Randomised crossover study on pulse oximeter readings from different sensors in very preterm infants.

OBJECTIVE: In extremely preterm infants, different target ranges for pulse oximeter saturation (SpO2) may affect mortality and morbidity. Thus, the impact of technical changes potentially affecting measurements should be assessed. We studied SpO2 readings from different sensors for systematic deviations. DESIGN: Single-centre, randomised, triple crossover study. SETTING: Tertiary neonatal intensive care unit. PATIENTS: 24 infants, born at <32 weeks' gestation, with current weight <1500 g and without right-to-left shunt via a patent ductus arteriosus. INTERVENTIONS: Simultaneous readings from three SpO2 sensors (Red Diamond (RD), Photoplethysmography (PPG), Low Noise Cabled Sensors (LNCS)) were logged at 0.5 Hz over 6 hour/infant and compared with LNCS as control using analysis of variance. Sensor position was randomly allocated and rotated every 2 hours. Seven different batches each were used. OUTCOMES: Primary outcome was the difference in SpO2 readings. Secondary outcomes were differences between sensors in the proportion of time within the SpO2-target range (90-95 (100)%). RESULTS: Mean gestational age at birth (±SD) was 274/7 (±23/7) weeks, postnatal age 20 (±20) days. 134 hours of recording were analysed. Mean SpO2 (±SD) was 94.0% (±3.8; LNCS) versus 92.2% (±4.0; RD; p<0.0001) and 94.5% (±3.9; PPG; p<0.0001), respectively. Mean SpO2 difference (95% CI) was -1.8% (-1.9 to -1.8; RD) and 0.5% (0.4 to 0.5; PPG). Proportion of time in target was significantly lower with RD sensors (84.8% vs 91.7%; p=0.0001) and similar with PPG sensors (91.1% vs 91.7%; p=0.63). CONCLUSION: There were systematic differences in SpO2 readings between RD sensors versus LNCS. These findings may impact mortality and morbidity of preterm infants, particularly when aiming for higher SpO2-target ranges (eg, 90-95%). TRIAL REGISTRATION NUMBER: DRKS00027285.

Parental perspectives about information and deferred versus two-stage consent in studies of neonatal asphyxia.

OBJECTIVE: The ALBINO Trial (NCT03162653) investigates effects of very early postnatal allopurinol on neurocognitive outcome following perinatal asphyxia where prenatal informed consent (IC) is impossible. Ethically and legally, waiver of consent and/or deferred consent (DC) is acceptable in such an emergency. Short oral/two-step consent (SOC, brief information and oral consent followed by IC) has recently been investigated. METHODS: Mixed-methods analysis of parental opinions on DC versus SOC in the context of neonatal asphyxia in a survey at two German centres. Prospective parents (ProP), parents of healthy newborns (PNeo) and parents of asphyxiated infants (PAx) born between 2006 and 2016 were invited. RESULTS: 108 of 422 parents participated (ProP:43; PNeo:35; PAx:30). Most parents trusted physicians, wanted preinterventional information and agreed that in emergencies interventions should begin immediately. Intergroup and intragroup variability existed for questions about DC and SOC. In the ALBINO Trial situation, 55% preferred SOC, and 26% reported DC without information might adversely affect their trust. Only 3% reported to potentially take legal action after DC. PAx were significantly more likely to support DC. PAx more frequently expressed positive emotions and appreciation for neonatal research. In open-ended questions, parents gave many constructive recommendations. CONCLUSION: In this survey, parents expressed diverse opinions on consent, but the majority preferred SOC over DC. Parents who had experienced emergency admission of their asphyxiated neonates were more trusting. Obtaining parental perspectives is essential when designing studies, while being cognisant that these groups of parents may not represent the opinion of all parents.

Quantifying workload using nonlinear dynamical measures of biomechanical parameters during cycling on a roller trainer.

The aim of the present study was to determine the effectiveness of nonlinear parameters in distinguishing individual workload in cycling by using bike-integrated sensor data. The investigation focused on two nonlinear parameters: The ML1, which analyzes the geometric median in phase space, and the maximum Lyapunov exponent as nonlinear measure of local system stability. We investigated two hypothesis: 1. ML1α, derived from kinematic crank data, is as good as ML1F, derived from force crank data, at distinguishing between individual load levels. 2. Increasing load during cycling leads to decreasing local system stability evidenced by linearly increasing maximal Lyapunov exponents generated from kinematic data. A maximal incremental cycling step test was conducted on an ergometer, generating complete datasets from 10 participants in a laboratory setting. Pedaling torque and kinematic data of the crank were recorded. ML1F, ML1α, and Lyapunov parameters (λst, λlt, ιst, ιlt) were calculated for each participant at comparable load levels. The results showed a significant linear increase in ML1α across three individual load levels, with a lower but still large effect compared to ML1F. The contrast analysis also confirmed a linearly increasing trend for λst across three load levels, but this was not confirmed for λlt. However, the intercepts ιst and ιlt of the short- and longterm divergence showed a statistically significant linear increase across the load levels. In summary, nonlinear parameters seem fundamentally suitable to distinguish individual load levels in cycling. It is concluded that higher load during cycling is associated with decreasing local system stability. These findings may aid in developing improved e-bike propulsion algorithms. Further research is needed to determine the impact of factors occurring in field application.

Comparison of statistical models for characterizing continuous differences between two biomechanical measurement systems.

Most biomechanical processes are continuous in nature. Measurement systems record this continuous behavior as curve data, which is often treated inappropriately in validation studies. The current paper compares different statistical models for analyzing the agreement of curves from two measurement systems. All models were evaluated in various error scenarios (simulated and real-world data). Excellent results were obtained using a functional method, with coverage probabilities close to the desired level in all data sets. Pointwise constructed bands had a lower coverage probability, but still contained most of the curve points and may thus be an option in scenarios where assumptions of functional models are violated (e.g., when curves are much noisier than those presented here, or in the presence of drift). Models that account for within-subject variation showed a higher coverage probability and less uncertainty about the variation of band limits. We hope this study, along with the provided research code, will inspire researchers to use methods for curve data more frequently and appropriately.

Effects of an active hand exoskeleton on forearm muscle activity in industrial assembly grips.

BACKGROUND: The Bioservo Ironhand® is a commercially available active hand exoskeleton for reducing grip-induced stress. OBJECTIVES: The study aimed at quantifying the effect of the Ironhand® exoskeleton on the myoelectric muscle activity of forearm flexor and extensor muscles in three relevant assembly grip tasks: 2-Finger-grip (2Finger), 5-Finger-grip (5Finger) and Full grip (FullGrip). METHODS: Twenty-two subjects were tested in three different exoskeleton conditions for each grip task (overall 3×3×10 = 90 repetitions in randomized order): Exoskeleton off (Off), Exoskeleton on, "locking tendency" 0% (On_LT0), and Exoskeleton on, "locking tendency" 85% (On_LT85). Muscle activity was measured at 25% of the participant's maximum grip force using two EMG sensors at the M. flexor digitorum superficialis (M.FDS) and one at the M. extensor digitorum (M.ED). RESULTS: The effect of the Ironhand® exoskeleton varied depending on the grip task and the participant's sex. A statistically significant reduction in muscle activity of the M.FDS was found only for male subjects in the FullGrip condition. No reduction of muscular activity in the M.FDS was found for the other grip tasks (2Finger, 5Finger). For the females in the 2Finger condition, mean muscle activity of M.FDS even increased significantly in On_LT0 compared to Off. Besides differences between grip tasks and sex, the current study revealed substantial individual differences. CONCLUSIONS: In addition to testing for statistical significance, a detailed exploratory analysis of exoskeleton effects at subject level should be performed to evaluate these from a safety and regulatory perspective.

Differential metabolism of choline supplements in adult volunteers.

BACKGROUND: Adequate intake of choline is essential for growth and homeostasis, but its supply does often not meet requirements. Choline deficiency decreases phosphatidylcholine (PC) and betaine synthesis, resulting in organ pathology, especially of liver, lung, and brain. This is of particular clinical importance in preterm infants and cystic fibrosis patients. We compared four different choline supplements for their impact on plasma concentration and kinetics of choline, betaine as a methyl donor and trimethylamine oxide (TMAO) as a marker of bacterial degradation prior to absorption. METHODS: Prospective randomized cross-over study (1/2020-4/2020) in six healthy adult men. Participants received a single dose of 550 mg/d choline equivalent in the form of choline chloride, choline bitartrate, α-glycerophosphocholine (GPC), and egg-PC in randomized sequence at least 1 week apart. Blood was taken from t = - 0.1-6 h after supplement intake. Choline, betaine, TMAO, and total PC concentrations were analyzed by tandem mass spectrometry. Results are shown as medians and interquartile range. RESULTS: There was no difference in the AUC of choline plasma concentrations after intake of the different supplements. Individual plasma kinetics of choline and betaine differed and concentrations peaked latest for PC (at ≈3 h). All supplements similarly increased plasma betaine. All water-soluble supplements rapidly increased TMAO, whereas egg-PC did not. CONCLUSION: All supplements tested rapidly increased choline and betaine levels to a similar extent, with egg-PC showing the latest peak. Assuming that TMAO may have undesirable effects, egg-PC might be best suited for choline supplementation in adults. STUDY REGISTRATION: This study was registered at "Deutsches Register Klinischer Studien" (DRKS) (German Register for Clinical Studies), 17.01.2020, DRKS00020454.

Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates.

BACKGROUND: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. OBJECTIVE: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. METHODS: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. RESULTS: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62-1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25-2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23-0.3) and 11 L (95% CI 9.9-12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31-0.42). CONCLUSION: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.

Catheter insertion depths in less-invasive surfactant administration.

INTRODUCTION: Less-invasive surfactant administration (LISA) under continuous positive airway pressure is increasingly used for the treatment of neonatal respiratory distress. Different procedures are described, but data on the optimal catheter insertion depth are sparse. OBJECTIVE: To generate data for recommending an optimal catheter insertion depth in LISA. METHODS: We examined 112 anterior-posterior chest X-rays from intubated infants and determined the carina's vertebral projection, whenever possible. After that, distances between the middle of cervical vertebra 4 (C4) and thoracic vertebra 2 and the middle of C4 to thoracic vertebra 3, respectively, were measured. Results were plotted against infant's weight. RESULTS: A weight-based chart and recommendations for the optimal intratracheal catheter position in infants with a body weight between 350 and 4000 g were created. CONCLUSIONS: Generated data offer standardisation and may thus help to find a balance between risk of surfactant reflux and unilateral surfactant administration.

Comparison of nostril sizes of newborn infants with outer diameter of endotracheal tubes.

BACKGROUND: Recommendations for endotracheal tube (ETT) size usually refer to the inner diameter (ID). Outer diameters (OD), however, vary greatly between manufacturers, which in some brands might cause difficulties in passing the ETT through the nostrils if choosing the nasal route for intubation. Even though the nostrils are dilatable by an ETT, it might be difficult to pass an ETT through the posterior naris (narrowest point of the nasal passage), if the OD is bigger than the nostrils. Therefore, nostril size may provide some guidance for the appropriate ETT size preventing unsuccessful intubation attempts. This study therefore compares nostril sizes of newborn infants with ODs of ETTs from several manufacturers. METHODS: This is a subgroup analysis of a prospective observational study, performed in a single tertiary perinatal centre in Germany. The diameter of the nostril of infants born between 34 and 41 weeks´ gestation was measured in 3D images using 3dMDvultus software and compared to the OD of ETT from five different manufacturers. RESULTS: Comparisons of nostril sizes with ODs of different ETTs were made for 99 infants with a mean (SD) birthweight of 3058g (559) [range: 1850-4100g]. Mean (SD) nostril size was 5.3mm (0.6). The OD of the 3.5mm ETT of different manufacturers ranged from 4.8-5.3mm and was thus larger than the nostril size of 20-46% of late preterm or term infants. Some OD of a 3.0mm ETT were even bigger than the OD of a 3.5mm ETT (e.g. the 3.0mm ETT from Rüsch® has an OD of 5.0mm while the 3.5mm ETT from Portex® has an OD of 4.8mm). CONCLUSIONS: Clinicians should be aware of the OD of ETTs to reduce unsuccessful intubation attempts caused by ETT sizes not fitting the nasal cavity. Generated data may help to adapt recommendations in future. TRIAL REGISTRATION: Subgroup analysis of the "Fitting of Commonly Available Face Masks for Late Preterm and Term Infants (CAFF)"-study: NCT03369028, www.ClinicalTrials.gov , December 11, 2017.

Icy road ahead-rapid adjustments of gaze-gait interactions during perturbed naturalistic walking.

Most humans can walk effortlessly across uniform terrain even when they do not pay much attention to it. However, most natural terrain is far from uniform, and we need visual information to maintain stable gait. Recent advances in mobile eye-tracking technology have made it possible to study, in natural environments, how terrain affects gaze and thus the sampling of visual information. However, natural environments provide only limited experimental control, and some conditions cannot safely be tested. Typical laboratory setups, in contrast, are far from natural settings for walking. We used a setup consisting of a dual-belt treadmill, 240\(^\circ\) projection screen, floor projection, three-dimensional optical motion tracking, and mobile eye tracking to investigate eye, head, and body movements during perturbed and unperturbed walking in a controlled yet naturalistic environment. In two experiments (N = 22 each), we simulated terrain difficulty by repeatedly inducing slipping through accelerating either of the two belts rapidly and unpredictably (Experiment 1) or sometimes following visual cues (Experiment 2). We quantified the distinct roles of eye and head movements for adjusting gaze on different time scales. While motor perturbations mainly influenced head movements, eye movements were primarily affected by the presence of visual cues. This was true both immediately following slips and-to a lesser extent-over the course of entire 5-min blocks. We find adapted gaze parameters already after the first perturbation in each block, with little transfer between blocks. In conclusion, gaze-gait interactions in experimentally perturbed yet naturalistic walking are adaptive, flexible, and effector specific.

Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance.

BACKGROUND: Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. OBJECTIVES: The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. METHODS: The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. RESULTS: Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). CONCLUSIONS: Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03162653.

Clinical evaluation of an application aid for less-invasive surfactant administration (LISA).

BACKGROUND: Less-invasive surfactant administration (LISA) is increasingly used. We investigated the feasibility of a new LISA-device (Neofact®) in neonates. DESIGN: Prospective observational pilot study with open-label LISA in two tertiary neonatal intensive care units. PATIENTS: 20 infants with a gestational age of ≥26+0/7 weeks and an indication for LISA (Respiratory Severity Score (RSS)≥5 or fraction of inspired oxygen (FiO2) ≥0.30). Infants with respiratory tract malformations or unavailability of an instructed neonatologist were excluded. MAIN OUTCOME MEASURES: Success of LISA, defined as laryngoscopy-confirmed intratracheal catheter position or a decrease in FiO2 by ≥0.05 or to 0.21, accompanied by an RSS decrease of ≥2; number of attempts needed for tracheal catheterisation. RESULTS: 20/57 screened infants were enrolled. Successful application occurred in 19/20 (95%). One application failed after three attempts. No device-related adverse events occurred. The median number of attempts was 2, success rate per attempt 19/31 (61%). CONCLUSION: LISA via Neofact® appears feasible.

Nasal insertion depths for neonatal intubation.

AIM: Data on the depth of nasal intubation in neonates are rare, although this is the preferred route in some countries. Therefore, recommendations on optimal nasal intubation depths based on gestational age (GA) and weight are desirable. METHODS: We determined the distances between the middle of thoracic vertebrae 2 (T2) and the tip of the endotracheal tube in 116 X-rays from nasally intubated neonates. The intubation depth (tip to nostril distance) that was documented in the digital patient's file was then corrected for this distance to reach an optimal nasal insertion depth. Results were plotted against the infant's GA and weight. RESULTS: GA-based and birthweight-based charts and formulas for the nasal intubation depth in infants with a GA between 24 and 43 weeks and body weight between 400 and 4500 g were created. CONCLUSIONS: Generated data may help in predicting optimal insertion depths for nasal intubation in neonates.

Microbiological analyses of nasally guided catheters after less invasive surfactant administration - a pilot study.

BACKGROUND: Respiratory distress syndrome (RDS) is a frequent complication of premature birth. Treating RDS by continuous positive airway pressure and less invasive surfactant administration (LISA) may reduce bronchopulmonary dysplasia. Surfactant, however, can be inactivated by bacterial infection. Therefore, potential routes of microbe transmission into the airway are of interest. The aim of this study was to evaluate microbiological contamination of catheters used for LISA procedures and its association with postnatal age. METHODS: Catheter tips used for LISA procedures via the nasal route (LISA-n) in infants with RDS were placed into a sterile eSwab container directly after the procedure, cultured and examined for microbiological contamination. RESULTS: Interpretable results could be collected from 20 catheter tips. Four showed positive culture results (20%) with microbes potentially associated with the development of early onset neonatal sepsis. Risk of positive microbe detection increased with postnatal age (< 4 h: 10%; 4-18 h: 20%; > 18 h: 40%). CONCLUSIONS: In this pilot study, the risk of tracheal microbe transmission following the LISA-n procedure increased with postnatal age. Although the clinical relevance of this finding is unclear, earlier surfactant administration might reduce the risk of catheter contamination. TRIAL REGISTRATION NUMBER: Substudy of the registered Trial: feasibility study - Neofact: NCT04086095, www.ClinicalTrials.gov, September 11, 2019.

Effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) on outcome of extremely preterm infants - study protocol of a randomized controlled parallel group multicenter trial for safety and efficacy.

BACKGROUND: Most extremely low gestational age neonates (ELGANS, postmenstrual age at birth (PMA) < 28 completed weeks) require supplemental oxygen and experience frequent intermittent hypoxemic and hyperoxemic episodes. Hypoxemic episodes and exposure to inadequately high concentrations of oxygen are associated with an increased risk of retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI), and death beyond 36 weeks PMA. Closed-loop automated control of the inspiratory fraction of oxygen (FiO2-C) reduces time outside the hemoglobin oxygen saturation (SpO2) target range, number and duration of hypo- and hyperoxemic episodes and caregivers' workload. Effects on clinically important outcomes in ELGANs such as ROP, BPD, NEC, NDI and mortality have not yet been studied. METHODS: An outcome-assessor-blinded, randomized controlled, parallel-group trial was designed and powered to study the effect of FiO2-C (in addition to routine manual control (RMC) of FiO2), compared to RMC only, on death and severe complications related to hypoxemia and/or hyperoxemia. 2340 ELGANS with a GA of 23 + 0/7 to 27 + 6/7 weeks will be recruited in approximately 75 European tertiary care neonatal centers. Study participants are randomly assigned to RMC (control-group) or FiO2-C in addition to RMC (intervention-group). Central randomization is stratified for center, gender and PMA at birth (< 26 weeks and ≥ 26 weeks). FiO2-C is provided by commercially available and CE-marked ventilators with an FiO2-C algorithm intended for use in newborn infants. The primary outcome variable (composite of death, severe ROP, BPD or NEC) is assessed at 36 weeks PMA (or, in case of ROP, until complete vascularization of the retina, respectively). The co-primary outcome variable (composite outcome of death, language/cognitive delay, motor impairment, severe visual impairment or hearing impairment) is assessed at 24 months corrected age. DISCUSSION: Short-term studies on FiO2-C showed improved time ELGANs spent within their assigned SpO2 target range, but effects of FiO2-C on clinical outcomes are yet unknown and will be addressed in the FiO2-C trial. This will ensure an appropriate assessment of safety and efficacy before FiO2-C may be implemented as standard therapy. TRIAL REGISTRATION: The study is registered at www.ClinicalTrials.gov: NCT03168516 , May 30, 2017.

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).

BACKGROUND: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. METHODS: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. DISCUSSION: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. TRIAL REGISTRATION: NCT03162653, www.ClinicalTrials.gov , May 22, 2017.

Phase space methods for non-linear analysis of pedalling forces in cycling.

INTRODUCTION: From the perspective of dynamic systems theory, stability and variability of biological signals are both understood as a functional adaptation to variable environmental conditions. In the present study, we examined whether this theoretical perspective is applicable to the pedalling movement in cycling. Non-linear measures were applied to analyse pedalling forces with varying levels of subjective load. MATERIALS AND METHODS: Ten subjects completed a 13-sector virtual terrain profile of 15 km total length on a roller trainer with varying degrees of virtual terrain inclination (resistance). The test was repeated two times with different instructions on how to alter the bikes gearing. During the experiment, pedalling force and heart rate were measured. Force-time curves were sequenced into single cycles, linearly interpolated in the time domain, and z-score normalised. The established time series was transferred into a two-dimensional phase space with limit cycle properties given the applied 25% phase shift. Different representations of the phase space attractor were calculated within each sector and used as non-linear measures assessing pedalling forces. RESULTS AND DISCUSSION: A contrast analysis showed that changes in pedalling load were strongly associated to changes in non-linear phase space attractor variables. For the subjects investigated in this study, this association was stronger than that between heart rate and resistance level. The results indicate systematic changes of the pedalling movement as an adaptive response to an externally determined increase in workload. Future research may utilise the findings from this study to investigate possible relationships between subjective measures of exhaustion, comfort, and discomfort with biomechanic characteristics of the pedalling movement and to evaluate connections with dynamic stability measures.

Reproducibility of Blood Lactate Concentration Rate under Isokinetic Force Loads.

(1) Background: Maximum isokinetic force loads show strongly increased post-load lactate concentrations and an increase in the maximum blood lactate concentration rate ( V ˙ Lamax), depending on load duration. The reproducibility of V ˙ Lamax must be known to be able to better assess training-related adjustments of anaerobic performance using isokinetic force tests. (2) Methods: 32 subjects were assigned to two groups and completed two unilateral isokinetic force tests (210° s-1, Range of Motion 90°) within seven days. Group 1 (n = 16; age 24.0 ± 2.8 years, BMI 23.5 ± 2.6 kg m-2, training duration: 4.5 ± 2.4 h week-1) completed eight repetitions and group 2 (n = 16; age 23.7 ± 1.9 years, BMI 24.6 ± 2.4 kg m-2, training duration: 5.5 ± 2.1 h week-1) completed 16 repetitions. To determine V ˙ Lamax, capillary blood (20 µL) was taken before and immediately after loading, and up to the 9th minute post-load. Reproducibility and variability was determined using Pearson and Spearman correlation analyses, and variability were determined using within-subject standard deviation (Sw) and Limits of Agreement (LoA) using Bland Altman plots. (3) Results: The correlation of V ˙ Lamax in group 1 was r = 0.721, and in group 2 r = 0.677. The Sw of V ˙ Lamax was 0.04 mmol L-1 s-1 in both groups. In group 1, V ˙ Lamax showed a systematic bias due to measurement repetition of 0.02 mmol L-1 s-1 in an interval (LoA) of ±0.11 mmol L-1 s-1. In group 2, a systematic bias of -0.008 mmol L-1 s-1 at an interval (LoA) of ±0.11 mmol L-1 s-1 was observed for repeated measurements of V ˙ Lamax. (4) Conclusions: Based on the existing variability, a reliable calculation of V ˙ Lamax seems to be possible with both short and longer isokinetic force loads. Changes in V ˙ Lamax above 0.11 mmol L-1 s-1 due to training can be described as a non-random increase or decrease in V ˙ Lamax.

Validation of an inertial measurement unit for the quantification of rearfoot kinematics during running.

BACKGROUND: The popular protocol used to study running motion suffers from problems that lead to a limited ability to generalize the obtained results. Inertial measurement units (IMU) appear to be promising in increasing ecological validity of the collected data. However, quantifying running kinematics utilizing IMU signals is complex and potentially affected by several well-established and less well-known errors. RESEARCH QUESTION: The purpose of this study was to examine the validity of kinematic variables obtained from a single, shoe-mounted IMU using an opto-electronic motion analysis reference system. METHODS: 51 recreational runners were analyzed, performing a single continuous run at three different speeds (10, 12, 15 km/h) on a treadmill. Descriptive statistics (Bland & Altman analysis, box plots, scatter plots) were employed to analyze the agreement between the two instruments. RESULTS: The findings of this study revealed considerable systematic and large random disagreement, which, in turn, is characterized by substantial inter-individual differences in the error distribution. These discrepancies may partly be explained by differences in foot strike behavior, resulting in varying degrees of vibration impact acting on the IMU. SIGNIFICANCE: Advances in IMU technology, as well as exploring new application approaches and signal processing strategies, might enhance the usability of IMUs in analyzing running kinematics.

QuickSF: A New Technique in Surfactant Administration.

BACKGROUND: Recent studies indicate an increasing use of less invasive surfactant administration. Different techniques have been shown with distinct risks and benefits. The aim of this study was to develop a new method that simplifies this procedure. OBJECTIVES: An applicator was developed and tested on a manikin to make tracheal surfactant application easier and faster. METHODS: A device for oral administration of a catheter into the trachea was developed. After refining, it was tested by 9 neonatologists on a manikin. The primary aim was device feasibility, which was defined as successful intubation within 30 s. RESULTS: The first device showed success in 30 of 33 measurements (90.9%). After refinement, the final device showed successful intubation in all 27 trials (100%). CONCLUSION: The new technique was feasible in this manikin test and should be confirmed in a clinical study.