Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation.

Nephronophthisis-related ciliopathies (NPHP-RC) comprises a group of inherited kidney diseases, caused by mutations in genes encoding proteins localizing to primary cilia. NPHP-RC represents one of the most frequent monogenic causes of renal failure within the first three decades of life, but its molecular disease mechanisms remain unclear. Here, we identified biallelic ANKS6 mutations in two affected siblings with late-onset chronic kidney disease by whole-exome sequencing. We employed patient-derived fibroblasts generating an in vitro model to study the precise biological impact of distinct human ANKS6 mutations, completed by immunohistochemistry studies on renal biopsy samples. Functional studies using patient-derived cells showed an impaired integrity of the ciliary inversin compartment with reduced cilia length. Further analyses demonstrated that ANKS6 deficiency leads to a dysregulation of Hippo-signaling through nuclear yes-associated protein (YAP) imbalance and disrupted ciliary localization of YAP. In addition, an altered transcriptional activity of canonical Wnt target genes and altered expression of non-phosphorylated (active) ß-catenin and phosphorylated glycogen synthase kinase 3ß were observed. Upon ciliation, ANKS6 deficiency revealed a deranged subcellular localization and expression of components of the endocytic recycling compartment. Our results demonstrate that ANKS6 plays a key role in regulating the Hippo pathway, and ANKS6 deficiency is linked to dysregulation of signaling pathways. Our study provides molecular clues in understanding pathophysiological mechanisms of NPHP-RC and may offer new therapeutic targets.

Enhancing interprofessional collaboration in paediatric training: Insights from profession-specific experiences and implications for future education.

AIM: There is limited evidence on trainees' and instructors' needs and perspectives concerning interprofessional simulation-based trainings. We aimed to study task distribution among team members, profession-specific learning effects and enhancing collaboration and competencies within medical teams. METHODS: This prospective study examined expectations and experiences of medical and nursing students during paediatric emergency training in a tertiary care centre with questionnaires before and after a training. Further, expert interviews were conducted to identify the needs for interprofessional training. Results were used to design a standardised checklist for structured preparation of interprofessional paediatric emergency management training. RESULTS: Of the nursing students, 82% initially intended to assume the role of the team leader, but only 5.8% did so during training. Both professions emphasised the significance of effective communication and transparent task distribution for successful collaboration. Experts highlighted the importance of proficiency in basic technical skills and identified non-technical skills such as closed-loop communication and the 10-4-10 principle as crucial for both professions. CONCLUSION: The study revealed profession-specific variations in the intention of acquiring the team leader or member role. Interprofessional training emerges as a potential strategy to dismantle these structures and promote shared responsibilities. The checklist aims to facilitate structured preparation of a training.

Longitudinal Reference Values for Cerebral Ventricular Size in Preterm Infants Born at 23-27 Weeks of Gestation.

OBJECTIVE: To establish longitudinal reference values for cerebral ventricular size in the most vulnerable patients at risk for intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilatation (PHVD). STUDY DESIGN: This retrospective study included neurologically healthy preterm neonates born at 230/7-266/7 weeks of gestational age between September 2011 and April 2019. Patients were treated at 2 Austrian tertiary centers, Medical University of Vienna and Medical University of Innsbruck. All available cerebral ultrasound scans until 30 weeks corrected age were analyzed. Ventricular measurements included ventricular index, anterior horn width (AHW), and thalamo-occipital distance (TOD) and longitudinal percentiles were created. RESULTS: The study cohort consisted of 244 preterm neonates, with a median gestational age of 253/7 weeks (IQR, 244/7-260/7 weeks) and a median birth weight of 735 g (IQR, 644-849 g). A total of 993 ultrasound scans were available for analysis, resulting in >1800 measurements of ventricular index, AHW, and TOD. Special attention was given to the 97th percentile as well as 2 mm and 4 mm above the 97th percentile, which are used internationally as cutoffs for intervention in the presence of PHVD. CONCLUSIONS: We present percentile charts based on a cohort of extremely premature infants including neonates born at the border of viability suited to follow-up the most vulnerable patients at risk for IVH and PHVD. Furthermore, we provide an extensive literature research and comparison of all available reference values, focusing on ventricular index, AHW, and TOD.

Interprofessional Paediatric High-Fidelity Simulation Training: A Mixed Methods Study of Experiences and Readiness among Nursing and Medical Students.

BACKGROUND: Training in communication skills between nursing and medical students during interprofessional paediatric emergency simulation training represents a significant aspect of safe patient care. Evidence highlights that poor communication in paediatric emergency scenarios jeopardises patient safety. Through realistic simulations, students practice the communication strategies of crisis resource management (CRM), such as "closed-loop communication", "speaking up", and "team time-out". AIMS: In this study, we aimed to evaluate the impact of interprofessional simulation on enhancing teamwork and communication skills. Additionally, we sought to assess the occurrence of contexts for the three CRM communication strategies during simulations. METHODS: Employing a mixed methods research design, the analysed students completed pre- and post-simulation online questionnaires. To measure attitudes towards interprofessional collaboration, we used the German version of the University of West England Interprofessional Questionnaire (UWE-IP_german), and to measure interprofessional attitudes, we used the Greifswald Questionnaire for the Measurement of Interprofessional Attitudes (Greif Mie), also in German, for both pre- and post-simulation. For qualitative video analysis, we utilised Grounded Theory Methodology (GTM). RESULTS: Following simulation training, we observed a significant improvement (p > 0.001) in the subscale "attitude towards interprofessional learning" of the UWE-IP_german among nursing and medical students. Medical students consistently exhibited a significantly (p < 0.001) more positive attitude towards other professionals in both the pre- and post-simulation assessments. Overall, all the students expressed satisfaction with the interprofessional simulation training. In the qualitative selective coding process, the central phenomenon "participation" could be identified in the coding paradigm. CONCLUSION: This study presents substantial evidence of the learning impact of interprofessional paediatric simulation training on nursing and medical students.

Brain Biometry Reveals Impaired Brain Growth in Preterm Neonates with Intraventricular Hemorrhage.

INTRODUCTION: Preterm birth and cerebral hemorrhage have adverse effects on brain development. Alterations in regional brain size on magnetic resonance imaging (MRI) can be assessed using 2D biometrical analysis, an easily applicable technique showing good correlation with 3D brain volumes. METHODS: This retrospective study included 74 preterm neonates with intraventricular hemorrhage (IVH) born <32+0 weeks of gestation between 2011 and 2019. Cerebral MRI was performed at term-equivalent age, and 2D measurement techniques were used for biometrical analysis and compared to normative data of two control groups. Finally, the correlation and association of brain parameters and patterns of impaired brain growth and outcome at 2 and 3 years of age were evaluated. RESULTS: Interhemispheric distance (IHD), the 3rd ventricle, and lateral ventricles presented larger, in contrast, cerebral biparietal width (cBPW), fronto-occipital diameter (FOD), and the length of the corpus callosum were smaller in IVH patients compared to respective controls. The strongest correlations with outcome were observed for the parameters FOD, anteroposterior diameter of the vermis, transverse cerebellar diameter (tCD), corpus callosum, 3rd ventricle, and left ventricular index. Patients with the small FOD, small BPW, and increased IHD pattern reached overall lower outcome scores at follow-up. DISCUSSION: Preterm neonates with IVH showed reduced total brain sizes and enlarged pericerebral spaces compared to neurologically healthy controls. Biometric analysis revealed that several 2D brain parameters as well as different patterns of impaired brain growth were associated with neurodevelopmental impairment in early childhood. These findings may support prediction of long-term outcome and parental counseling in patients with IVH.

Real-Time Intubation and Ventilation Feedback: A Randomized Controlled Simulation Study.

BACKGROUNDS: This study aimed to determine the best educational application of a respiratory function monitor and a video laryngoscope. METHODS: This study was a randomized controlled simulation-based trial, including 167 medical students. Participants had to execute ventilation and intubation maneuvers on a newborn manikin. Participants were randomized into 3 groups. In group A (no-access), the feedback devices were not visible but recording. In group B (supervisor-access), the feedback devices were visible to the supervisor only. In group C (full-access), both the participant and the supervisor had visual access. RESULTS: The two main outcome variables were the percentage of ventilations within the tidal volume target range (4-8mL/kg) and the number of intubation attempts. Group C achieved the highest percentage of ventilations within the tidal volume target range (full-access 63.6%, supervisor-access 51.0%, no-access 31.1%, P < .001) and the lowest mask leakage (full-access 34.9%, supervisor-access 46.6%, no-access 61.6%; A to B: P < .001, A to C: P < .001, B to C: P = .003). Overall, group C achieved superior ventilation quality regarding primary and secondary outcome measures. The number of intubation attempts until success was lowest in the full-access group (full-access: 1.29, supervisor-access: 1.77, no-access: 2.43; A to B: P = .001, A to C: P < .001, B to C: P = .015). CONCLUSIONS: Our findings confirm that direct visual access to feedback devices for supervisor and trainees alike considerably benefits outcomes and can contribute to the future of clinical education.

Provider Visual Attention Correlates With the Quality of Pediatric Resuscitation: An Observational Eye-Tracking Study.

Background: Eye-tracking devices are an innovative tool to understand providers' attention during stressful medical tasks. The knowledge about what gaze behaviors improve (or harm) the quality of clinical care can substantially improve medical training. The aim of this study is to identify gaze behaviors that are related to the quality of pediatric resuscitation. Methods: Forty students and healthcare providers performed a simulated pediatric life support scenario, consisting of a chest compression task and a ventilation task, while wearing eye-tracking glasses. Skill Reporter software measured chest compression (CC) quality and Neo Training software measured ventilation quality. Main eye-tracking parameters were ratio [the number of participants who attended a certain area of interest (AOI)], dwell time (total amount of time a participant attended an AOI), the number of revisits (how often a participant returned his gaze to an AOI), and the number of transitions between AOIs. Results: The most salient AOIs were infant chest and ventilation mask (ratio = 100%). During CC task, 41% of participants also focused on ventilation bag and 59% on study nurse. During ventilation task, the ratio was 61% for ventilation bag and 36% for study nurse. Percentage of correct CC rate was positively correlated with dwell time on infant chest (p = 0.044), while the overall CC quality was negatively correlated with dwelling outside of pre-defined task-relevant AOIs (p = 0.018). Furthermore, more dwell time on infant chest predicted lower leakage (p = 0.042). The number of transitions between AOIs was unrelated to CC parameters, but correlated negatively with mask leak during ventilations (p = 0.014). Participants with high leakage shifted their gaze more often between ventilation bag, ventilation mask, and task-irrelevant environment. Conclusion: Infant chest and ventilation mask are the most salient AOIs in pediatric basic life support. Especially the infant chest AOI gives beneficial information for the resuscitation provider. In contrast, attention to task-irrelevant environment and frequent gaze shifts seem to harm the quality of care.

The role of triggering receptor expressed on myeloid cells 2 in Parkinson's disease and other neurodegenerative disorders.

Parkinson's disease (PD) is a progressive neurological disorder marked by cardinal clinical symptoms such as rigor, tremor, and akinesia. Albeit a loss of dopaminergic neurons from the substantia nigra pars compacta is causative for the movement impairments found in patients, molecular reasoning for this loss is still incomplete. In recent years, triggering factor expressed on myeloid cells (TREM2) gained attention in the field of neurodegeneration as it could be associated with different neurodegenerative disorders. Primarily identified as a risk factor in Alzheimer's disease, variants in TREM2 were linked to PD and multiple sclerosis, too. Expressed on phagocytic cells, such as macrophages and microglia, TREM2 puts the focus on inflammation associated conditions in PD and provides a molecular target that could at least partly explain the role of immune cells in PD. Here, we summarize expression patterns and molecular functions of TREM2, recapitulate on its role in inflammation, phagocytosis and cell survival, before turning to neurodegenerative disorders with an emphasis on PD.

Human Cerebrospinal fluid promotes long-term neuronal viability and network function in human neocortical organotypic brain slice cultures.

Pathophysiological investigation of CNS-related diseases, such as epilepsy or neurodegenerative disorders, largely relies on histological studies on human post mortem tissue, tissue obtained by biopsy or resective surgery and on studies using disease models including animal models, heterologous expression systems or cell culture based approaches. However, in general it remains elusive to what extent results obtained in model systems can be directly translated to the human brain, calling for strategies allowing validation or even primary investigation in live human CNS tissue. In the work reported here, we prepared human organotypic slice cultures from access tissue of resective epilepsy surgery. Employing different culture conditions, we systematically compared artificial culturing media versus human cerbrospinal fluid (hCSF) obtained from patients with normal pressure hydrocephalus (NPH). Presented data demonstrates sustained cortical neuronal survival including not only maintenance of typical cellular electrophysiological properties and activity, such as robust action potential generation and synaptic connectivity, but also preservation of tonic and phasic network activity up to several weeks in vitro. As clearly delineated by immunocytochemistry, single cell patch clamp and extracellular recordings, we find that in contrast to artificial culturing media, hCSF significantly enhances neuron viability and maintenance of network activity.

Isolated limb perfusion for an irresectable melanoma recurrence in a Jehovah's witness.

Isolated limb perfusion (ILP) is a treatment option for irresectable melanoma lesions, because with ILP 20-fold higher concentrations of chemotherapy can be achieved locally than is systemically possible and high response rates are subsequently achieved. Jehovah's witnesses do not accept any form of blood transfusion, either autologous or homologous blood or only blood products. The use of an extracorporeal circuit, without the use of any blood products is acceptable for Jehovah's witnesses. The case of a 59-year-old Jehovah's witness with an irresectable melanoma recurrence for which an ILP. Because of adequate blood flow through the perfused limb, the limb did not become acidotic, even though there was a significant drop in the Hb concentration in the limb during the ILP. Isolated limb perfusions without the use of any blood transfusion products are technically possible, but an adequate preoperative hemoglobin concentration is a prerequisite.