Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy.

BACKGROUND: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols. OBJECTIVES AND METHODS: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated. RESULTS: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment. CONCLUSIONS: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

Long-term neurological and neurodevelopmental outcome of neonatal listeriosis in France: a prospective, matched, observational cohort study.

BACKGROUND: Maternal-neonatal listeriosis is a rare and serious infection. The long-term outcome of surviving infants with early-onset or late-onset listeriosis remains unknown. We aimed to determine the long-term neurological and neurodevelopmental outcome of neonatal listeriosis. METHODS: In this prospective, matched, observational cohort study, we evaluated children born with microbiologically confirmed maternal-neonatal listeriosis in the French MONALISA cohort. At age 5 years, children underwent neurological and neurodevelopmental assessments of sensory deficits, executive function, adaptive behaviour, and cognitive and motor coordination function. The cognitive domain was assessed using the French version of the Wechsler Preschool and Primary Scale of Intelligence, fourth edition, and scored by Full Scale Intelligence Quotient (FSIQ). The motor domain was assessed by physical examination designed to screen for cerebral palsy and developmental coordination disorder. Executive functioning was assessed using the statue and inhibition subtests of Neuropsychological Assessment, second version. The sensory domain was assessed by parental interview, medical report, and clinical assessment. Adaptive behaviour was measured using the Vineland-II behaviour scale from parent-reported assessments of functional communication, socialisation, daily living, and motor skills. Results were compared with gestational age-matched children from two national prospective cohorts: EPIPAGE-2 (preterm infants) and ELFE (term infants from a general population of infants >32 weeks gestation). This study is registered with ClinicalTrials.gov (NCT02580812). FINDINGS: Of 59 children who were alive and eligible to participate in the study, 53 (median age 5 years, IQR 5-6) were enrolled for neurodevelopmental assessments between Oct 26, 2016, and Oct 29, 2019. Of 53 children, 31 (58%) had been born preterm, 22 (42%) had early-onset systemic infection, 18 (34%) had early-onset non-systemic infection, and six (11%) had late-onset systemic infection, all with meningitis. 29 (66%) of 44 children, in whom neurodevelopmental disabilities scores were available, developed at least one disability; eight (18%) children had severe neurodevelopmental disabilities. Of four children with late-onset infection and in whom neurodevelopmental disabilities scores were available, three developed at least one neurodevelopmental disability. Neurological and neurodevelopmental outcomes of children with neonatal listeriosis did not differ from those of gestational age-matched control children without infection (relative risk [RR] of at least one disability 0·99 [95% CI 0·65-1·51; p=0·97]; RR of FSIQ less than -1 SD 0·92 [0·54-1·54; p=0·74]). INTERPRETATION: These results highlight the burden of persistent disability and dominant contribution of prematurity to long-term outcomes in children born with neonatal listeriosis. The findings support the implementation of systematic long-term screening and provision of tailored education and special needs support. FUNDING: Institut Pasteur, Inserm, French Public Health Agency, Contrat de Recherche Clinique, and Assistance Publique-Hôpitaux de Paris.

Sickle Cell Disease: From Genetics to Curative Approaches.

Sickle cell disease (SCD) is a monogenic blood disease caused by a point mutation in the gene coding for ß-globin. The abnormal hemoglobin [sickle hemoglobin (HbS)] polymerizes under low-oxygen conditions and causes red blood cells to sickle. The clinical presentation varies from very severe (with acute pain, chronic pain, and early mortality) to normal (few complications and a normal life span). The variability of SCD might be due (in part) to various genetic modulators. First, we review the main genetic factors, polymorphisms, and modifier genes that influence the expression of globin or otherwise modulate the severity of SCD. Considering SCD as a complex, multifactorial disorder is important for the development of appropriate pharmacological and genetic treatments. Second, we review the characteristics, advantages, and disadvantages of the latest advances in gene therapy for SCD, from lentiviral-vector-based approaches to gene-editing strategies.

Pediatric Tumors and Developmental Anomalies: A French Nationwide Cohort Study.

OBJECTIVE: To assess the associations between congenital abnormalities and pediatric malignancies and evaluate the potential underlying molecular basis by collecting information on pediatric patients with cancer and congenital abnormalities. STUDY DESIGN: Tumeur Et Développement is a national, prospective, and retrospective multicenter study recording data of children with cancer and congenital abnormalities. When feasible, blood and tumoral samples are collected for virtual biobanking. RESULTS: From June 2013 to December 2019, 679 associations between pediatric cancers and congenital abnormalities were recorded. The most represented cancers were central nervous system tumors (n = 139; 20%), leukemia and myelodysplastic syndromes (n = 123; 18.1%), and renal tumors (n = 101; 15%). Congenital abnormalities were not related to any known genetic disorder in 66.5% of cases. In this group, the most common anomaly was intellectual disability (22.3%), followed by musculoskeletal (14.2%) and genitourinary anomalies (12.4%). Intellectual disability was mostly associated with hematologic malignancies. Embryonic tumors (neuroblastoma, Wilms tumor, and rhabdomyosarcoma) were associated with consistent abnormalities, sometimes with a close anatomical neighborhood between the abnormality and the neoplasm. CONCLUSIONS: In the first Tumeur Et Développement analysis, 3 major themes have been identified: (1) germline mutations with or without known cancer predisposition, (2) postzygotic events responsible for genomic mosaicism, (3) coincidental associations. New pathways involved in cancer development need to be investigated to improve our understanding of childhood cancers.

Analysis of the impact of the SARS-CoV-2 infection on the pediatric population hospitalized during the pandemic in the Greater Paris University Hospitals.

Background: The clinical characteristics, disease progression and outcome in children affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appear significantly milder compared to older individuals. Nevertheless, the trends in hospitalization and clinical characteristics in the pediatric population seem to be different over time across the different epidemic waves. Objective: Our aim was to understand the impact of the different COVID-19 variants in the pediatric population hospitalized in the Pediatric Departments of the Public Hospital in the Greater Paris area by the analysis performed with the Assistance Publique-Hopitaux de Paris (AP-HP) Health Data Warehouse. Methods: This is a retrospective cohort study including 9,163 patients under 18 years of age, hospitalized from 1 March 2020 to 22 March 2022, in the Paris area, with confirmed infection by SARS-CoV-2. Three mutually exclusive groups with decreasing severity (Pediatric Inflammatory Multisystem Syndrome (PIMS), symptomatic infection, mild or asymptomatic infection) were defined and described regarding demography, medical history, complication of the SARS-CoV-2 infection, and treatment during admission. Temporal evolution was described by defining three successive waves (March-September 2020, October 2020-October 2021, and November 2021-March 2022) corresponding to the emergence of the successive variants. Results: In the study period, 9,163 pediatric patients with SARS-CoV-2 infection were hospitalized in 21 AP-HP hospitals. The number of patients with SARS-CoV-2 infection increased over time for each wave of the pandemic (the mean number of patients per month during the first wave was 332, 322 during the 2nd, and 595 during the third wave). In the medical history, the most associated concomitant disease was chronic respiratory disease. Patients hospitalized during the third wave presented a higher incidence of pulmonary involvement (10.2% compared to 7% and 6.5% during the first and second waves, respectively). The highest incidence of PIMS was observed during the first and second waves (4.2% in the first and second waves compared to 2.3% in the 3rd wave). Discussion: This analysis highlighted the high incidence of hospitalized children in the Greater Paris Area during the third wave of SARS-CoV-2 pandemic corresponding to the Omicron Covid-19 variant, which is probably an expression of a concomitant SARS-CoV-2, while a decreased incidence of PIMS complication was observed during the same period.

Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients.

BACKGROUND: Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments for severe combined immunodeficiency (SCID). Late-onset posttreatment manifestations (such as persistent hepatitis) are not uncommon. OBJECTIVE: We sought to characterize the prevalence and pathophysiology of persistent hepatitis in transplanted SCID patients (SCIDH+) and to evaluate risk factors and treatments. METHODS: We used various techniques (including pathology assessments, metagenomics, single-cell transcriptomics, and cytometry by time of flight) to perform an in-depth study of different tissues from patients in the SCIDH+ group and corresponding asymptomatic similarly transplanted SCID patients without hepatitis (SCIDH-). RESULTS: Eleven patients developed persistent hepatitis (median of 6 years after HSCT or GT). This condition was associated with the chronic detection of enteric viruses (human Aichi virus, norovirus, and sapovirus) in liver and/or stools, which were not found in stools from the SCIDH- group (n = 12). Multiomics analysis identified an expansion of effector memory CD8+ T cells with high type I and II interferon signatures. Hepatitis was associated with absence of myeloablation during conditioning, split chimerism, and defective B-cell function, representing 25% of the 44 patients with SCID having these characteristics. Partially myeloablative retransplantation or GT of patients with this condition (which we have named as "enteric virus infection associated with hepatitis") led to the reconstitution of T- and B-cell immunity and remission of hepatitis in 5 patients, concomitantly with viral clearance. CONCLUSIONS: Enteric virus infection associated with hepatitis is related to chronic enteric viral infection and immune dysregulation and is an important risk for transplanted SCID patients with defective B-cell function.

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy.

X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPß expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD.

Saliva for molecular detection of SARS-CoV-2 in pre-school and school-age children.

SARS-CoV-2 diagnosis is a cornerstone for the management of coronavirus disease 2019 (COVID-19). Numerous studies have assessed saliva performance over nasopharyngeal sampling (NPS), but data in young children are still rare. We explored saliva performance for SARS-CoV-2 detection by RT-PCR according to the time interval from initial symptoms or patient serological status. We collected 509 NPS and saliva paired samples at initial diagnosis from 166 children under 12 years of age (including 57 children under 6), 106 between 12 and 17, and 237 adults. In children under 12, overall detection rate for SARS-CoV-2 was comparable in saliva and NPS, with an overall agreement of 89.8%. Saliva sensitivity was significantly lower than that of NPS (77.1% compared to 95.8%) in pre-school and school-age children but regained 96% when considering seronegative children only. This pattern was also observed to a lesser degree in adolescents but not in adults. Sensitivity of saliva was independent of symptoms, in contrary to NPS, whose sensitivity decreased significantly in asymptomatic subjects. Performance of saliva is excellent in children under 12 at early stages of infection. This reinforces saliva as a collection method for early and unbiased SARS-CoV-2 detection and a less invasive alternative for young children.

Long-term outcomes of lentiviral gene therapy for the ß-hemoglobinopathies: the HGB-205 trial.

Sickle cell disease (SCD) and transfusion-dependent ß-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34+ cells transduced ex vivo with lentiviral vector BB305 that encodes the anti-sickling ßA-T87Q-globin expressed in the erythroid lineage. HGB-205 is a phase 1/2, open-label, single-arm, non-randomized interventional study of 2-year duration at a single center, followed by observation in long-term follow-up studies LTF-303 ( NCT02633943 ) and LTF-307 ( NCT04628585 ) for TDT and SCD, respectively. Inclusion and exclusion criteria were similar to those for allogeneic transplantation but restricted to patients lacking geno-identical, histocompatible donors. Four patients with TDT and three patients with SCD, ages 13-21 years, were treated after busulfan myeloablation 4.6-7.9 years ago, with a median follow-up of 4.5 years. Key primary endpoints included mortality, engraftment, replication-competent lentivirus and clonal dominance. No adverse events related to the drug product were observed. Clinical remission and remediation of biological hallmarks of the disease have been sustained in two of the three patients with SCD, and frequency of transfusions was reduced in the third. The patients with TDT are all transfusion free with improvement of dyserythropoiesis and iron overload.

Pharmacokinetics of tranexamic acid after intravenous, intramuscular, and oral routes: a prospective, randomised, crossover trial in healthy volunteers.

BACKGROUND: In response to the World Health Organization call for research on alternative routes for tranexamic acid (TXA) administration in women with postpartum haemorrhage, we examined the pharmacokinetics of TXA after i.v., i.m., or oral administration. METHODS: We conducted a randomised, open-label, crossover trial in 15 healthy volunteers who received i.v. TXA 1 g, i.m. TXA 1 g, or oral TXA solution 2 g. Blood samples were drawn up to 24 h after administration. Tranexamic acid concentration was measured with liquid chromatography-mass spectrometry, and the parameters of the pharmacokinetic models were estimated using population pharmacokinetics. RESULTS: The median time to reach a concentration of 10 mg L-1 was 3.5 min for the i.m. route and 66 min for the oral route, although with the oral route the target concentration was reached in only 11 patients. Median peak concentrations were 57.5, 34.4, and 12.8 mg L-1 for i.v., i.m., and oral routes, respectively. A two-compartment open model with body weight as the main covariate best fitted the data. For a 70 kg volunteer, the population estimates were 10.1 L h-1 for elimination clearance, 15.6 L h-1 for intercompartmental clearance, 7.7 L for the volume of central compartment, and 10.8 L for the volume of the peripheral compartment. Intramuscular and oral bioavailabilities were 1.0 and 0.47, respectively, showing that i.m. absorption is fast and complete. Adverse events were mild and transient, mainly local reactions and low-intensity pain. CONCLUSIONS: The i.m. (but not oral) route appears to be an efficient alternative to i.v. tranexamic acid. Studies in pregnant women are needed to examine the impact of pregnancy on the pharmacokinetics. CLINICAL TRIAL REGISTRATION: EudraCT 2019-000285-38; NCT03777488.

Clinical Validation of a Volumetric Absorptive Micro-Sampling Device for Pharmacokinetic Studies With Tranexamic Acid.

We assessed the accuracy of tranexamic acid (TXA) concentrations measured in capillary whole blood using volumetric absorptive micro-sampling (VAMS) devices. Paired venous and VAMS capillary blood samples were collected from 15 healthy volunteers participating in a pharmacokinetic study of alternative routes (oral, IM and IV) of administering TXA. To assess accuracy across a range of concentrations, blood was drawn at different times after TXA administration. We measured TXA concentrations in plasma, whole blood from samples collected by venepuncture and whole blood from venous and capillary samples collected using VAMS devices. TXA was measured using a validated high sensitivity liquid chromatography - mass spectrometry method. We used Bland-Altman plots to describe the agreement between the TXA concentrations obtained with the different methods. In the 42 matched samples, the mean plasma TXA concentration was 14.0 mg/L (range 2.6-36.5 mg/L) whereas the corresponding whole blood TXA concentration was 7.7 mg/L (range 1.6-17.5 mg/L). When comparing TXA concentrations in VAMS samples of venous and capillary whole blood, the average bias was 0.07 mg/L (lower and upper 95% limits of agreement: -2.1 and 2.2 mg/L respectively). When comparing TXA concentrations in venous whole blood and VAMS capillary whole blood, the average bias was 0.7 mg/L (limits of agreement: -2.7 and 4.0 mg/L). Volumetric absorptive micro-sampling devices are sufficiently accurate for use in pharmacokinetic studies of tranexamic acid treatment in the range of plasma concentrations relevant for the assessment of fibrinolysis inhibition.

Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.

BACKGROUND: Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. CASE REPORT: A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. CONCLUSION: Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.

Modulators of CFTR. Updates on clinical development and future directions.

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.

Autophagy-mediated metabolic effects of aspirin.

Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b-/- or Bcln1+/-) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.

Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies.

Mutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15-25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 n = 3; APDS2 n = 4) received seletalisib; five completed the phase 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b study, patients had improved peripheral lymphadenopathy (n = 2), lung function (n = 1), thrombocyte counts (n = 1), and chronic enteropathy (n = 1). Overall, effects were maintained in the extension. In the phase 1b study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase 1b study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase 1b study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk-benefit profile was maintained for ≤96 wk.

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease.

Background: The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Methods: Urine samples were collected from 19 CF patients (among those 7 were treated by cystic fibrosis transmembrane conductance regulator (CFTR) modulators), and 8 healthy subjects. Urine exosomal protein content was determined by high resolution mass spectrometry. Results: A heatmap of the differentially expressed proteins in urinary exosomes showed a clear separation between control and CF patients. Seventeen proteins were upregulated in CF patients (including epidermal growth factor receptor (EGFR); proteasome subunit beta type-6, transglutaminases, caspase 14) and 118 were downregulated (including glutathione S-transferases, superoxide dismutase, klotho, endosomal sorting complex required for transport, and matrisome proteins). Gene set enrichment analysis revealed 20 gene sets upregulated and 74 downregulated. Treatment with CFTR modulators yielded no significant modification of the proteomic content. These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Increased expression of EGFR and decreased expression of klotho and matrisome might play a central role in this CF kidney signature by inducing oxidation, inflammation, accelerated senescence, and abnormal tissue repair. Conclusions: Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications.

Cell-Cycle Arrest Biomarkers: Usefulness for Cardiac Surgery-Related Acute Kidney Injury in Neonates and Infants.

OBJECTIVES: Cell cycle arrest urine biomarkers have recently been shown to be early indicators of acute kidney injury in various clinical settings in critically ill adults and children. The product of tissue inhibitor metalloproteinase -1 and insulin-like growth factor binding protein-7 concentrations/1,000 (TIMP-1) × (IGFBP-7) provides stratification of acute kidney injury-risk in adults with critical illness. The present study explores the predictive accuracy of (TIMP-1) × (IGFBP-7) measured early after cardiopulmonary bypass for cardiac surgery-related acute kidney injury in neonates and infants, a population in whom such data are not yet available. DESIGN: Prospective, observational. SETTING: A tertiary referral pediatric cardiac ICU. PATIENTS: Fifty-seven neonates and 110 infants undergoing surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: (TIMP-1) × (IGFBP-7) was measured on the NephroCheck (Astute Medical, San Diego, CA) platform preoperatively, less than 1 hour of cardiopulmonary bypass and 1-3 hours of cardiopulmonary bypass. The incidence of postoperative acute kidney injury, dialysis, and/or death were compared among quintiles of postoperative (TIMP-1) × (IGFBP-7). Multivariable regression was used to assess the added predictive value for renal events of (TIMP-1) × (IGFBP-7) over clinical models. Basal (TIMP-1) × (IGFBP-7) increased with age at surgery (regression coefficient = 0.004 ± 0.001; p = 0.005). (TIMP-1) × (IGFBP-7) increased after cardiopulmonary bypass. Neonates had lower postoperative (TIMP-1) × (IGFBP-7) compared with older infants, despite undergoing longer surgeries and experiencing a higher incidence of postoperative renal events. (TIMP-1) × (IGFBP-7) was not associated with acute kidney injury, dialysis, and/or death and was not a predictor of the aforementioned events when added to a clinical acute kidney injury model including age, duration of cardiopulmonary bypass, and mechanical ventilation prior to surgery. CONCLUSIONS: These findings question the usefulness of (TIMP-1) × (IGFBP-7) for the prediction of cardiac surgery-related acute kidney injury in neonates and infants when measured within 3 hours of cardiopulmonary bypass.

Tranexamic acid through intravenous, intramuscular and oral routes: an individual participant data meta-analysis of pharmacokinetic studies in healthy volunteers.

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta-analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J-STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two-compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well-designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.

Sotatercept, a novel transforming growth factor ß ligand trap, improves anemia in ß-thalassemia: a phase II, open-label, dose-finding study.

ß-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin ß globin chains, leads to ineffective erythropoiesis and chronic anemia that may require blood transfusions. Sotatercept (ACE-011) acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor ß superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent ß -thalassemia and 30 patients with non-transfusion-dependent ß-thalassemia were enrolled at seven centers in four countries between November 2012 and November 2014. Patients were treated with sotatercept at doses of 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg to determine a safe and effective dose. Doses were administered by subcutaneous injection every 3 weeks. Patients were treated for ≤22 months. Response was assessed as a ≥20% reduction in transfusion burden sustained for 24 weeks in transfusion-dependent ß-thalassemia patients, and an increase in hemoglobin level of ≥1.0 g/dL sustained for 12 weeks in non-transfusion-dependent ß-thalassemia patients. Sotatercept was well tolerated. After a median treatment duration of 14.4 months (range 0.6-35.9), no severe life-threatening adverse events were observed. Thirteen percent of patients reported serious but manageable adverse events. The active dose of sotatercept was ≥0.3 mg/kg for patients with non-transfusion-dependent ß-thalassemia and ≥0.5 mg/kg for those with transfusion-dependent ß-thalassemia. Of 30 non-transfusion-dependent ß-thalassemia patients treated with ≥0.1 mg/kg sotatercept, 18 (60%) achieved a mean hemoglobin increase ≥1.0 g/dL, and 11 (37%) an increase ≥1.5 g/dL, sustained for ≥12 weeks. Four (100%) transfusion-dependent ß-thalassemia patients treated with 1.0 mg/kg sotatercept achieved a transfusion-burden reduction of ≥20%. Sotatercept was effective and well tolerated in patients with ß-thalassemia. Most patients with non-transfusion-dependent ß-thalassemia treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent ß-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirements. This trial was registered at ClinicalTrials.gov with the number NCT01571635.

Microscopically positive resection margin after hepatoblastoma resection: what is the impact on prognosis? A Childhood Liver Tumours Strategy Group (SIOPEL) report.

BACKGROUND: To evaluate the impact of a microscopically positive resection margin (microPRM) on the outcome of hepatoblastoma patients pretreated with chemotherapy. METHODS: Local recurrence and survival rates of 431 children treated in the SIOPEL 2 and 3 trials were analysed comparing 58 patients with microPRM with 371 who had a complete resection (CR) and who were then stratified by risk category. The tumour was standard-risk in 312 patients and high-risk (PRETEXT IV and/or extrahepatic disease and/or α-fetoprotein [AFP]<100 ng/ml) in 117 patients. All received cisplatinum-based neoadjuvant and postoperative chemotherapy as per protocol. Apart from one microPRM patient who went on to transplant, none received any additional local treatment. RESULTS: With a median follow-up of 67 months, local relapse occurred in 3/58 patients with microPRM (5%) and in 23/371 (6%) patients with CR. The 5-year overall survival (OS) was 91% (95% confidence interval [CI] 80%-96%) for the microPRM and 92% (95% CI 89%-95%) for the CR group. The 5-year event-free survival (EFS) was 86% (95% CI 74%-93%) for the microPRM and 86% (95% CI 82%-89%) for the CR group. Neither OS nor EFS was statistically significantly different between the two groups, neither overall nor when risk group stratified. CONCLUSIONS: In the context of cisplatin-based chemotherapy, the presence of microPRM did not influence the outcome even without additional local treatment. Although CR remains the aim, microPRM does not necessitate mandatory second look surgery. A 'wait and see policy' is warranted if postoperative chemotherapy is administered and AFP levels and imaging become normal.