Live Rotavirus Vaccination Appears Low-risk in Infants Born to Mothers With Inflammatory Bowel Disease on Biologics.

BACKGROUND & AIMS: Biologic therapies in the context of inflammatory bowel disease and pregnancy lead to improved maternal and fetal outcomes. Placental transfer results in detectable drug concentrations in infants. Rotavirus infection results in diarrheal related hospitalizations; however, the live oral vaccine is not currently recommended in biologic exposed infants. The aim of this study was to assess the effect of maternal biologic therapies on the infant immune system and safety of live rotavirus vaccination in biologic-exposed infants. METHODS: Biologic-exposed infants underwent standardized clinical assessments, drug concentration, and immune function testing (complete blood count, differential, immunoglobulin levels, extended B-cell and T-cell subset enumeration, Recent Thymic Emigrants, regulatory T-cell numbers, mitogen stimulation assays, and review of T-cell Receptor Excision Circles in the newborn screen). Rotavirus vaccine-specific adverse effects following immunizations up to 42 days post the last dose of the vaccine series were recorded. RESULTS: There were 57 infants born to 52 mothers with inflammatory bowel disease exposed to infliximab (n = 21), adalimumab (n = 19), vedolizumab (n = 10), and ustekinumab (n = 7) in the third trimester for a median of 39 weeks (interquartile range, 38-39 weeks) at delivery. Immunologic assessments validated for age were normal in all infants despite median infliximab concentrations of 6.1 ug/mL (range, 0.4-28.8 ug/mL), adalimumab concentrations of 1.7 ug/mL (range, 0.7-7.9 ug/mL), ustekinumab concentrations of 0.6 ug/mL (range, 0-1.1), and undetectable for vedolizumab at 10.7 weeks (interquartile range, 9.4-12.4) of age. The live oral rotavirus vaccine series was provided to 50 infants with the first dose given at a median of 13 weeks of age. No adverse effects following immunization were reported. CONCLUSION: Immune function testing was normal, and administration of live rotavirus vaccination appeared low-risk in biologic-exposed infants irrespective of circulating drug levels.

MFGE8 in exosomes derived from mesenchymal stem cells prevents esophageal stricture after endoscopic submucosal dissection in pigs.

BACKGROUND: Endoscopic submucosal dissection (ESD) is the current standard treatment for early-stage esophageal neoplasms. However, the postoperative esophageal stricture after extensive mucosal dissection remains a severe challenge with limited effective treatments available. In this study, we introduced a chitosan/gelatin (ChGel) sponge encapsulating the adipose mesenchymal stem cells (ADMSCs)-derived exosomes (ChGelMSC-Exo) for the prevention of esophageal stenosis after ESD in a porcine model. RESULTS: Pigs were randomly assigned into (1) ChGelMSC-Exo treatment group, (2) ChGelPBS group, and (3) the controls. Exosome treatments were applied immediately on the day after ESD as well as on day 7. Exosome components crucial for wound healing were investigated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and small RNA sequencing. ChGelMSC-Exo treatment significantly reduced mucosal contraction on day 21, with less fiber accumulation and inflammatory infiltration, and enhanced angiogenesis when compared with the control and ChGelPBS groups. The anti-fibrotic effects following MSC-Exo treatment were further found to be associated with the anti-inflammatory M2 polarization of the resident macrophages, especially within the M2b subset characterized by the reduced TGFß1 secretion, which sufficiently inhibited inflammation and prevented the activation of myofibroblast with less collagen production at the early stage after ESD. Moreover, the abundant expression of exosomal MFGE8 was identified to be involved in the transition of the M2b-macrophage subset through the activation of MFGE8/STAT3/Arg1 axis. CONCLUSIONS: Our study demonstrates that exosomal MFGE8 significantly promotes the polarization of the M2b-macrophage subset, consequently reducing collagen deposition. These findings suggest a promising potential for MSC-Exo therapy in preventing the development of esophageal stricture after near-circumferential ESD.

Walking the talk for dementia: A unique immersive, embodied, and multi-experiential initiative.

Coping with dementia requires an integrated approach encompassing personal, health, research, and community domains. Here we describe "Walking the Talk for Dementia," an immersive initiative aimed at empowering people with dementia, enhancing dementia understanding, and inspiring collaborations. This initiative involved 300 participants from 25 nationalities, including people with dementia, care partners, clinicians, policymakers, researchers, and advocates for a 4-day, 40 km walk through the Camino de Santiago de Compostela, Spain. A 2-day symposium after the journey provided novel transdisciplinary and horizontal structures, deconstructing traditional hierarchies. The innovation of this initiative lies in its ability to merge a physical experience with knowledge exchange for diversifying individuals' understanding of dementia. It showcases the transformative potential of an immersive, embodied, and multi-experiential approach to address the complexities of dementia collaboratively. The initiative offers a scalable model to enhance understanding, decrease stigma, and promote more comprehensive and empathetic dementia care and research.

Neutrophil-Derived Protein S100A8/A9 Alters the Platelet Proteome in Acute Myocardial Infarction and Is Associated With Changes in Platelet Reactivity.

OBJECTIVE: Platelets are central to acute myocardial infarction (MI). How the platelet proteome is altered during MI is unknown. We sought to describe changes in the platelet proteome during MI and identify corresponding functional consequences. Approach and Results: Platelets from patients experiencing ST-segment-elevation MI (STEMI) before and 3 days after treatment (n=30) and matched patients with severe stable coronary artery disease before and 3 days after coronary artery bypass grafting (n=25) underwent quantitative proteomic analysis. Elevations in the proteins S100A8 and S100A9 were detected at the time of STEMI compared with stable coronary artery disease (S100A8: FC, 2.00; false discovery rate, 0.05; S100A9: FC, 2.28; false discovery rate, 0.005). During STEMI, only S100A8 mRNA and protein levels were correlated in platelets (R=0.46, P=0.012). To determine whether de novo protein synthesis occurs, activated platelets were incubated with 13C-labeled amino acids for 24 hours and analyzed by mass spectrometry. No incorporation was confidently detected. Platelet S100A8 and S100A9 was strongly correlated with neutrophil abundance at the time of STEMI. When isolated platelets and neutrophils were coincubated under quiescent and activated conditions, release of S100A8 from neutrophils resulted in uptake of S100A8 by platelets. Neutrophils released S100A8/A9 as free heterodimer, rather than in vesicles or extracellular traps. In the community-based Bruneck study (n=338), plasma S100A8/A9 was inversely associated with platelet reactivity-an effect abrogated by aspirin. CONCLUSIONS: Leukocyte-to-platelet protein transfer may occur in a thromboinflammatory environment such as STEMI. Plasma S100A8/A9 was negatively associated with platelet reactivity. These findings highlight neutrophils as potential modifiers for thrombotic therapies in coronary artery disease.

Trends among platelet function, arterial calcium, and vascular function measures.

Arterial tonometry and vascular calcification measures are useful in cardiovascular disease (CVD) risk assessment. Prior studies found associations between tonometry measures, arterial calcium, and CVD risk. Activated platelets release angiopoietin-1 and other factors, which may connect vascular structure and platelet function. We analyzed arterial tonometry, platelet function, aortic, thoracic and coronary calcium, and thoracic and abdominal aorta diameters measured in the Framingham Heart Study Gen3/NOS/OMNI-2 cohorts (n = 3,429, 53.7% women, mean age 54.4 years ±9.3). Platelet reactivity in whole blood or platelet-rich plasma was assessed using 5 assays and 7 agonists. We analyzed linear mixed effects models with platelet reactivity phenotypes as outcomes, adjusting for CVD risk factors and family structure. Higher arterial calcium trended with higher platelet reactivity, whereas larger aortic diameters trended with lower platelet reactivity. Characteristic impedance (Zc) and central pulse pressure positively trended with various platelet traits, while pulse wave velocity and Zc negatively trended with collagen, ADP, and epinephrine traits. All results did not pass a stringent multiple test correction threshold (p < 2.22e-04). The diameter trends were consistent with lower shear environments invoking less platelet reactivity. The vessel calcium trends were consistent with subclinical atherosclerosis and platelet activation being inter-related.

What is the context? Prior research has reported that measures of vascular system-influencing proteins such as angiopoietin-2, arterial calcium plaque formation, and arterial stiffness assessed by tonometry are associated with CVD risk.Since activated platelets produce and release vascular proteins like angiopoietin when activated, and microparticles that interact with endothelium, release of the foregoing mediators could provide one way in which vascular structure and platelet function influence each other.To our knowledge, no prior studies have directly investigated associations between these measures in a large sample. This investigation relates platelet function to arterial tonometry, aortic and arterial diameter, and arterial calcium measures in the Framingham Heart Study (FHS) Gen3/NOS/OMNI-2 cohorts (n = 3,429).What's new? Generally, higher arterial calcium measures trended with higher platelet reactivity, whereas larger aortic diameters trended with lower platelet reactivity.Arterial tonometry measures had positive and negative trends with platelet functions, including platelet measures with opposite relations to negative-inverse carotid-femoral pulse wave velocity (niCFPWV) and characteristic impedance (Zc). All tonometry, calcium, and diameter results did not reach a more stringent multiple testing threshold (p < 2.22e-04).What's the impact? The aortic diameter trends are consistent with lower shear stress invoking less platelet reactivity.The vessel calcium trends are consistent with increased vascular calcium buildup that could provoke platelet activation, thereby contributing to increased blood clot risk. Conversely, increased platelet activation could contribute to increased inflammation and thrombosis, leading to calcification in the arterial wall.

Chinese (Mandarin) translation of the incremental shuttle walk test and its validity and reliability: A cross-sectional study.

Background/Purpose: To date, there are no published validated Chinese versions of the incremental shuttle walk test (ISWT) instructions despite its wide clinical applications. Translation of the Chinese ISWT instruction is done in an ad-hoc manner within the Chinese-speaking populations, affecting the test's reliability and validity since translation can differ significantly between individuals. This warrants the need for psychometric testing of such translation. Objectives: To develop a Chinese (Mandarin) version of the ISWT instructions (ISWT-CHN) that is conceptually equivalent to the original English version (ISWT-ENG) and establish its reliability and validity. Methods: Forward and backward translations from the ISWT-ENG were done to generate the ISWT-CHN. Face and content validity was determined during the translation process. Intra-rater and inter-rater reliability of the ISWT-CHN, construct and criterion validity were established by analysing the ISWT and the gold standard cardiopulmonary exercise test results. Results: The Item-Content validity index (I-CVI), Scale-level-Content validity index (S-CVI), and content validity ratio (CVR) of the ISWT-CHN were 1.0. Intra-class Correlation Coefficient (ICC) for inter-rater reliability between two raters were excellent (ICC=0.99, 95% CI 0.97-1.0, p<0.001; SEM=0.85 m, MDC=2.35 m). The intra-rater reliability of both Raters A (ICC=0.92, 95% CI 0.53-0.98, p=0.003; SEM=35 m, MDC=97 m) and B (ICC=0.90, 95% CI 0.76-0.96, p<0.001; SEM=32 m, MDC=88 m) were good. In a sample of 32 healthy participants, both ISWT-CHN and ISWT-ENG instruction results showed low-positive correlations with the VO2max determined from the cardiopulmonary exercise test (r = 0.439, p<0.001; r=0.448, p<0.001). There is a very high correlation between ISWT-ENG and ISWT-CHN results with no statistically significant differences (r=0.967, p<0.001). The construct and criterion validity of the ISWT-CHN were established. Conclusion: This study developed the ISWT-CHN and showed that it is a valid and reliable measure conceptually comparable to the ISWT-ENG. It will benefit the determination of functional exercise capacity in Chinese-speaking populations. Key messages: •This study is aimed to develop a Chinese (Mandarin) version of the ISWT instructions.•The ISWT Chinese translation is valid and reliable that is conceptually comparable to the original English instruction.•The translated ISWT-Chinese instruction will enable the use of ISWT among the Chinese-speaking populations.

Normative reference values and regression equations to predict the 6-minute walk distance in the Asian adult population aged 21-80 years.

Summary at a glance: The 6-min walk test (6MWT) is a widely used field walking test. This study reports the normative reference values (NRV) of distance walked during 6MWT (6MWD) in healthy Singaporeans (aged 21-80) and updates the 6MWD reference equations. This information may facilitate the interpretation of the 6MWD in clinical populations. Ethics approval: The Singapore Institute of Technology-Institutional Review Board (SIT-IRB Project Number: 2019099) approved this study to be carried out from June 2019 to January 2021. All participants gave written informed consent before data collection began. Background: The six-minute walk test (6MWT) is a widely adopted submaximal field-walking test to evaluate functional exercise capacity. This validated test is a reliable, safe, inexpensive, and straightforward assessment tool commonly used as an outcome measure, using the distance walked (6MWD) as the primary outcome. An earlier study has established the normative reference values (NRV) and equation in healthy Singaporeans - however, the small sample size and narrow age range curb adequate representation of the adult population profile. Objectives: This study aims to update the NRV and reference equations to predict the distance walked during 6MWT (6MWD) for healthy Singaporeans aged 21-80. Methods: This cross-sectional study recruited community-dwelling healthy subjects aged 21-80 via convenience sampling. Each subject completed two trials of 6MWT according to the standard protocol. Primary outcome measures included 6MWD, pre-and post-test heart rate (HR), oxygen saturation, and blood pressure (BP). Results: 172 healthy Singaporeans (females=90, males=82) participated. The overall mean 6MWD was 578.00±75.38 metres. The age-stratified mean 6MWD ranged from 601.3±71.79 metres (aged 21-39) to 519.02±55.42 metres (aged 60-80). Age, gender, and percentage maximum HR predicted (%PredHRmax) were the most significant variables (p<0.001). 6MWD reference equation=288.282(height,m)+27.463×Gender (male=1;female=0)+4.349(%predHRmax)+1.191 (HR reserve, bpm) -185.431-1.343(age,years)-1.614 (weight, kg), R2=58%. Applying equations from other studies to the Singaporean population resulted in an overestimation of the 6MWD. Conclusion: This study updated the NRV and reference equations of 6MWD for healthy Singaporeans aged between 21-80 years. This update revises the local benchmarks of 6MWD in Singapore, a widely adopted outcome measure.

Identification of a homozygous recessive variant in PTGS1 resulting in a congenital aspirin-like defect in platelet function.

We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in PTGS1 (the gene encoding cyclo-oxygenase 1, COX-1, the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COX-derived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 (TXA2) formation by platelets, urinary TXA2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.

Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin.

Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A2 , a pro-thrombotic eicosanoid. However, the non-platelet actions of aspirin limit its antithrombotic effects. Here, we used platelet-COX-1-ko mice to define the platelet and non-platelet eicosanoids affected by aspirin. Mass-spectrometry analysis demonstrated blood from platelet-COX-1-ko and global-COX-1-ko mice produced similar eicosanoid profiles in vitro: for example, formation of TxA2 , prostaglandin (PG) F2α , 11-hydroxyeicosatraenoic acid (HETE), and 15-HETE was absent in both platelet- and global-COX-1-ko mice. Conversely, in vivo, platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-ko or aspirin-treated control mice, notably significantly higher levels of PGI2 metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA2 and PGE2 . Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI2 and PGD2 at non-platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular system and linked them to anti- and pro-thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen antithrombotic protection.

Implementation and evaluation of a curriculum on the assessment and treatment of disruptive behaviour disorders.

Disruptive behaviour disorders (DBDs)-which can include or be comorbid with disorders such as attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder and disruptive mood dysregulation disorder-are commonly seen in paediatric practice. Given increases in the prescribing of atypical antipsychotics for children and youth, it is imperative that paediatric trainees in Canada receive adequate education on the optimal treatment of DBDs. We describe the development, dissemination, and evaluation of a novel paediatric resident curriculum for the assessment and treatment of DBDs in children and adolescents. Pre-post-evaluation of the curriculum showed improved knowledge in participants.

The Chinese (Mandarin) instructions of the 6-minute walk test: A validation study.

BACKGROUND/OBJECTIVE: To date, a validated Chinese (Mandarin) six-minute walk test (6MWT) translated instruction is not available. Translation of the Chinese 6MWT instruction is done in an ad hoc manner within the Chinese-speaking populations. This study aimed to develop a set of valid and reliable Chinese (Mandarin) instructions of the 6MWT. METHODS: Translation was performed from the original English instruction via the recommended "Process of translation and adaptation of instruments" by the World Health Organization to generate the Chinese instructions. The Chinese instructions were tested with 52 healthy adult participants for its validity. Each participant underwent three 6MWTs and a cardiopulmonary exercise test. Randomization allowed participants to undergo the walk test in both the original English and the new Chinese instructions. Face and content validity, intra-rater and inter-rater reliability of the Chinese instructions of the 6MWT were established through the translation process. Criterion validity was established by analyzing the results of the 6MWT and cardiopulmonary exercise test. RESULTS: Intraclass correlation coefficient for inter-rater reliability was excellent ( ICC = 0 . 999 , 95% confidence interval = 0 . 996 -1.000). Similarly, the intra-rater reliability across the three raters was high (R1: ICC = 0 . 996 , 95% confidence interval ( CI )= 0 . 812 -1.000; R2: ICC = 1 . 000 , 95% CI = 0 . 994 -1.000; R3: ICC = 1 . 000 , 95% CI = 0 . 998 -1.000). The 6-min walk distances collected from the Chinese and English instructed trials correlated positively with the maximal oxygen consumption ( r = 0 . 315 , p = 0 . 023 ; r = 0 . 309 , p = 0 . 026 ). CONCLUSION: This is the first study to develop and validate the Chinese (Mandarin) instructions of the 6MWT, and the translation is as reliable and valid as the original English instructions.

2019 American Heart Association Focused Update on Pediatric Basic Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

This 2019 focused update to the American Heart Association pediatric basic life support guidelines follows the 2019 systematic review of the effects of dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) on survival of infants and children with out-of-hospital cardiac arrest. This systematic review and the primary studies identified were analyzed by the Pediatric Task Force of the International Liaison Committee on Resuscitation. It aligns with the International Liaison Committee on Resuscitation's continuous evidence review process, with updates published when the International Liaison Committee on Resuscitation completes a literature review based on new published evidence. This update summarizes the available pediatric evidence supporting DA-CPR and provides treatment recommendations for DA-CPR for pediatric out-of-hospital cardiac arrest. Four new pediatric studies were reviewed. A systematic review of this data identified the association of a significant improvement in the rates of bystander CPR and in survival 1 month after cardiac arrest with DA-CPR. The writing group recommends that emergency medical dispatch centers offer DA-CPR for presumed pediatric cardiac arrest, especially when no bystander CPR is in progress. No recommendation could be made for or against DA-CPR instructions when bystander CPR is already in progress.

2019 American Heart Association Focused Update on Pediatric Advanced Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

This 2019 focused update to the American Heart Association pediatric advanced life support guidelines follows the 2018 and 2019 systematic reviews performed by the Pediatric Life Support Task Force of the International Liaison Committee on Resuscitation. It aligns with the continuous evidence review process of the International Liaison Committee on Resuscitation, with updates published when the International Liaison Committee on Resuscitation completes a literature review based on new published evidence. This update provides the evidence review and treatment recommendations for advanced airway management in pediatric cardiac arrest, extracorporeal cardiopulmonary resuscitation in pediatric cardiac arrest, and pediatric targeted temperature management during post-cardiac arrest care. The writing group analyzed the systematic reviews and the original research published for each of these topics. For airway management, the writing group concluded that it is reasonable to continue bag-mask ventilation (versus attempting an advanced airway such as endotracheal intubation) in patients with out-of-hospital cardiac arrest. When extracorporeal membrane oxygenation protocols and teams are readily available, extracorporeal cardiopulmonary resuscitation should be considered for patients with cardiac diagnoses and in-hospital cardiac arrest. Finally, it is reasonable to use targeted temperature management of 32°C to 34°C followed by 36°C to 37.5°C, or to use targeted temperature management of 36°C to 37.5°C, for pediatric patients who remain comatose after resuscitation from out-of-hospital cardiac arrest or in-hospital cardiac arrest.

Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of Urinary PGI-M and TX-M.

RATIONALE: The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A2, which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A2 are formed after the concerted actions of cPLA2α (cytosolic phospholipase A2) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF1α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A2 formation within the circulation and used to explain COX biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. OBJECTIVE: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA2α, causing almost complete loss of prostacyclin and thromboxane A2, who was transplanted with a normal kidney resulting in an experimental scenario of whole-body cPLA2α knockout, kidney-specific knockin. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A2 in the circulation. METHODS AND RESULTS: Metabolites were measured using liquid chromatography-tandem mass spectrometry. Endothelial cells were grown from blood progenitors. Before kidney transplantation, the patient's endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-keto-prostaglandin F1α) and thromboxane A2 (measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. After transplantation and the establishment of normal renal function, the levels of PGI-M and TX-M in the patient's urine rose to within normal ranges, whereas endothelial production of prostacyclin and platelet production of thromboxane A2 remained negligible. CONCLUSIONS: These data show that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromboxane A2 by platelets in the general circulation. Previous work relying on urinary metabolites of prostacyclin and thromboxane A2 as markers of whole-body endothelial and platelet function now requires reevaluation.

Review of the pharmacokinetics and metabolism of triclopyr herbicide in mammals: Impact on safety assessments.

A review of pharmacokinetic and metabolism studies show that triclopyr is well absorbed from the oral route in numerous species (≥80%), primarily as parent compound. Absorption is quite rapid in rats, dogs and human volunteers. Plasma or blood clearance is also rapid (t1/2 3-9 h), except for dog (12-96 h). Systemic exposure is not dose-proportional: in the rat above 20 mg/kg (dietary) or between 3 and 60 mg/kg (gavage), or in dogs above 5 mg/kg, with systemic exposure in human more comparable to rat than dog. Triclopyr is highly bound to protein in rat, dog and human plasma (≥97% at or below 7 µg/mL), indicating that species differences in systemic exposure are not due to differences in the free fraction of this test material in plasma. An in vitro flux study in renal proximal tubule cells showed that net renal transport of triclopyr is in the direction of secretion in rat and human donors, while reabsorption predominated in the dog, possibly via organic anion transporters such as OAT1/3. These results fit well into the framework of utilizing metabolism and toxicokinetics across species and exposure levels to allow for toxicity testing in the most relevant species as well as at proper dose levels.

PBPK model reporting template for chemical risk assessment applications.

Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental chemicals. This harmonized reporting template can be adopted and customized by public health agencies receiving PBPK model submission, and it can also serve as general guidance for submitting PBPK-related studies for publication in journals or other modeling sharing purposes. The current effort represents one of several ongoing collaborations among the PBPK modeling and risk assessment communities to promote, when appropriate, incorporating PBPK modeling to characterize the influence of pharmacokinetics on safety decisions made by regulatory agencies.

2018 American Heart Association Focused Update on Pediatric Advanced Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

This 2018 American Heart Association focused update on pediatric advanced life support guidelines for cardiopulmonary resuscitation and emergency cardiovascular care follows the 2018 evidence review performed by the Pediatric Task Force of the International Liaison Committee on Resuscitation. It aligns with the International Liaison Committee on Resuscitation's continuous evidence review process, and updates are published when the group completes a literature review based on new published evidence. This update provides the evidence review and treatment recommendation for antiarrhythmic drug therapy in pediatric shock-refractory ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest. As was the case in the pediatric advanced life support section of the "2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care," only 1 pediatric study was identified. This study reported a statistically significant improvement in return of spontaneous circulation when lidocaine administration was compared with amiodarone for pediatric ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest. However, no difference in survival to hospital discharge was observed among patients who received amiodarone, lidocaine, or no antiarrhythmic medication. The writing group reaffirmed the 2015 pediatric advanced life support guideline recommendation that either lidocaine or amiodarone may be used to treat pediatric patients with shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways.

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.

Exploring paediatric residents' perceptions of competency in neonatal intensive care.

Assessment and stabilization of the newborn are expected competencies of trainees graduating from Canadian paediatrics residency training programs. There is limited evidence regarding the optimal approach to training, and whether such competencies are actually achieved by graduates. A national, cross-sectional survey was developed to explore paediatrics residents' self-reported experiences in performing neonatal procedures and resuscitation skills. Survey questions were constructed based on the review of the Royal College of Physicians and Surgeons of Canada objectives of training in paediatrics to include activities necessary in the assessment and stabilization of the newborn. The survey was distributed to residents across Canada. A total of 138 residents from 15 Canadian paediatrics residency training programs completed the survey. A minority of residents (17%) reported independently performing resuscitative skills (positive pressure ventilation, intubation and umbilical line insertion). Of all the different neonatal procedural skills, only lumbar puncture was reported as an activity that residents on average performed independently by senior years of training. Our study showed a direct relationship between the number of completed blocks of Neonatal Intensive Care Unit (NICU) and self-reported experiences in providing NICU resuscitation skills and procedures. We found an inverse relationship between the exposure to cross-cover calls and such experiences. Our study showed that a minority of paediatrics residents self-report evidence of competency in performing neonatal procedures and resuscitation skills. As residency programs are transitioning toward competence-based education, it is important to gain more insights with respect to strengths, deficiencies and opportunities for paediatrics residency training in terms of NICU experiences.

Association of MicroRNAs and YRNAs With Platelet Function.

RATIONALE: Platelets shed microRNAs (miRNAs). Plasma miRNAs change on platelet inhibition. It is unclear whether plasma miRNA levels correlate with platelet function. OBJECTIVE: To link small RNAs to platelet reactivity. METHODS AND RESULTS: Next-generation sequencing of small RNAs in plasma revealed 2 peaks at 22 to 23 and 32 to 33 nucleotides corresponding to miRNAs and YRNAs, respectively. Among YRNAs, predominantly, fragments of RNY4 and RNY5 were detected. Plasma miRNAs and YRNAs were measured in 125 patients with a history of acute coronary syndrome who had undergone detailed assessment of platelet function 30 days after the acute event. Using quantitative real-time polymerase chain reactions, 92 miRNAs were assessed in patients with acute coronary syndrome on different antiplatelet therapies. Key platelet-related miRNAs and YRNAs were correlated with platelet function tests. MiR-223 (rp=0.28; n=121; P=0.002), miR-126 (rp=0.22; n=121; P=0.016), and other abundant platelet miRNAs and YRNAs showed significant positive correlations with the vasodilator-stimulated phosphoprotein phosphorylation assay. YRNAs, miR-126, and miR-223 were also among the small RNAs showing the greatest dependency on platelets and strongly correlated with plasma levels of P-selectin, platelet factor 4, and platelet basic protein in the population-based Bruneck study (n=669). A single-nucleotide polymorphism that facilitates processing of pri-miR-126 to mature miR-126 accounted for a rise in circulating platelet activation markers. Inhibition of miR-126 in mice reduced platelet aggregation. MiR-126 directly and indirectly affects ADAM9 and P2Y12 receptor expression. CONCLUSIONS: Levels of platelet-related plasma miRNAs and YRNAs correlate with platelet function tests in patients with acute coronary syndrome and platelet activation markers in the general population. Alterations in miR-126 affect platelet reactivity.