium Passage in Very Low Birth Weight Infants?- A Prospective Randomized Controlled Trial

<div><p>Background</p><p>To determine whether the complementary approach of visceral manipulative osteopathic treatment accelerates complete meconium excretion and improves feeding tolerance in very low birth weight infants.</p><p>Methods</p><p>This study was a prospective, randomized, controlled trial in premature infants with a birth weight <1500 g and a gestational age <32 weeks who received a visceral osteopathic treatment 3 times during their first week of life or no treatment.</p><p>Results</p><p>Passage of the last meconium occurred after a median of 7.5 days (95% confidence interval: 6–9 days, n = 21) in the intervention group and after 6 days (95% confidence interval: 5-9 days, n = 20,) in the control group (p = 0.11). However, osteopathic treatment was associated with a 8 day longer time to full enteral feedings (p = 0.02), and a 34 day longer hospital stay (Median = 66 vs. 100 days i.e.; p=0.14). Osteopathic treatment was tolerated well and no adverse events were observed.</p><p>Conclusions</p><p>Visceral osteopathic treatment of the abdomen did not accelerate meconium excretion in VLBW (very low birth weight)-infants. However infants in the osteopathic group had a longer time to full enteral feedings and a longer hospital stay, which could represent adverse effects. Based on our trial results, we cannot recommend visceral osteopathic techniques in VLBW-infants.</p><p>Trial registration</p><p>Clinical trials.gov: <a href="https://clinicaltrials.gov/ct2/show/NCT02140710" target="_blank">NCT02140710</a></p></div

Data on respiratory support.

<p>Data on respiratory support.</p

Enemas or suppositories applied in the study (Fisher exact-test).

<p>Enemas or suppositories applied in the study (Fisher exact-test).</p

Demographic characteristics of the study population (Mann- Whitney- U test).

<p>Demographic characteristics of the study population (Mann- Whitney- U test).</p