Diagnostic Validation of the Updated Pediatric Sepsis Biomarker Risk II for Acute Kidney Injury Prediction Model in Pediatric Septic Shock.

Objectives: We previously derived the updated Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (PERSEVERE-II AKI) prediction model, which had robust diagnostic test characteristics for severe AKI on day 3 (D3 severe AKI) of septic shock. We now sought to validate this model in an independent cohort of children to the one in which the model was developed.

Design: A secondary analysis of a multicenter, prospective, observational study carried out from January 2019 to December 2022.

Variations in Alarm Burden, Source, and Cause Across Inpatient Units at a Children's Hospital.

Background And Objectives: Alarms at hospitals are frequent and can lead to alarm fatigue posing patient safety risks. We aimed to describe alarm burden over a 1-year period and explored variations in alarm rates stratified by unit type, alarm source, and cause.

Methods: A retrospective study of inpatient alarm and patient census data at 1 children's hospital from January 1, 2019, to December 31, 2019, including 8 inpatient units: 6 medical/surgical unit (MSU), 1 PICU, and 1 NICU.

Prognostic and predictive value of endothelial dysfunction biomarkers in sepsis-associated acute kidney injury: risk-stratified analysis from a prospective observational cohort of pediatric septic shock.

Background: Sepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI.

Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.

Background: Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults.

Serum renin and prorenin concentrations predict severe persistent acute kidney injury and mortality in pediatric septic shock.

Background: Studies in critically ill adults demonstrate associations between serum renin concentrations (a proposed surrogate for renin-angiotensin-aldosterone system dysregulation) and poor outcomes, but data in critically ill children are lacking. We assessed serum renin + prorenin concentrations in children with septic shock to determine their predictive ability for acute kidney injury (AKI) and mortality.

Methods: We conducted a secondary analysis of a multicenter observational study of children aged 1 week to 18 years admitted to 14 pediatric intensive care units (PICUs) with septic shock and residual serum available for renin + prorenin measurement.

Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.

Sepsis is associated with significant mortality, yet there are no efficacious therapies beyond antibiotics and supportive care. In adult sepsis studies, PCSK9 loss-of-function (LOF) and inhibition has shown therapeutic promise, likely through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance. In contrast, we previously demonstrated higher mortality in septic juvenile hosts with LOF.

Biocrust Amendments to Topsoils Facilitate Biocrust Restoration in a Post-mining Arid Environment.

Soil cryptogamic biocrusts provide many ecological functions in arid zone ecosystems, though their natural reestablishment in disturbed areas is slow. Accelerating reestablishment of biocrusts may facilitate the establishment of vascular plant communities within the timeframes of restoration targets (typically 5-15 years). One technique is to inoculate the soil surface using slurries of biocrust material harvested from another site.

Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospective observational study.

Background: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock.

Addressing unmet needs in rare bleeding disorders: selected poster extracts of recent research in hemophilia A and von Willebrand disease presented at the 14th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) (Feb 3-5, 2021; virtual congress).

Hemophilia A and von Willebrand disease (VWD) are inherited rare bleeding disorders affecting normal hemostasis. Patients with VWD, especially those with severe disease types, share some similarities to patients with hemophilia A in their burden of disease: they suffer from an increased risk of potentially severe and life-threatening bleeds and associated long-term consequences, such as impaired joint health and overall lower quality of life. However, the two bleeding disorders differ in their primary cause and affected patient population, and comprise a range of different bleeding phenotypes with varying unmet needs.

Recalibration of the Renal Angina Index for Pediatric Septic Shock.

Introduction: Sepsis-associated acute kidney injury (AKI) is a common diagnosis in children that is associated with poor outcomes. The lack of therapeutic options once present makes early identification of at-risk patients essential. The renal angina index (RAI) has been previously validated to predict severe AKI in heterogeneous populations of critically ill children.

Cardiac critical care of the post-operative congenital heart disease patient.

Cardiac critical care has become an increasingly complex subspecialty, involving multiple subspecialists to support patients with congenital heart disease. This requires understanding of their physiology and the impact of medical interventions. The purpose of this article is to provide a concise review of the current strategies utilized by cardiac intensivists to optimize outcomes for this vulnerable patient population, with the goal of broadening the knowledge of other members of the multi-disciplinary team.

Proprotein Convertase Subtilisin/Kexin Type 9 Loss-of-Function Is Detrimental to the Juvenile Host With Septic Shock.

Objectives: Proprotein convertase subtilisin/kexin type 9 is a central regulator of lipid metabolism and has been implicated in regulating the host response to sepsis. Proprotein convertase subtilisin/kexin type 9 loss-of-function is associated with improved sepsis outcomes in the adult host through increased hepatic bacterial clearance. Thus, there is interest in leveraging proprotein convertase subtilisin/kexin type 9 inhibitors as a therapeutic strategy in adults with sepsis.

PERSEVERE Biomarkers Predict Severe Acute Kidney Injury and Renal Recovery in Pediatric Septic Shock.

Acute kidney injury (AKI), a common complication of sepsis, is associated with substantial morbidity and mortality and lacks definitive disease-modifying therapy. Early, reliable identification of at-risk patients is important for targeted implementation of renal protective measures. The updated Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) is a validated, multibiomarker prognostic enrichment strategy to estimate baseline mortality risk in pediatric septic shock.

SHP656, a polysialylated recombinant factor VIII (PSA-rFVIII): First-in-human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A.

Introduction: SHP656 is the first factor VIII (FVIII) product developed using polysialylation (PSA) technology, in which full-length recombinant (r) FVIII (anti-haemophilic factor [recombinant]) is conjugated with a 20 kDa PSA polymer.

Aim: To compare the safety, immunogenicity and pharmacokinetics of SHP656 vs the parent rFVIII (octocog alfa) after single infusions of 25-75 IU/kg in patients with severe haemophilia A (FVIII activity <1%).

Methods: Multinational, phase 1, prospective, open-label, two-period, fixed-sequence, dose-escalation trial (clinicaltrials.

Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model.

Sepsis remains a major public health problem with no major therapeutic advances over the last several decades. The clinical and biological heterogeneity of sepsis have limited success of potential new therapies. Accordingly, there is considerable interest in developing a precision medicine approach to inform more rational development, testing, and targeting of new therapies.

Hyperchloremia Is Associated With Complicated Course and Mortality in Pediatric Patients With Septic Shock.

Objective: Hyperchloremia is associated with poor outcome among critically ill adults, but it is unknown if a similar association exists among critically ill children. We determined if hyperchloremia is associated with poor outcomes in children with septic shock.

Design: Retrospective analysis of a pediatric septic shock database.

Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response.

Objective: We previously identified septic shock endotypes A and B based on 100 genes reflecting adaptive immunity and glucocorticoid receptor signaling. The endotypes differ with respect to outcome and corticosteroid responsiveness. We determined whether endotypes change during the initial 3 days of illness, and whether changes are associated with outcomes.

Structure and Properties of Some Layered UO Phases: A Density Functional Theory Study.

UO is the boundary composition between the fluorite and the layered structures of the UO system and the least studied oxide in the group. δ-UO is the only layered structure proposed so far experimentally, although evidence of fluorite-based phases has also been reported. Our DFT work explores possible structures of UO stoichiometry by starting from existing MO structures (where M is an actinide or transition metal) and replacing the M ions with uranium ions.

Improved Risk Stratification in Pediatric Septic Shock Using Both Protein and mRNA Biomarkers. PERSEVERE-XP.

Rationale: We previously derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate baseline mortality risk in children with septic shock. The PERSEVERE biomarkers are serum proteins selected from among the proteins directly related to 80 mortality risk assessment genes. The initial approach to selecting the PERSEVERE biomarkers left 68 genes unconsidered.

Multiple Organ Dysfunction in Children Mechanically Ventilated for Acute Respiratory Failure.

Objectives: The impact of extrapulmonary organ dysfunction, independent from sepsis and lung injury severity, on outcomes in pediatric acute respiratory failure is unclear. We sought to determine the frequency, timing, and risk factors for extrapulmonary organ dysfunction and the independent association of multiple organ dysfunction syndrome with outcomes in pediatric acute respiratory failure.

Design: Secondary observational analysis of the Randomized Evaluation of Sedation Titration for Respiratory Failure cluster-randomized prospective clinical trial conducted between 2009 and 2013.

Glucocorticoid Receptor Polymorphisms and Outcomes in Pediatric Septic Shock.

Objective: Polymorphisms of the glucocorticoid receptor gene are associated with outcome and corticosteroid responsiveness among patients with inflammatory disorders. We conducted a candidate gene association study to test the hypothesis that these polymorphisms are associated with outcome and corticosteroid responsiveness among children with septic shock.

Design: We genotyped 482 children with septic shock for the presence of two glucocorticoid receptor polymorphisms (rs56149945 and rs41423247) associated with increased sensitivity and one glucocorticoid receptor polymorphism (rs6198) associated with decreased sensitivity to corticosteroids.

Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B-LONG): results from a multicentre, non-randomised phase 3 study.

Background: Kids B-LONG was a multicentre, open-label, phase 3 study assessing the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) in previously treated paediatric patients younger than 12 years with severe haemophilia B.

Methods: The study enrolled 30 previously treated boys younger than 12 years with haemophilia B (≤2 IU/dL [≤2%] endogenous coagulation factor IX [FIX] activity). All patients were initially given rFIXFc prophylaxis (50-60 IU/kg) once per week with adjustments to dose (≤100 IU/kg per infusion) or dosing frequency (up to two times per week) as needed.

Long-term safety and efficacy of extended-interval prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) in subjects with haemophilia B.

The safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents ≥12 years) and Kids B-LONG (children <12 years) studies of subjects with haemophilia B (≤2 IU/dl). Here, we report interim, long-term safety and efficacy data from B-YOND, the rFIXFc extension study. Eligible subjects who completed B-LONG or Kids B-LONG could enrol in B-YOND.

Pediatric Sepsis Biomarker Risk Model-II: Redefining the Pediatric Sepsis Biomarker Risk Model With Septic Shock Phenotype.

Objective: The Pediatric Sepsis Biomarker Risk Model (PERSEVERE), a pediatric sepsis risk model, uses biomarkers to estimate baseline mortality risk for pediatric septic shock. It is unknown how PERSEVERE performs within distinct septic shock phenotypes. We tested PERSEVERE in children with septic shock and thrombocytopenia-associated multiple organ failure (TAMOF), and in those without new onset thrombocytopenia but with multiple organ failure (MOF).