A common method to quantify chronic stress is the analysis of stress markers in keratinized matrices such as hair or nail. In this study, we aimed to validate a sensitive liquid chromatography–tandem ...mass spectrometry (LC–MS/MS) method for the combined quantification of steroid hormones and endocannabinoids (eCBs) in the keratinized matrix nail. Furthermore, we aimed to investigate the suitability of the nail matrix for the detection of these stress markers in a pilot study. An LC–MS/MS method was used for the simultaneous identification and quantification of four eCBs (2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA)) and five steroid hormones (cortisol, cortisone, androstenedione, progesterone, testosterone) in human nails using a surrogate analyte method for each analyte. The method was validated in terms of selectivity, response factor, linearity, limit of quantification (LOQ), precision, accuracy, matrix effect, recovery, robustness, and autosampler stability. Nail samples were extracted for 1 h with methanol following a clean-up with a fully automated supported liquid extraction (SLE). The influence of nail weight on the quantification was investigated by using 0.5–20 mg of nail sample. As a proof of concept, nail samples (
N
= 57) were analyzed from a cohort representing newborns (1 month old), children (between 1 and 10 years), and adults (up to 43 years). It could be shown that the established workflow using a 1 hour extraction and clean-up by SLE was very robust and resulted in a short sample preparation time. The LC–MS/MS method was successfully validated. Matrix effects with ion enhancement occurred mainly for 2-AG. Sample weights below 5 mg showed variations in quantification for some analytes. Certain analytes such as PEA and progesterone could be accurately quantified at a sample weight lower than 5 mg. This is the first study where steroids and eCBs could be simultaneously detected and quantified in infant and adult nails. These results show that nails may serve as an alternative keratinized matrix (compared to hair) for the retrospective monitoring of cumulative eCB and steroid hormone levels. The combined assessment of eCBs and steroids from nails could provide a new approach to gain new insights into stress exposure in newborns and adults.
Graphical abstract
Very preterm birth often results in the development of bronchopulmonary dysplasia (BPD) with an inverse correlation of gestational age and birthweight. This very preterm population is especially ...exposed to interventions, which affect the development of BPD.
The goal of our review is to summarize the evidence on these daily procedures and provide evidence-based recommendations for the management of BPD.
We conducted a systematic literature research using MEDLINE/PubMed on antenatal corticosteroids, surfactant-replacement therapy, caffeine, ventilation strategies, postnatal corticosteroids, inhaled nitric oxide, inhaled bronchodilators, macrolides, patent ductus arteriosus, fluid management, vitamin A, treatment of pulmonary hypertension and stem cell therapy.
Evidence provided by meta-analyses, systematic reviews, randomized controlled trials (RCTs) and large observational studies are summarized as a narrative review.
There is strong evidence for the use of antenatal corticosteroids, surfactant-replacement therapy, especially in combination with noninvasive ventilation strategies, caffeine and lung-protective ventilation strategies. A more differentiated approach has to be applied to corticosteroid treatment, the management of patent ductus arteriosus (PDA), fluid-intake and vitamin A supplementation, as well as the treatment of BPD-associated pulmonary hypertension. There is no evidence for the routine use of inhaled bronchodilators and prophylactic inhaled nitric oxide. Stem cell therapy is promising, but should be used in RCTs only.
To compare the rates of retinopathy of prematurity (ROP) and treatment of ROP by laser or intravitreal anti-vascular endothelial growth factor among preterm neonates from high-income countries ...participating in the International Network for Evaluating Outcomes (iNeo) of neonates.
A retrospective cohort study was conducted on extremely preterm infants weighing <1500 g at 24
to 27
weeks' gestation who were admitted to neonatal units in Australia/New Zealand, Canada, Finland, Israel, Japan, Spain, Sweden, Switzerland, Tuscany (Italy) and the UK between 2007 and 2013. Pairwise comparisons of ROP treatment in survivors between countries were evaluated by Poisson and multivariable logistic regression analyses after adjustment for confounders. A composite outcome of death or ROP treatment was compared between countries using logistic regression and standardised ratios.
Of 48 087 infants included in the analysis, 81.8% survived to 32 weeks postmenstrual age, and 95% of survivors were screened for ROP. Rates of any ROP ranged from 25.2% to 91.0% in Switzerland and Japan, respectively, among those examined. The overall rate of those receiving treatment was 24.9%, which varied from 4.3% to 30.4%. Adjusted risk ratios for ROP treatment were lower for Switzerland in all pairwise comparisons, whereas Japan displayed significantly higher ratios. Comparisons of the composite outcome between countries revealed similar, but less marked differences.
Rates of any ROP and ROP treatment varied significantly between iNeo members, while an overall decline in ROP treatment was observed during the study period. It is unclear whether these variations represent differences in care practices, diagnosis and/or treatment thresholds.
To evaluate the proportion of neonatal intensive care units with facilities supporting parental presence in their infants’ rooms throughout the 24-hour day (ie, infant-parent rooms) in high-income ...countries and to analyze the association of this with outcomes of extremely preterm infants.
In this survey and linked cohort study, we analyzed unit design and facilities for parents in 10 neonatal networks of 11 countries. We compared the composite outcome of mortality or major morbidity, length of stay, and individual morbidities between neonates admitted to units with and without infant-parent rooms by linking survey responses to patient data from 2015 for neonates of less than 29 weeks of gestation.
Of 331 units, 13.3% (44/331) provided infant-parent rooms. Patient-level data were available for 4662 infants admitted to 159 units in 7 networks; 28% of the infants were cared for in units with infant-parent rooms. Neonates from units with infant-parent rooms had lower odds of mortality or major morbidity (aOR, 0.76; 95% CI, 0.64-0.89), including lower odds of sepsis and bronchopulmonary dysplasia, than those from units without infant-parent rooms. The adjusted mean length of stay was 3.4 days shorter (95%, CI –4.7 to −3.1) in the units with infant-parent rooms.
The majority of units in high-income countries lack facilities to support parents' presence in their infants' rooms 24 hours per day. The availability vs absence of infant-parent rooms was associated with lower odds of composite outcome of mortality or major morbidity and a shorter length of stay.
There are significant international variations in chronic lung disease rates among very preterm infants yet there is little data on international variations in respiratory strategies.
To evaluate ...practice variations in the respiratory management of extremely preterm infants born at < 29 weeks' gestational age (GA) among 10 neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of Neonates collaboration.
A web-based survey was sent to the representatives of 390 neonatal intensive care units from Australia/New Zealand, Canada, Finland, Illinois (USA), Israel, Japan, Spain, Sweden, Switzerland, and Tuscany (Italy). Responses were based on practices in 2015.
Overall, 321 of the 390 units responded (82%). The majority of units within networks (40-92%) mechanically ventilate infants born at 23-24 weeks' GA on continuous positive airway pressure (CPAP) with 30-39% oxygen in respiratory distress within 48 h after birth, but the proportion of units that offer mechanical ventilation for infants born at 25-26 weeks' GA at similar settings varied significantly (20-85% of units within networks). The most common respiratory strategy for infants born at 27-28 weeks' GA on CPAP with 30-39% oxygen with respiratory distress within 48 h after birth used by units also varied significantly among networks: mechanical ventilation (0-60%), CPAP (3-82%), intubation and surfactant administration with immediate extubation (0-75%), and less invasive surfactant administration (0-68%).
There are marked variations but also similarities in respiratory management of extremely preterm infants between networks. Further collaboration and exploration is needed to better understand the association of these variations in practice with pulmonary outcomes.
WHAT IS KNOWN ON THE SUBJECT? Red blood cell transfusions are frequently used in the care of newborns, particularly premature infants. Some countries have guidelines regarding preparation, indication ...and administration of red blood cells in newborns. There are no such guidelines in Switzerland. WHAT DOES THE CURRENT STUDY ADD? This study analysed the results of two national surveys, one among blood transfusion services and the other among neonatal units in Switzerland. The results demonstrate considerable heterogeneity and a lack of "unité de doctrine". Establishment of national guidelines would be helpful and warranted.
The aim of the study was to analyse Swiss practices in blood transfusion services and neonatal units for the preparation and administration of red blood cells in newborns.
Two questionnaires were developed and their results analysed. A first questionnaire was developed for the Swiss blood transfusion services and local hospital haematology laboratories, and a second for the neonatal units in Switzerland.
18/25 (72%) of laboratories and 26/29 (90%) of neonatal units performing red blood cell transfusions participated. Responses revealed a lack of consensus for the majority of questions. Differences were found in all steps of the process, from preparation (testing, irradiation, splitting, shelf life and storage of blood bags) to indication and administration (volume, speed, vascular access, patient monitoring) of red blood cells. Forty-six percent of neonatal units stated that they apply internal guidelines. Nevertheless, all but two would welcome the establishment of national recommendations.
This study confirmed the large variety in neonatal red blood cell transfusion practices in Switzerland. In the absence of clear evidence, national guidelines - as applied in other countries - would foster a common policy among Swiss neonatologists and facilitate the implementation of a national database for future research and comparison with international literature.
A count of 3 neonatal morbidities (bronchopulmonary dysplasia, brain injury, and severe retinopathy of prematurity) strongly predict the risk of death or neurosensory impairment in extremely low ...birth weight infants who survive to 36 weeks' postmenstrual age. Neonatal infection has also been linked with later impairment. We examined whether the addition of infection to the count of 3 neonatal morbidities further improves the prediction of poor outcome.
We studied 944 infants who participated in the Trial of Indomethacin Prophylaxis in Preterms and survived to 36 weeks' postmenstrual age. Culture-proven sepsis, meningitis, and stage II or III necrotizing enterocolitis were recorded prospectively. We investigated the incremental prognostic importance of neonatal infection by adding terms for the different types of infection to a logistic model that already contained terms for the count of bronchopulmonary dysplasia, brain injury, and severe retinopathy. Poor outcome at 18 months of age was death or survival with 1 or more of the following: cerebral palsy, cognitive delay, severe hearing loss, and bilateral blindness.
There were 414 (44%) infants with at least 1 episode of infection or necrotizing enterocolitis. Meningitis and the presence of any type of infection added independent prognostic information to the morbidity-count model. The odds ratio associated with infection or necrotizing enterocolitis in this model was 50% smaller than the odds ratio associated with each count of the other 3 neonatal morbidities. Meningitis was rare and occurred in 22 (2.3%) of 944 infants.
In this cohort of extremely low birth weight infants who survived to 36 weeks' postmenstrual age, neonatal infection increased the risk of a late death or survival with neurosensory impairment. However, infection was a weaker predictor of poor outcome than bronchopulmonary dysplasia, brain injury, and severe retinopathy.
Necrotizing enterocolitis (NEC) is the most common serious acquired disease of the gastrointestinal tract in preterm infants. Probiotic bacteria are live microbial supplements that colonize the ...gastrointestinal tract and potentially provide benefit to the host.
To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and other morbidities in preterm infants.
A meta-analysis was performed in accordance with the Cochrane Neonatal Review Group methods. Preterm infants <37 weeks' gestational age and/or <2,500 g birth weight were included. Literature searches were made of MEDLINE, EMBASE, Cochrane Library Controlled Trials Register (CENTRAL), and abstracts of annual meetings of the Society for Pediatric Research and the European Society of Pediatric Research.
Nine eligible trials randomizing 1,425 infants were included. Included trials were highly variable with regard to enrollment criteria, baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. In a meta-analysis, enteral probiotics supplementation significantly reduced the incidence of severe NEC typical RR 0.32 (95% CI 0.17, 0.60) and mortality typical RR 0.43 (95% CI 0.25, 0.75). There was no evidence of significant reduction of nosocomial sepsis typical RR 0.93 (95% CI 0.73, 1.19) or days on total parenteral nutrition weighted mean difference -1.9 (95% CI -4.6, 0.77). The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. The included trials reported no systemic infection with the probiotics supplemental organism.
Enteral supplementation of probiotics reduces the risk of severe NEC and mortality in preterm infants. A large randomized controlled trial is required to investigate the benefit and safety profile of probiotics supplementation in ELBW infants.
Stopping randomized trials early because of an apparent benefit is becoming more common. To protect and promote the interests of trial participants, investigators may feel obligated to stop a trial ...early because of the apparent benefit of a study treatment (compared with placebo or other treatment). There are, however, serious ethical problems with doing so. Truncated trials systematically overestimate treatment effects; in cases where the number of accrued outcome events is small, the overestimation may be very large. Generating seriously inflated estimates of treatment effect violates the ethical research requirement of scientific validity. Subsequent use of inflated estimates to inform clinical decision making and practice guidelines violates the ethical requirements of social value and a favorable risk-benefit ratio. Researchers should ensure that a large number of outcome events accrues before stopping a trial and then continue recruitment to assess whether positive trends continue. This can balance the need to protect research participants with the ethical requirements of scientific validity, social value, and a favorable risk-benefit ratio.
Long-term survival after premature birth is significantly determined by development of morbidities, primarily affecting the cardio-respiratory or central nervous system. Existing studies are limited ...to pairwise morbidity associations, thereby lacking a holistic understanding of morbidity co-occurrence and respective risk profiles.
Our study, for the first time, aimed at delineating and characterizing morbidity profiles at near-term age and investigated the most prevalent morbidities in preterm infants: bronchopulmonary dysplasia (BPD), pulmonary hypertension (PH), mild cardiac defects, perinatal brain pathology and retinopathy of prematurity (ROP). For analysis, we employed two independent, prospective cohorts, comprising a total of 530 very preterm infants: AIRR ("Attention to Infants at Respiratory Risks") and NEuroSIS ("Neonatal European Study of Inhaled Steroids"). Using a data-driven strategy, we successfully characterized morbidity profiles of preterm infants in a stepwise approach and (1) quantified pairwise morbidity correlations, (2) assessed the discriminatory power of BPD (complemented by imaging-based structural and functional lung phenotyping) in relation to these morbidities, (3) investigated collective co-occurrence patterns, and (4) identified infant subgroups who share similar morbidity profiles using machine learning techniques.
First, we showed that, in line with pathophysiologic understanding, BPD and ROP have the highest pairwise correlation, followed by BPD and PH as well as BPD and mild cardiac defects. Second, we revealed that BPD exhibits only limited capacity in discriminating morbidity occurrence, despite its prevalence and clinical indication as a driver of comorbidities. Further, we demonstrated that structural and functional lung phenotyping did not exhibit higher association with morbidity severity than BPD. Lastly, we identified patient clusters that share similar morbidity patterns using machine learning in AIRR (n=6 clusters) and NEuroSIS (n=8 clusters).
By capturing correlations as well as more complex morbidity relations, we provided a comprehensive characterization of morbidity profiles at discharge, linked to shared disease pathophysiology. Future studies could benefit from identifying risk profiles to thereby develop personalized monitoring strategies.
AIRR: DRKS.de, DRKS00004600, 28/01/2013. NEuroSIS: ClinicalTrials.gov, NCT01035190, 18/12/2009.
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