Cerebral Oximetry Monitoring in Extremely Preterm Infants.

BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).

Organ Dysfunction in Children With Blood Culture-Proven Sepsis: Comparative Performance of Four Scores in a National Cohort Study.

OBJECTIVES: Previous studies applying Sepsis-3 criteria to children were based on retrospective analyses of PICU cohorts. We aimed to compare organ dysfunction criteria in children with blood culture-proven sepsis, including emergency department, PICU, and ward patients, and to assess relevance of organ dysfunctions for mortality prediction. DESIGN: We have carried out a nonprespecified, secondary analysis of a prospective dataset collected from September 2011 to December 2015. SETTING: Emergency departments, wards, and PICUs in 10 tertiary children's hospitals in Switzerland. PATIENTS: Children younger than 17 years old with blood culture-proven sepsis. We excluded preterm infants and term infants younger than 7 days old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the 2005 International Pediatric Sepsis Consensus Conference (IPSCC), Pediatric Logistic Organ Dysfunction-2 (PELOD-2), pediatric Sequential Organ Failure Assessment (pSOFA), and Pediatric Organ Dysfunction Information Update Mandate (PODIUM) scores, measured at blood culture sampling, to predict 30-day mortality. We analyzed 877 sepsis episodes in 807 children, with a 30-day mortality of 4.3%. Percentage with organ dysfunction ranged from 32.7% (IPSCC) to 55.3% (pSOFA). In adjusted analyses, the accuracy for identification of 30-day mortality was area under the curve (AUC) 0.87 (95% CI, 0.82-0.92) for IPSCC, 0.83 (0.76-0.89) for PELOD-2, 0.85 (0.78-0.92) for pSOFA, and 0.85 (0.78-0.91) for PODIUM. When restricting scores to neurologic, respiratory, and cardiovascular dysfunction, the adjusted AUC was 0.89 (0.84-0.94) for IPSCC, 0.85 (0.79-0.91) for PELOD-2, 0.87 (0.81-0.93) for pSOFA, and 0.88 (0.83-0.93) for PODIUM. CONCLUSIONS: IPSCC, PELOD-2, pSOFA, and PODIUM performed similarly to predict 30-day mortality. Simplified scores restricted to neurologic, respiratory, and cardiovascular dysfunction yielded comparable performance.

C-Reactive Protein, Procalcitonin, and White Blood Count to Rule Out Neonatal Early-onset Sepsis Within 36 Hours: A Secondary Analysis of the Neonatal Procalcitonin Intervention Study.

BACKGROUND: Neonatal early-onset sepsis (EOS) is one of the main causes of global neonatal mortality and morbidity, and initiation of early antibiotic treatment is key. However, antibiotics may be harmful. METHODS: We performed a secondary analysis of results from the Neonatal Procalcitonin Intervention Study, a prospective, multicenter, randomized, controlled intervention study. The primary outcome was the diagnostic accuracy of serial measurements of C-reactive protein (CRP), procalcitonin (PCT), and white blood count (WBC) within different time windows to rule out culture-positive EOS (proven sepsis). RESULTS: We analyzed 1678 neonates with 10 899 biomarker measurements (4654 CRP, 2047 PCT, and 4198 WBC) obtained within the first 48 hours after the start of antibiotic therapy due to suspected EOS. The areas under the curve (AUC) comparing no sepsis vs proven sepsis for maximum values of CRP, PCT, and WBC within 36 hours were 0.986, 0.921, and 0.360, respectively. The AUCs for CRP and PCT increased with extended time frames up to 36 hours, but there was no further difference between start to 36 hours vs start to 48 hours. Cutoff values at 16 mg/L for CRP and 2.8 ng/L for PCT provided a sensitivity of 100% for discriminating no sepsis vs proven sepsis. CONCLUSIONS: Normal serial CRP and PCT measurements within 36 hours after the start of empiric antibiotic therapy can exclude the presence of neonatal EOS with a high probability. The negative predictive values of CRP and PCT do not increase after 36 hours.

Stratification of Culture-Proven Early-Onset Sepsis Cases by the Neonatal Early-Onset Sepsis Calculator: An Individual Patient Data Meta-Analysis.

OBJECTIVES: To provide a comprehensive assessment of case stratification by the Neonatal Early-Onset Sepsis (EOS) Calculator, a novel tool for reducing unnecessary antibiotic treatment. STUDY DESIGN: A systematic review with individual patient data meta-analysis was conducted, extending PROSPERO record CRD42018116188. Cochrane, PubMed/MEDLINE, EMBASE, Web of Science, Google Scholar, and major conference proceedings were searched from 2011 through May 1, 2020. Original data studies including culture-proven EOS case(s) with EOS Calculator application, independent from EOS Calculator development, and including representative birth cohorts were included. Relevant (individual patient) data were extracted from full-text and data queries. The main outcomes were the proportions of EOS cases assigned to risk categories by the EOS Calculator at initial assessment and within 12 hours. Evidence quality was assessed using Newcastle-Ottawa scale, Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies, and GRADE tools. RESULTS: Among 543 unique search results, 18 were included, totaling more than 459 000 newborns. Among 234 EOS cases, EOS Calculator application resulted in initial assignments to (strong consideration of) empiric antibiotic administration for 95 (40.6%; 95% CI, 34.2%-47.2%), more frequent vital signs for 36 (15.4%; 95% CI, 11.0%-20.7%), and routine care for 103 (44.0%; 95% CI, 37.6%-50.6%). By 12 hours of age, these proportions changed to 143 (61.1%; 95% CI, 54.5%-67.4%), 26 (11.1%; 95% CI, 7.4%-15.9%), and 65 (27.8%; 95% CI, 22.1%-34.0%) of 234 EOS cases, respectively. CONCLUSIONS: EOS Calculator application assigns frequent vital signs or routine care to a substantial proportion of EOS cases. Clinical vigilance remains essential for all newborns.

Cost impact of procalcitonin-guided decision making on duration of antibiotic therapy for suspected early-onset sepsis in neonates.

BACKGROUNDS: The large, international, randomized controlled NeoPInS trial showed that procalcitonin (PCT)-guided decision making was superior to standard care in reducing the duration of antibiotic therapy and hospitalization in neonates suspected of early-onset sepsis (EOS), without increased adverse events. This study aimed to perform a cost-minimization study of the NeoPInS trial, comparing health care costs of standard care and PCT-guided decision making based on the NeoPInS algorithm, and to analyze subgroups based on country, risk category and gestational age. METHODS: Data from the NeoPInS trial in neonates born after 34 weeks of gestational age with suspected EOS in the first 72 h of life requiring antibiotic therapy were used. We performed a cost-minimization study of health care costs, comparing standard care to PCT-guided decision making. RESULTS: In total, 1489 neonates were included in the study, of which 754 were treated according to PCT-guided decision making and 735 received standard care. Mean health care costs of PCT-guided decision making were not significantly different from costs of standard care (€3649 vs. €3616). Considering subgroups, we found a significant reduction in health care costs of PCT-guided decision making for risk category 'infection unlikely' and for gestational age ≥ 37 weeks in the Netherlands, Switzerland and the Czech Republic, and for gestational age < 37 weeks in the Czech Republic. CONCLUSIONS: Health care costs of PCT-guided decision making of term and late-preterm neonates with suspected EOS are not significantly different from costs of standard care. Significant cost reduction was found for risk category 'infection unlikely,' and is affected by both the price of PCT-testing and (prolonged) hospitalization due to SAEs.

Whole-exome Sequencing for the Identification of Rare Variants in Primary Immunodeficiency Genes in Children With Sepsis: A Prospective, Population-based Cohort Study.

BACKGROUND: The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes. METHODS: We conducted a multicenter, population-based, prospective study including previously healthy children aged ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported. RESULTS: There were 176 children presenting with 185 sepsis episodes who underwent WES (median age, 52 months; interquartile range, 15.4-126.4). There were 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants that were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories, as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants. CONCLUSIONS: Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected variants of uncertain significance in PID genes in 1 out of 5 children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations.

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-ß, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.

Burden of Streptococcus pneumoniae Sepsis in Children After Introduction of Pneumococcal Conjugate Vaccines: A Prospective Population-based Cohort Study.

BACKGROUND: Population-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on burden of pneumococcal sepsis in children are lacking. We aimed to assess this burden following introduction of PCV-13 in a nationwide cohort study. METHODS: The Swiss Pediatric Sepsis Study (September 2011 to December 2015) prospectively recruited children <17 years of age with blood culture-proven sepsis due to Streptococcus pneumoniae, meeting criteria for systemic inflammatory response syndrome. Infection with vaccine serotype in children up to date with PCV immunization was defined as vaccine failure. Main outcomes were admission to pediatric intensive care unit (PICU) and length of hospital stay (LOS). RESULTS: Children with pneumococcal sepsis (n = 117) accounted for a crude incidence of 2.0 per 100 000 children (95% confidence interval [CI] 1.7-2.4) and 25% of community-acquired sepsis episodes. Case fatality rate was 8%. Forty-two (36%) patients required PICU admission. Children with meningitis (29; 25%) were more often infected by serotypes not included in PCV (69% vs 31%; P < .001). Sixteen (26%) of 62 children up to date with PCV immunization presented with vaccine failure, including 11 infected with serotype 3. In multivariable analyses, children with meningitis (odds ratio [OR] 6.8; 95% CI 2.4-19.3; P < .001) or infected with serotype 3 (OR 2.8; 95% CI 1.1-7.3; P = .04) were more often admitted to PICU. Children infected with serotype 3 had longer LOS (ß coefficient 0.2, 95% CI .1-1.1; P = .01). CONCLUSIONS: The incidence of pneumococcal sepsis in children shortly after introduction of PCV-13 remained substantial. Meningitis mostly due to non-vaccine serotypes and disease caused by serotype 3 represented significant predictors of severity.

Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns).

BACKGROUND: Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment. METHODS: We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932. FINDINGS: Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI -4·6 to 4·8) in the intention-to-treat analysis (5 [0·6%] of 866 neonates in the procalcitonin group vs 4 [0·5%] of 844 neonates in the standard group) and 0·1% (-5·2 to 5·3) in the per-protocol analysis (5 [0·7%] of 745 neonates in the procalcitonin group vs 4 [0·6%] of 663 neonates in the standard group). INTERPRETATION: Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death. FUNDING: The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.

Neonatal Sepsis of Early Onset, and Hospital-Acquired and Community-Acquired Late Onset: A Prospective Population-Based Cohort Study.

OBJECTIVE: To assess the epidemiology of blood culture-proven early- (EOS) and late-onset neonatal sepsis (LOS). STUDY DESIGN: All newborn infants admitted to tertiary care neonatal intensive care units in Switzerland and presenting with blood culture-proven sepsis between September 2011 and December 2015 were included in the study. We defined EOS as infection occurring <3 days after birth, and LOS as infection ≥3 days after birth. Infants with LOS were classified as having community-acquired LOS if onset of infection was ≤48 hours after admission, and hospital-acquired LOS, if onset was >48 hours after admission. Incidence was estimated based on the number of livebirths in Switzerland and adjusted for the proportion of admissions at centers participating in the study. RESULTS: We identified 444 episodes of blood culture-proven sepsis in 429 infants; 20% of cases were EOS, 62% hospital-acquired LOS, and 18% community-acquired LOS. The estimated national incidence of EOS, hospital-acquired LOS, and community-acquired LOS was 0.28 (95% CI 0.23-0.35), 0.86 (0.76-0.97), and 0.28 (0.23-0.34) per 1000 livebirths. Compared with EOS, hospital-acquired LOS occurred in infants of lower gestational age and was more frequently associated with comorbidities. Community-acquired LOS was more common in term infants and in male infants. Mortality was 18%, 12%, and 0% in EOS, hospital-acquired LOS, and community-acquired LOS, and was higher in preterm infants, in infants with septic shock, and in those requiring mechanical ventilation. CONCLUSIONS: We report a high burden of sepsis in neonates with considerable mortality and morbidity. EOS, hospital-acquired LOS, and community-acquired LOS affect specific patient subgroups and have distinct clinical presentation, pathogens and outcomes.

Use of simulation-based medical training in Swiss pediatric hospitals: a national survey.

BACKGROUND: Simulation-based medical training (SBMT) is a powerful tool for continuing medical education. In contrast to the Anglo-Saxon medical education community, up until recently, SBMT was scarce in continental Europe's pediatric health care education: In 2009, only 3 Swiss pediatric health care institutions used SBMT. The Swiss catalogue of objectives in Pediatrics does not acknowledge SBMT. The aim of this survey is to describe and analyze the current state of SBMT in Swiss pediatric hospitals and health care departments. METHODS: A survey was carried out with medical education representatives of every institution. SBMT was defined as any kind of training with a mannequin excluding national and/or international standardized courses. The survey reference day was May 31st 2015. RESULTS: Thirty Swiss pediatric hospitals and health care departments answered our survey (response rate 96.8%) with 66.6% (20 out of 30) offering SBMT. Four of the 20 hospitals offering SMBT had two independently operating training simulation units, resulting in 24 educational units as the basis for our SBMT analysis. More than 90% of the educational units offering SBMT (22 out of 24 units) were conducting in-situ training and 62.5% (15 out of 24) were using high-technology mannequins. Technical skills, communication and leadership ranked among the top training priorities. All institutions catered to inter-professional participants. The vast majority conducted training that was neither embedded within a larger educational curriculum (19 out of 24: 79.2%) nor evaluated (16 out of 24: 66.6%) by its participants. Only 5 institutions (20.8%) extended their training to at least two thirds of their hospital staff. CONCLUSIONS: Two thirds of the Swiss pediatric hospitals and health care departments are offering SBMT. Swiss pediatric SBMT is inter-professional, mainly in-situ based, covering technical as well as non-technical skills, and often employing high-technology mannequins. The absence of a systematic approach and reaching only a small number of healthcare employees were identified as shortcomings that need to be addressed.

Normal values for pancreatic stone protein in different age groups.

BACKGROUND: Pancreatic stone protein (PSP) has been identified as a promising sepsis marker in adults, children and neonates. However, data on population-based reference values are lacking. This study aimed to establish age-specific reference values for PSP. METHODS: PSP was determined using a specific ELISA. PSP serum concentrations were determined in 372 healthy subjects including 217 neonates, 94 infants and children up to 16 years, and 61 adults. The adjacent categories method was used to determine which age categories had significantly different PSP concentrations. RESULTS: PSP circulating levels were not gender-dependent and ranged from 1.0 to 99.4 ng/ml with a median of 9.2 ng/ml. PSP increased significantly between the age categories, from a median of 2.6 ng/ml in very preterm newborns, to 6.3 ng/ml in term newborns, to 16.1 ng/ml in older children (p < 0.001). PSP levels were higher on postnatal day three compared to levels measured immediately post delivery (p < 0.001). Paired umbilical artery and umbilical vein samples were strongly correlated (p < 0.001). Simultaneously obtained capillary heel-prick versus venous samples showed a good level of agreement for PSP (Rho 0.89, bias 19 %). CONCLUSIONS: This study provides age-specific normal values that may be used to define cut-offs for future trials on PSP. We demonstrate an age-dependent increase of PSP from birth to childhood.

Inter-professional in-situ simulated team and resuscitation training for patient safety: Description and impact of a programmatic approach.

BACKGROUND: Inter-professional teamwork is key for patient safety and team training is an effective strategy to improve patient outcome. In-situ simulation is a relatively new strategy with emerging efficacy, but best practices for the design, delivery and implementation have yet to be evaluated. Our aim is to describe and evaluate the implementation of an inter-professional in-situ simulated team and resuscitation training in a teaching hospital with a programmatic approach. METHODS: We designed and implemented a team and resuscitation training program according to Kern's six steps approach for curriculum development. General and specific needs assessments were conducted as independent cross-sectional surveys. Teamwork, technical skills and detection of latent safety threats were defined as specific objectives. Inter-professional in-situ simulation was used as educational strategy. The training was embedded within the workdays of participants and implemented in our highest acuity wards (emergency department, intensive care unit, intermediate care unit). Self-perceived impact and self-efficacy were sampled with an anonymous evaluation questionnaire after every simulated training session. Assessment of team performance was done with the team-based self-assessment tool TeamMonitor applying Van der Vleuten's conceptual framework of longitudinal evaluation after experienced real events. Latent safety threats were reported during training sessions and after experienced real events. RESULTS: The general and specific needs assessments clearly identified the problems, revealed specific training needs and assisted with stakeholder engagement. Ninety-five interdisciplinary staff members of the Children's Hospital participated in 20 in-situ simulated training sessions within 2 years. Participant feedback showed a high effect and acceptance of training with reference to self-perceived impact and self-efficacy. Thirty-five team members experiencing 8 real critical events assessed team performance with TeamMonitor. Team performance assessment with TeamMonitor was feasible and identified specific areas to target future team training sessions. Training sessions as well as experienced real events revealed important latent safety threats that directed system changes. CONCLUSIONS: The programmatic approach of Kern's six steps for curriculum development helped to overcome barriers of design, implementation and assessment of an in-situ team and resuscitation training program. This approach may help improve effectiveness and impact of an in-situ simulated training program.

Pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sIAHP in CA1 pyramidal neurons by activating multiple signaling pathways.

The slow afterhyperpolarizing current (sIAHP ) is a calcium-dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sIAHP is a well-known target of modulation by several neurotransmitters acting via the cyclic AMP (cAMP) and protein kinase A (PKA)-dependent pathway. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP) and its receptors are present in the hippocampal formation. In this study we have investigated the effect of PACAP on the sIAHP and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sIAHP , resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sIAHP by PACAP is mediated by PAC1 and VPAC1 receptors. Inhibition of PKA reduced the effect of PACAP on sIAHP, suggesting that PACAP exerts part of its inhibitory effect on sIAHP by increasing cAMP and activating PKA. The suppression of sIAHP by PACAP was also strongly hindered by the inhibition of p38 MAP kinase (p38 MAPK). Concomitant inhibition of PKA and p38 MAPK indicates that these two kinases act in a sequential manner in the same pathway leading to the suppression of sIAHP. Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sIAHP in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sIAHP through the activation of multiple signaling pathways, most prominently cAMP/PKA and p38 MAPK. Our findings disclose a novel modulatory action of p38 MAPK on intrinsic excitability and the sIAHP, underscoring the role of this current as a neuromodulatory hub regulated by multiple protein kinases in cortical neurons.

Optimisation of simulated team training through the application of learning theories: a debate for a conceptual framework.

BACKGROUND: As a conceptual review, this paper will debate relevant learning theories to inform the development, design and delivery of an effective educational programme for simulated team training relevant to health professionals. DISCUSSION: Kolb's experiential learning theory is used as the main conceptual framework to define the sequence of activities. Dewey's theory of reflective thought and action, Jarvis modification of Kolb's learning cycle and Schön's reflection-on-action serve as a model to design scenarios for optimal concrete experience and debriefing for challenging participants' beliefs and habits. Bandura's theory of self-efficacy and newer socio-cultural learning models outline that for efficient team training, it is mandatory to introduce the social-cultural context of a team. SUMMARY: The ideal simulated team training programme needs a scenario for concrete experience, followed by a debriefing with a critical reflexive observation and abstract conceptualisation phase, and ending with a second scenario for active experimentation. Let them re-experiment to optimise the effect of a simulated training session. Challenge them to the edge: The scenario needs to challenge participants to generate failures and feelings of inadequacy to drive and motivate team members to critical reflect and learn. Not experience itself but the inadequacy and contradictions of habitual experience serve as basis for reflection. Facilitate critical reflection: Facilitators and group members must guide and motivate individual participants through the debriefing session, inciting and empowering learners to challenge their own beliefs and habits. To do this, learners need to feel psychological safe. Let the group talk and critical explore. Motivate with reality and context: Training with multidisciplinary team members, with different levels of expertise, acting in their usual environment (in-situ simulation) on physiological variables is mandatory to introduce cultural context and social conditions to the learning experience. Embedding in situ team training sessions into a teaching programme to enable repeated training and to assess regularly team performance is mandatory for a cultural change of sustained improvement of team performance and patient safety.

Game changer or gimmick: inflammatory markers to guide antibiotic treatment decisions in neonatal early-onset sepsis.

BACKGROUND: The diagnosis of neonatal early-onset sepsis (EOS) is challenging, and inflammatory markers are widely used to guide decision-making and therapies. OBJECTIVES: This narrative review presents the current state of knowledge regarding the diagnostic value and potential pitfalls in the interpretation of inflammatory markers for EOS. SOURCES: PubMed until October 2022 and searched references in identified articles using the search terms: neonatal EOS, biomarker or inflammatory marker, and antibiotic therapy or antibiotic stewardship. CONTENT: In situations with a high or low probability of sepsis, the measurements of inflammatory markers have no impact on the decision to start or stop antibiotics and are just gimmick, whereas they may be a game changer for neonates with intermediate risk and therefore an unclear situation. There is no single or combination of inflammatory markers that can predict EOS with high probability, allowing us to make decisions regarding the start of antibiotics based only on inflammatory markers. The main reason for the limited accuracy is most probably the numerous noninfectious conditions that influence the levels of inflammatory markers. However, there is evidence that C-reactive protein and procalcitonin have good negative predictive accuracy to rule out sepsis within 24 to 48 hours. Nevertheless, several publications have reported more investigations and prolonged antibiotic treatments with the use of inflammatory markers. Given the limitations of current strategies, using an algorithm with only moderate diagnostic accuracy may have a positive impact, as reported for the EOS calculator and the NeoPInS algorithm. IMPLICATIONS: As the decision regarding the start of antibiotic therapy is different from the process of stopping antibiotics, the accuracy of inflammatory markers needs to be evaluated separately. Novel machine learning-based algorithms are required to improve accuracy in the diagnosis of EOS. In the future, inflammatory markers included in algorithms may be a game changer reducing bias and noise in the decision-making process.

Functional analysis of missense mutations in Kv8.2 causing cone dystrophy with supernormal rod electroretinogram.

Mutations in KCNV2 have been proposed as the molecular basis for cone dystrophy with supernormal rod electroretinogram. KCNV2 codes for the modulatory voltage-gated potassium channel α-subunit, Kv8.2, which is incapable of forming functional channels on its own. Functional heteromeric channels are however formed with Kv2.1 in heterologous expression systems, with both α-subunit genes expressed in rod and cone photoreceptors. Of the 30 mutations identified in the KCNV2 gene, we have selected three missense mutations localized in the potassium channel pore and two missense mutations localized in the tetramerization domain for analysis. We characterized the differences between homomeric Kv2.1 and heteromeric Kv2.1/Kv8.2 channels and investigated the influence of the selected mutations on the function of heteromeric channels. We found that two pore mutations (W467G and G478R) led to the formation of nonconducting heteromeric Kv2.1/Kv8.2 channels, whereas the mutations localized in the tetramerization domain prevented heteromer generation and resulted in the formation of homomeric Kv2.1 channels only. Consequently, our study suggests the existence of two distinct molecular mechanisms involved in the disease pathology.

Small-conductance Ca2+-activated K+ channels modulate action potential-induced Ca2+ transients in hippocampal neurons.

In hippocampal pyramidal neurons, voltage-gated Ca(2+) channels open in response to action potentials. This results in elevations in the intracellular concentration of Ca(2+) that are maximal in the proximal apical dendrites and decrease rapidly with distance from the soma. The control of these action potential-evoked Ca(2+) elevations is critical for the regulation of hippocampal neuronal activity. As part of Ca(2+) signaling microdomains, small-conductance Ca(2+)-activated K(+) (SK) channels have been shown to modulate the amplitude and duration of intracellular Ca(2+) signals by feedback regulation of synaptically activated Ca(2+) sources in small distal dendrites and dendritic spines, thus affecting synaptic plasticity in the hippocampus. In this study, we investigated the effect of the activation of SK channels on Ca(2+) transients specifically induced by action potentials in the proximal processes of hippocampal pyramidal neurons. Our results, obtained by using selective SK channel blockers and enhancers, show that SK channels act in a feedback loop, in which their activation by Ca(2+) entering mainly through L-type voltage-gated Ca(2+) channels leads to a reduction in the subsequent dendritic influx of Ca(2+). This underscores a new role of SK channels in the proximal apical dendrite of hippocampal pyramidal neurons.

Reliability of team-based self-monitoring in critical events: a pilot study.

BACKGROUND: Teamwork is a critical component during critical events. Assessment is mandatory for remediation and to target training programmes for observed performance gaps. METHODS: The primary purpose was to test the feasibility of team-based self-monitoring of crisis resource management with a validated teamwork assessment tool. A secondary purpose was to assess item-specific reliability and content validity in order to develop a modified context-optimised assessment tool.We conducted a prospective, single-centre study to assess team-based self-monitoring of teamwork after in-situ inter-professional simulated critical events by comparison with an assessment by observers. The Mayo High Performance Teamwork Scale (MHPTS) was used as the assessment tool with evaluation of internal consistency, item-specific consensus estimates for agreement between participating teams and observers, and content validity. RESULTS: 105 participants and 58 observers completed the MHPTS after a total of 16 simulated critical events over 8 months. Summative internal consistency of the MHPTS calculated as Cronbach's alpha was acceptable with 0.712 for observers and 0.710 for participants. Overall consensus estimates for dichotomous data (agreement/non-agreement) was 0.62 (Cohen's kappa; IQ-range 0.31-0.87). 6/16 items had excellent (kappa > 0.8) and 3/16 good reliability (kappa > 0.6). Short questions concerning easy to observe behaviours were more likely to be reliable. The MHPTS was modified using a threshold for good reliability of kappa > 0.6. The result is a 9 item self-assessment tool (TeamMonitor) with a calculated median kappa of 0.86 (IQ-range: 0.67-1.0) and good content validity. CONCLUSIONS: Team-based self-monitoring with the MHPTS to assess team performance during simulated critical events is feasible. A context-based modification of the tool is achievable with good internal consistency and content validity. Further studies are needed to investigate if team-based self-monitoring may be used as part of a programme of assessment to target training programmes for observed performance gaps.