Summary
Objective
Increased activity of T‐type Ca2+ channels is linked to idiopathic generalized epilepsies, thus blocking these channels may be a new treatment option. ACT‐709478 is an orally ...available triple T‐type Ca2+ channel blocker. The aim of this first‐in‐man study was to investigate the pharmacokinetics, pharmacodynamics, tolerability, and safety of single doses of ACT‐709478 in healthy subjects.
Methods
This double‐blind, placebo‐controlled, randomized study included 65 healthy male subjects. Ascending single oral doses of 1‐400 mg ACT‐709478 or placebo were administered to sequential groups of eight subjects (6 on active, 2 on placebo). Effect of food was tested in a crossover part at 60 mg. Blood and saliva sampling for pharmacokinetic evaluations and safety assessments was performed regularly. Effects on the central nervous system were assessed with a battery of pharmacodynamic tests.
Results
The maximum plasma concentration (Cmax) was reached within 3 to 4 hours (≤60 mg) and within 20 to 28 hours (>60 mg), and across all dose levels the terminal half‐life (95% confidence interval) ranged from 36 (29‐45) to 43 (22‐86) hours. Multiple peaks were observed and Cmax and area under the plasma concentration‐time curve (AUC)0‐∞ increased in a less than dose‐proportional manner. A 1.6‐fold increase in Cmax and no change in AUC0‐∞ was observed in fed compared to fasted conditions. A significant correlation (P < 0.0001) between plasma and saliva concentrations was established using linear regression. All adverse events were transient and of mild or moderate intensity. No treatment‐related effects on vital signs, clinical laboratory, telemetry, or electrocardiography were detected. The results of pharmacodynamic tests did not show relevant mean changes compared to baseline or placebo.
Significance
ACT‐709478 exhibits good tolerability and safety after single‐dose administration and its pharmacokinetic and pharmacodynamic properties warrant further investigations.
Aims
Targeting the complement factor 5a receptor 1 (C5a1 receptor) offers potential to treat various autoimmune diseases. The C5a1 receptor antagonist ACT‐1014‐6470 was well tolerated in a ...single‐ascending dose study in healthy subjects. This double‐blind, randomized, placebo‐controlled study aimed to investigate the safety, tolerability, pharmacokinetics (PK) and target engagement of multiple‐ascending doses of ACT‐1014‐6470.
Methods
Per dose level, 10 healthy male and female subjects of nonchildbearing potential (1:1 sex ratio) were enrolled to assess 30, 60 and 120 mg ACT‐1014‐6470 administered twice daily for 4.5 days under fed conditions. Adverse events, clinical laboratory data, vital signs, electrocardiogram and PK blood samples were collected up to 120 h post last dose and ex vivo stimulated matrix metalloproteinase 9 was quantified as target engagement biomarker. At the 60‐mg dose level, PK samples were collected until 8 weeks post last dose.
Results
The total adverse event number was 57 and no treatment‐related safety pattern was apparent. At steady state, ACT‐1014‐6470 reached maximum plasma concentrations after 2–3 h and the half‐life estimated up to Day 10 was 115–146 h across dose levels. Exposure parameters increased dose‐proportionally, steady state was attained between Day 3–5, and ACT‐1014‐6470 accumulated 2‐fold. At the 60‐mg dose level, ACT‐1014‐6470 was quantifiable until 8 weeks after the last dose. Matrix metalloproteinase 9 release was suppressed to endogenous background concentrations up to the last sampling time point, confirming sustained target engagement of ACT‐1014‐6470.
Conclusion
The compound was generally safe and well tolerated at all dose levels, warranting further clinical investigations.
The aim of the presented review is to summarize the literature data on the accuracy and clinical applicability of artificial intelligence (AI) models as a valuable alternative to the current ...guidelines in predicting cardiac resynchronization therapy (CRT) response and phenotyping of patients eligible for CRT implantation. This systematic review was performed according to the PRISMA guidelines. After a search of Scopus, PubMed, Cochrane Library, and Embase databases, 675 records were identified. Twenty supervised (prediction of CRT response) and 9 unsupervised (clustering and phenotyping) AI models were analyzed qualitatively (22 studies, 14,258 patients). Fifty-five percent of AI models were based on retrospective studies. Unsupervised AI models were able to identify clusters of patients with significantly different rates of primary outcome events (death, heart failure event). In comparison to the guideline-based CRT response prediction accuracy of 70%, supervised AI models trained on cohorts with > 100 patients achieved up to 85% accuracy and an AUC of 0.86 in their prediction of response to CRT for echocardiographic and clinical outcomes, respectively. AI models seem to be an accurate and clinically applicable tool in phenotyping of patients eligible for CRT implantation and predicting potential responders. In the future, AI may help to increase CRT response rates to over 80% and improve clinical decision-making and prognosis of the patients, including reduction of mortality rates. However, these findings must be validated in randomized controlled trials.
Around 140 million children are born every year and post-natal transition is uncomplicated in the vast majority. However, around 5%-15% of neonates receive supportive interventions during transition. ...Recent data on the interventions used is scarce. More data on the frequencies with which these interventions are used is needed to evaluate neonatal resuscitation, guide recommendations and to generate hypotheses for further research. The following protocol describes an international, multicentre survey on the interventions currently applied during neonatal resuscitation.
To determine the frequencies at which different supportive interventions recommended by European Resuscitation Council (ERC) guidelines for neonatal resuscitation are used. To compare the frequencies between hospitals and patient groups and to investigate possible factors influencing any differences found.
Participating hospitals will collect data on all interventions performed during neonatal resuscitation over a period of 6 months. All hospitals providing perinatal care are eligible regardless of size and designated level of neonatal care. Every neonate requiring more interventions than basic drying and tactile stimulation during the first 30 min of life will be included. The targeted sample size is at least 4,000 neonates who receive interventions. After anonymization, the data is pooled in a common database and descriptive and statistical analysis is performed globally and in subgroups. Possible correlations will be investigated with phi coefficient and chi square testing.
Consent of the institutional review board of the Technical University Dresden was obtained for the local data collection under the number BO-EK-198042022. Additionally, approval of local ethical or institutional review boards will be obtained by the participating hospitals if required. Results will be published in peer-reviewed journals and presented at suitable scientific conferences.
Telemedical infrastructure for patient assessment, care and follow-up as well as interdisciplinary exchange can contribute to ensuring patient care that is close to home and meets the highest quality ...standards, even outside specialised centres. In neonatology, synchronous audio-visual communication across institutions has been used for many years, especially in the Anglo-American countries. Areas of application include extended neonatal primary care and resuscitation, specific diagnostic applications, e.g. ROP screening and echocardiography, as well as parental care, regular telemedical ward rounds and further training of medical staff, especially using simulation training. For the implementation of such telemedical infrastructures, certain organisational, medical-legal and technical requirements for hardware, software and structural and process organisation must be met. The concrete realisation of a telemedical infrastructure currently being implemented for the region of Eastern Saxony is demonstrated here using the example of the Saxony Center for feto/neonatal Health (SCFNH). Within the framework of feto-neonatal competence networks such as the SCFNH, the quality of medical care, patient safety and satisfaction in a region can be increased by means of a comprehensive, well-structured and established telemedical infrastructure.
Excellence in feto-neonatal care forms the basis for health in adulthood and requires a collaboration of stakeholders in the health care system. As in other regions, demographic changes such as rural ...depopulation pose a risk to feto-neonatal care in Eastern Saxony. Areas in need of regional, perinatal collaboration have been identified: (I) multi-professional counselling of families with a suspected fetal disease, (II) immediately available expertise of a neonatologist during neonatal resuscitation, (III) evidence-based neonatal antibiotic therapy, (IV) backtransfer of extremely preterm infants or sick neonates, and (V) adequate psychosocial support of families with extremely preterm infants or sick neonates. Telemedicine enables regional partners to communicate efficiently and gives an audiovisual impression of the patient. The Saxony Center for feto/neonatal Health (SCFNH) collaborates with regional partners to establish a feto-neonatal telemedicine network "Sichere Geburt". The network will be scientifically evaluated and might be of help as a model for other regions with structural challenges.
Shape analysis of infant’s heads is crucial to diagnose cranial deformities and evaluate head growth. Currently available 3D imaging systems can be used to create 3D head models, promoting the ...clinical practice for head evaluation. However, manual analysis of 3D shapes is difficult and operator-dependent, causing inaccuracies in the analysis. This study aims to validate an automatic landmark detection method for head shape analysis. The detection results were compared with manual analysis in three levels: (1) distance error of landmarks; (2) accuracy of standard cranial measurements, namely cephalic ratio (CR), cranial vault asymmetry index (CVAI), and overall symmetry ratio (OSR); and (3) accuracy of the final diagnosis of cranial deformities. For each level, the intra- and interobserver variability was also studied by comparing manual landmark settings. High landmark detection accuracy was achieved by the method in 166 head models. A very strong agreement with manual analysis for the cranial measurements was also obtained, with intraclass correlation coefficients of 0.997, 0.961, and 0.771 for the CR, CVAI, and OSR. 91% agreement with manual analysis was achieved in the diagnosis of cranial deformities. Considering its high accuracy and reliability in different evaluation levels, the method showed to be feasible for use in clinical practice for head shape analysis.
Graphical Abstract
Advances in neonatal care have resulted in improved outcomes for high-risk newborns with technologies playing a significant part although many were developed for the neonatal intensive care unit. The ...care provided in the delivery room (DR) during the first few minutes of life can impact short- and long-term neonatal outcomes. Increasingly, technologies have a critical role to play in the DR particularly with monitoring and information provision. However, the DR is a unique environment and has major challenges around the period of foetal to neonatal transition that need to be overcome when developing new technologies. This review focuses on current DR technologies as well as those just emerging and further over the horizon. We identify what key opinion leaders in DR care think of current technologies, what the important DR measures are to them, and which technologies might be useful in the future. We link these with key technologies including respiratory function monitors, electoral impedance tomography, videolaryngoscopy, augmented reality, video recording, eye tracking, artificial intelligence, and contactless monitoring. Encouraging funders and industry to address the unique technological challenges of newborn care in the DR will allow the continued improvement of outcomes of high-risk infants from the moment of birth. IMPACT: Technological advances for newborn delivery room care require consideration of the unique environment, the variable patient characteristics, and disease states, as well as human factor challenges. Neonatology as a speciality has embraced technology, allowing its rapid progression and improved outcomes for infants, although innovation in the delivery room often lags behind that in the intensive care unit. Investing in new and emerging technologies can support healthcare providers when optimising care and could improve training, safety, and neonatal outcomes.
In this report, we applied a special localization microscopy technique (Spectral Precision Distance/Spatial Position Determination Microscopy/SPDM) to quantitatively analyze the effect of influenza A ...virus (IAV) infection on the spatial distribution of individual HGFR (Hepatocyte Growth Factor Receptor) proteins on the membrane of human epithelial cells at the single molecule resolution level. We applied this SPDM method to Alexa 488 labeled HGFR proteins with two different ligands. The ligands were either HGF (Hepatocyte Growth Factor), or IAV. In addition, the HGFR distribution in a control group of mock-incubated cells without any ligands was investigated. The spatial distribution of 1×106 individual HGFR proteins localized in large regions of interest on membranes of 240 cells was quantitatively analyzed and found to be highly non-random. Between 21% and 24% of the HGFR molecules were located in 44,304 small clusters with an average diameter of 54nm. The mean density of HGFR molecule signals per individual cluster was very similar in control cells, in cells with ligand only, and in IAV infected cells, independent of the incubation time. From the density of HGFR molecule signals in the clusters and the diameter of the clusters, the number of HGFR molecule signals per cluster was estimated to be in the range between 4 and 11 (means 5–6). This suggests that the membrane bound HGFR clusters form small molecular complexes with a maximum diameter of few tens of nm, composed of a relatively low number of HGFR molecules. This article is part of a Special Issue entitled: Viral Membrane Proteins — Channels for Cellular Networking.
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•A localization microscopy technique (SPDM) was used to study virus–cell interaction.•The spatial distribution of HGFR proteins on the cell membrane was highly non-random.•Around 20% of the HGFR molecules were located in small clusters with an average diameter of 54nm.•The density of HGFR molecule signals per cluster was independent of the treatment.•The results suggest that the HGFR clusters form small molecular complexes.
Arterial catheterization is a routine procedure in extremely preterm neonates. Umbilical arterial catheters (UACs) are typically used for this purpose, but life-threatening complications have been ...described. Peripheral arterial lines (PALs) might offer a valuable alternative, but their feasibility in extremely preterm newborns is unclear.
To investigate efficacy and complications of PALs in extremely preterm neonates.
Retrospective analysis of patients born below 26 weeks of gestation in 2011-2014 (cohort 1, UAC as primary arterial access) and 2015-2019 (cohort 2, PAL as primary arterial access). Arterial line placement during their first 14 days of life, duration of arterial access, reasons for discontinuation, and long-term complications were recorded from health records.
In total, 161 of 202 newborns had an arterial line during their first 14 days of life. In cohort 2, the life span of a PAL was significantly longer than that in cohort 1. Signs of dysfunction were the primary reason to discontinue a PAL. Signs of peripheral ischemia were present in 36 of 105 cases (34%) when the PAL was removed but persisted in only 2 patients. UAC-associated persistent ischemic damage occurred in 2 of 97 patients.
PALs are a valuable alternative to UACs even in preterm newborns below 26 weeks of gestational age. A special focus on ischemic complications is warranted. Prospective, multicenter studies to verify safety and efficacy of arterial line management and complications in extremely preterm infants are warranted.
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