Ventilator-induced endothelial activation and inflammation in the lung and distal organs

Introduction Results from clinical studies have provided evidence for the importance of leukocyte-endothelial interactions in the pathogenesis of pulmonary diseases such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), as well as in systemic events like sepsis and multiple organ failure (MOF). The present study was designed to investigate whether alveolar stretch due to mechanical ventilation (MV) may evoke endothelial activation and inflammation in healthy mice, not only in the lung but also in organs distal to the lung. Methods Healthy male C3H/HeN mice were anesthetized, tracheotomized and mechanically ventilated for either 1, 2 or 4 hours. To study the effects of alveolar stretch in vivo, we applied a MV strategy that causes overstretch of pulmonary tissue i.e. 20 cmH(2)O peak inspiratory pressure (PIP) and 0 cmH(2)O positive end expiratory pressure (PEEP). Non-ventilated, shamoperated animals served as a reference group (non-ventilated controls, NVC). Results Alveolar stretch imposed by MV did not only induce de novo synthesis of adhesion molecules in the lung but also in organs distal to the lung, like liver and kidney. No activation was observed in the brain. In addition, we demonstrated elevated cytokine and chemokine expression in pulmonary, hepatic and renal tissue after MV which was accompanied by enhanced recruitment of granulocytes to these organs. Conclusions Our data implicate that MV causes endothelial activation and inflammation in mice without pre-existing pulmonary injury, both in the lung and distal organs

Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease

The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood

IL1RL1 Gene Variants and Nasopharyngeal IL1RL-a Levels Are Associated with Severe RSV Bronchiolitis: A Multicenter Cohort Study

Targets for intervention are required for respiratory syncytial virus (RSV) bronchiolitis, a common disease during infancy for which no effective treatment exists. Clinical and genetic studies indicate that IL1RL1 plays an important role in the development and exacerbations of asthma. Human IL1RL1 encodes three isoforms, including soluble IL1RL1-a, that can influence IL33 signalling by modifying inflammatory responses to epithelial damage. We hypothesized that IL1RL1 gene variants and soluble IL1RL1-a are associated with severe RSV bronchiolitis.We studied the association between RSV and 3 selected IL1RL1 single-nucleotide polymorphisms rs1921622, rs11685480 or rs1420101 in 81 ventilated and 384 non-ventilated children under 1 year of age hospitalized with primary RSV bronchiolitis in comparison to 930 healthy controls. Severe RSV infection was defined by need for mechanical ventilation. Furthermore, we examined soluble IL1RL1-a concentration in nasopharyngeal aspirates from children hospitalized with primary RSV bronchiolitis. An association between SNP rs1921622 and disease severity was found at the allele and genotype level (p = 0.011 and p = 0.040, respectively). In hospitalized non-ventilated patients, RSV bronchiolitis was not associated with IL1RL1 genotypes. Median concentrations of soluble IL1RL1-a in nasopharyngeal aspirates were >20-fold higher in ventilated infants when compared to non-ventilated infants with RSV (median [and quartiles] 9,357 [936-15,528] pg/ml vs. 405 [112-1,193] pg/ml respectively; p<0.001).We found a genetic link between rs1921622 IL1RL1 polymorphism and disease severity in RSV bronchiolitis. The potential biological role of IL1RL1 in the pathogenesis of severe RSV bronchiolitis was further supported by high local concentrations of IL1RL1 in children with most severe disease. We speculate that IL1RL1a modifies epithelial damage mediated inflammatory responses during RSV bronchiolitis and thus may serve as a novel target for intervention to control disease severity

Angiopoietin-1 Treatment Reduces Inflammation but Does Not Prevent Ventilator-Induced Lung Injury

Background: Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI). Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang)-Tie2 system plays a role in the development of VILI. The present study was designed to examine the effects of mechanical ventilation on the Ang-Tie2 system in lung tissue. Moreover, we evaluated whether treatment with Ang-1, a Tie2 receptor agonist, protects against inflammation, vascular leakage and impaired gas exchange induced by mechanical ventilation. Methods: Mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with either an inspiratory pressure of 10 cmH(2)O ('low' tidal volume similar to 7.5 ml/kg; LVT) or 18 cmH(2)O ('high' tidal volume similar to 15 ml/kg; HVT). At initiation of HVT-ventilation, recombinant human Ang-1 was intravenously administered (1 or 4 mu g per animal). Non-ventilated mice served as controls. Results: HVT-ventilation influenced the Ang-Tie2 system in lungs of healthy mice since Ang-1, Ang-2 and Tie2 mRNA were decreased. Treatment with Ang-1 increased Akt-phosphorylation indicating Tie2 signaling. Ang-1 treatment reduced infiltration of granulocytes and expression of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1 and interleukin (IL)-1 beta caused by HVT-ventilation. Importantly, Ang-1 treatment did not prevent vascular leakage and impaired gas exchange in HVT-ventilated mice despite inhibition of inflammation, vascular endothelial growth factor (VEGF) and Ang-2 expression. Conclusions: Ang-1 treatment downregulates pulmonary inflammation, VEGF and Ang-2 expression but does not protect against vascular leakage and impaired gas exchange induced by HVT-ventilatio

Global molecular diversity of RSV - the "INFORM RSV" study

Background: Respiratory syncytial virus (RSV) is a global cause of severe respiratory morbidity and mortality in infants. While preventive and therapeutic interventions are being developed, including antivirals, vaccines and monoclonal antibodies, little is known about the global molecular epidemiology of RSV. INFORM is a prospective, multicenter, global clinical study performed by ReSViNET to investigate the worldwide molecular diversity of RSV isolates collected from children less than 5 years of age. Methods: The INFORM study is performed in 17 countries spanning all inhabited continents and will provide insight into the molecular epidemiology of circulating RSV strains worldwide. Sequencing of > 4000 RSV-positive respiratory samples is planned to detect temporal and geographical molecular patterns on a molecular level over five consecutive years. Additionally, RSV will be cultured from a subset of samples to study the functional implications of specific mutations in the viral genome including viral fitness and susceptibility to different monoclonal antibodies. Discussion: The sequencing and functional results will be used to investigate susceptibility and resistance to novel RSV preventive or therapeutic interventions. Finally, a repository of globally collected RSV strains and a database of RSV sequences will be created.</div

Games to support teaching clinical reasoning in health professions education: a scoping review

ABSTRACTIntroduction Given the complexity of teaching clinical reasoning to (future) healthcare professionals, the utilization of serious games has become popular for supporting clinical reasoning education. This scoping review outlines games designed to support teaching clinical reasoning in health professions education, with a specific emphasis on their alignment with the 8-step clinical reasoning cycle and the reflective practice framework, fundamental for effective learning.Methods A scoping review using systematic searches across seven databases (PubMed, CINAHL, ERIC, PsycINFO, Scopus, Web of Science, and Embase) was conducted. Game characteristics, technical requirements, and incorporation of clinical reasoning cycle steps were analyzed. Additional game information was obtained from the authors.Results Nineteen unique games emerged, primarily simulation and escape room genres. Most games incorporated the following clinical reasoning steps: patient consideration (step 1), cue collection (step 2), intervention (step 6), and outcome evaluation (step 7). Processing information (step 3) and understanding the patient’s problem (step 4) were less prevalent, while goal setting (step 5) and reflection (step 8) were least integrated.Conclusion All serious games reviewed show potential for improving clinical reasoning skills, but thoughtful alignment with learning objectives and contextual factors is vital. While this study aids health professions educators in understanding how games may support teaching of clinical reasoning, further research is needed to optimize their effective use in education. Notably, most games lack explicit incorporation of all clinical reasoning cycle steps, especially reflection, limiting its role in reflective practice. Hence, we recommend prioritizing a systematic clinical reasoning model with explicit reflective steps when using serious games for teaching clinical reasoning

Development of entrustable professional activities for paediatric intensive care fellows: A national modified Delphi study

Contains fulltext : 232752.pdf (Publisher’s version ) (Open Access)Entrustable professional activities (EPAs), as a focus of learner assessment, are supported by validity evidence. An EPA is a unit of professional practice requiring proficiency in multiple competencies simultaneously, that can be entrusted to a sufficiently competent learner. Taken collectively, a set of EPAs define and inform the curriculum of a specialty training. The goal of this study was to develop a set of EPAs for Dutch PICU fellows. A multistage methodology was employed incorporating sequential input from task force members, a medical education expert, PICU fellowship program directors, and PICU physicians and fellows via a modified three-round Delphi study. In the first modified Delphi round, experts rated indispensability and clarity of preliminary EPAs. In the subsequent rounds, aggregated scores for each EPA and group comments were provided. In round two, respondents rated indispensability and clarity of revised EPAs. Round three was used to gain explicit confirmation of suitability to implement these EPAs. Based on median ratings and content validity index (CVI) analysis for indispensability in the first two rounds, all nine preliminary EPAs covered activities that were deemed essential to the clinical practice of PICU physicians. Based on median ratings and CVI analysis for clarity however, four EPAs needed revision. With an agreement percentage of 93-100% for all individual EPAs as well as the set as a whole, a high degree of consensus among experts was reached in the third round. The resulting nine PICU EPAs provide a succinct overview of the core tasks of Dutch PICU physicians. These EPAs were created as an essential first step towards developing an assessment system for PICU fellows, grounded in core professional activities. The robust methodology used, may have broad applicability for other (sub)specialty training programs aiming to develop specialty specific EPAs

Leerdoelen over kinder- en jeugdpsychiatrie in de opleiding psychiatrie: een delphistudie

BACKGROUND: The new Dutch training plan for psychiatrists puts more emphasis on life course psychiatry. Subsequently, adjustments in the educational program regarding child and adolescent psychiatric knowledge, skills and attitudes are needed. AIM: A broadly supported agreement and consensus on Dutch national learning objectives of education in child and adolescent psychiatry. METHOD: With a modified Delphi method, a set of preliminary learning objectives formulated by a working group of experts was presented to trainees (n = 9), adult psychiatrists (n = 12), child and adolescent psychiatrists (n = 17) and adult patients and their relatives (n = 15). In two rounds, the learning objectives were commented on, supplemented, scored for relevance and prioritized. RESULTS: Out of 27 original learning objectives, 20 were assessed as important or necessary by over 80% of the respondents (knowledge 7/9, skills 8/10, attitudes 5/8). Two learning objectives were rejected (less than 60% considered these to be important or necessary). Seven learning objectives were re-assessed in a second round as these were modified (5) or added (2). Four of them were rated as important or necessary by over 80% of participants. The following goals were most often prioritized: knowledge about healthy development and intergenerational issues; ability to make contact with children and families and to integrate protective and risk factors of the child and environment; and knowing one&rsquo;s own limitations of child psychiatric themes. CONCLUSION: A Delphi study helped gain support from stakeholders for adjustments in training and education by creating consensus about child psychiatric learning goals for general psychiatric training

Leerdoelen over kinder- en jeugdpsychiatrie in de opleiding psychiatrie: een delphistudie

BACKGROUND: The new Dutch training plan for psychiatrists puts more emphasis on life course psychiatry. Subsequently, adjustments in the educational program regarding child and adolescent psychiatric knowledge, skills and attitudes are needed. AIM: A broadly supported agreement and consensus on Dutch national learning objectives of education in child and adolescent psychiatry. METHOD: With a modified Delphi method, a set of preliminary learning objectives formulated by a working group of experts was presented to trainees (n = 9), adult psychiatrists (n = 12), child and adolescent psychiatrists (n = 17) and adult patients and their relatives (n = 15). In two rounds, the learning objectives were commented on, supplemented, scored for relevance and prioritized. RESULTS: Out of 27 original learning objectives, 20 were assessed as important or necessary by over 80% of the respondents (knowledge 7/9, skills 8/10, attitudes 5/8). Two learning objectives were rejected (less than 60% considered these to be important or necessary). Seven learning objectives were re-assessed in a second round as these were modified (5) or added (2). Four of them were rated as important or necessary by over 80% of participants. The following goals were most often prioritized: knowledge about healthy development and intergenerational issues; ability to make contact with children and families and to integrate protective and risk factors of the child and environment; and knowing one&rsquo;s own limitations of child psychiatric themes. CONCLUSION: A Delphi study helped gain support from stakeholders for adjustments in training and education by creating consensus about child psychiatric learning goals for general psychiatric training