Face validity of the Kids' ITP Tools (KIT) in the era of thrombopoietin receptor agonists.

The Kids' ITP Tools (KIT) is a questionnaire to assess quality of life of children with immune thrombocytopenia (ITP). The aim of this study was to update this previously validated tool to align with changes in clinical practice, specifically, treatment with thrombopoietin receptor agonists (TPO-RAs). Children aged 1-18 with ITP and/or their families were recruited to participate in interviews to review the KIT. Twenty-six interviews were conducted. Based on interview data from children and families, current guidelines, and expert opinion, five changes were made to the KIT in order to improve its face validity.

Evaluating the impact of thrombopoietin receptor agonist medications on patient outcomes and quality of life in paediatric immune thrombocytopenia through semi-structured interviews.

Over the last decade, treatment of immune thrombocytopenia (ITP) in children has advanced to include thrombopoietin receptor agonist (TPO-RA) medications. Concurrently, there has been an increased emphasis on patient-reported outcomes-especially quality of life-to guide treatment. Assessing the impact of TPO-RAs on quality of life in paediatric ITP is therefore a priority. In this single-centre integrative mixed-methods study, a cohort of children with ITP prescribed a TPO-RA was identified. These children and/or their caregivers were invited to participate in semi-structured interviews focussed on quality-of-life measures. Independently, a retrospective chart review collected ITP-related data (platelet count, bleeding events) and TPO-RA data (dosing, side effects). Among the 23 eligible patients, 20 were represented in interviews. On chart review, 11/20 patients responded to TPO-RA by meeting platelet count criteria of ≥50 × 109 /L for six or more weeks in the absence of rescue therapy. In interviews with these children and/or their parents, 19/20 expressed the TPO-RA had 'worked', with 11/20 reporting benefit to mood and 11/20 reporting increased participation in activities/sports. Concerns were raised in interviews about TPO-RA medication cost (17/20), medication administration (10/20) and potential side effects (10/20). In conclusion, this study suggests that TPO-RA use in children with ITP improves quality of life.

A cost-utility analysis of thrombopoietin receptor agonists for treating pediatric immune thrombocytopenia purpura after failure of first-line therapies.

BACKGROUND: Thrombopoietin receptor agonists (TPO-RAs) have emerged as a recommended treatment for children with persistent and/or chronic immune thrombocytopenic purpura (ITP). The purpose of this study was to evaluate the cost-effectiveness of TPO-RAs relative to treatment without TPO-RAs (non-TPO-RAs/usual care) for ITP in children who do not respond to first-line therapy and in whom splenectomy is not recommended in Ontario, Canada, from a hospital payer perspective. PROCEDURE: A 2-year Markov model with an embedded decision tree was used. Data on medications used, dose, response rate, bleeding, and emergency treatment events were collected from the Hospital for Sick Children in Toronto. The health outcomes were described in quality-adjusted life-years (QALYs). Health-state utilities were derived from the peer-reviewed literature. Scenario analyses, deterministic, and probabilistic sensitivity analyses were conducted. Economic costs were measured in 2021 Canadian dollars ($1.00 = US$0.80) RESULTS: TPO-RAs are estimated to result in an increased cost of $27,118 and a QALY gain of 0.21 compared to non-TPO-RAs over a 2-year horizon, resulting in an incremental cost-effectiveness ratio (ICER) of $129,133. In a 5-year scenario analysis, the ICER fell to $76,403. In the probabilistic sensitivity analysis, TPO-RAs exhibit a 40.0% probability of being cost-effective at a conventional ($100,000) willingness-to-pay threshold per QALY gained. CONCLUSIONS: Further assessment of the long-term efficacy of TPO-RAs is warranted to obtain more precise long-term estimates. As the costs of TPO-RAs decline with the introduction of generic formulations, TPO-RAs may be increasingly cost-effective.

Peripheral venous catheter collection of immune effector cells and hematopoietic stem cells is feasible and safe in older pediatric patients.

BACKGROUND: The Collection of hematopoietic stem cells (HSC) and immune effector cells (IEC) has unique challenges in children. To maintain adequate blood flow, central venous catheters (CVCs) remain the standard of care in many centers, but are associated with procedural risks and increased resource utilization. The goal of this study was to determine feasibility and safety of peripheral venous catheter (PVC) cell collection in older children. METHODS: Patients and donors requiring venous access with weight >25 kg, age >8 years were screened for PVC collection via 18G PVCs. Those with poor venous access (on history/exam/pre-screening ultrasound) or unable to maintain suitable procedural position were excluded. Comparison was made to CVC collections in a matched patient cohort. RESULTS: Thirty-eight individuals were screened and met age/weight criteria for PVC collection. Five did not have PVC collection attempted due to poor access (n = 4) or behavioral concerns (n = 1). Thirty-three had PVC collection attempt (HSC = 22; IEC = 11) with median age 15.3 year (range 9.7-18.0) and weight 58.5 kg (range 27.9-115.4). Thirty-two of 33 (97%) patients were collected successfully by PVC without adverse events. Comparing PVC to matched CVC collection cohort (n = 18), there was no significant difference in flow rate (48.2 mL/h vs 53.9 mL/h, p = 0.12), collection time (266 min vs 262 min, p = 0.85) or collection efficiency (IEC/CD3 60.9% vs 60.8% p = 0.99; HSC/CD34 53.6% vs 41.3% p = 0.05). CONCLUSION: PVC collection of HSC and IEC is feasible and safe in older children with comparable collection efficiency to CVC collections. Ultrasound screening may reduce failure rates. PVC collections can reduce the risk of CVC insertions and associated healthcare costs.

Fetal therapy using rapamycin for a rapidly enlarging, obstructive, cervical lymphatic malformation: a case report.

WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?: Fetal lymphatic malformations (LMs) can be detected on prenatal ultrasound and until recently, therapeutic options were limited. Recently the mammalian target of rapamycin inhibitor rapamycin has emerged as a safe, effective therapy for children with LMs and multiple studies have demonstrated improved efficacy if started early. WHAT DOES THIS STUDY ADD?: We report the first in-utero therapy with rapamycin for a rapidly enlarging, obstructive, fetal cervical LM. Fetal therapy with rapamycin was safe and effective in managing this severe malformation, despite rapamycin being started only in the last 6.5 weeks of pregnancy. We speculate that had rapamycin been commenced earlier, the reduction in mass size might have been even greater.

Asymptomatic Pulmonary Artery Embolization by a Port-a-Cath Fragment in a Child With Acute Lymphoblastic Leukemia.

Broken catheter embolism is a rare but often fatal complication of implantable venous access devices. Prompt removal is key to avoiding an adverse outcome.

Uric Acid as a predictor of adverse maternal and perinatal outcomes in women hospitalized with preeclampsia.

OBJECTIVE: Elevated serum uric acid is commonly observed in women with preeclampsia, but its utility in predicting adverse outcomes has recently been disputed. Our goal was to analyze data from a large cohort of women with preeclampsia to determine the utility of serum uric acid in predicting adverse maternal and perinatal outcomes. METHODS: Data were obtained from an ongoing international prospective study of women admitted to hospital with preeclampsia (Pre-eclampsia Integrated Estimate of RiSk). Univariate logistic regression was used to determine the relationship between serum uric acid concentration (both absolute and gestational-age corrected [Z score]) and adverse outcomes (maternal and perinatal). Analyses were conducted to compare cohorts of women with preeclampsia as defined by hypertension and proteinuria versus hypertension and hyperuricemia. RESULTS: Uric acid Z score was associated with adverse perinatal outcome (OR 1.5; 95% CI 1.4 to 1.7) and had a point estimate > 0.7 (area under the curve receiver operating characteristic 0.72; 95% CI 0.69 to 0.74). Serum uric acid concentration also showed a significant association with adverse maternal outcomes, but the point estimate was < 0.7. No significant differences were observed between groups in which preeclampsia was defined by hypertension and proteinuria and by hypertension and hyperuricemia. CONCLUSION: In women admitted to hospital with preeclampsia, the serum uric acid concentration, corrected for gestational age via a Z score, is clinically useful in predicting adverse perinatal outcomes but not maternal outcomes.

Objectif : Bien qu'un taux sérique élevé d'acide urique soit couramment constaté chez les femmes qui présentent une prééclampsie, son utilité pour ce qui est de la prévision des issues indésirables a récemment été remise en question. Nous avions pour objectif d'analyser les données issues d'une importante cohorte de femmes présentant une prééclampsie, afin de déterminer l'utilité du taux sérique d'acide urique pour ce qui est de la prévision des issues indésirables maternelles et périnatales. Méthodes : Les données ont été tirées d'une étude prospective internationale toujours en cours qui porte sur des femmes hospitalisées présentant une prééclampsie (Pre-eclampsia Integrated Estimate of RiSk). Une régression logistique univariée a été utilisée pour déterminer la relation entre la concentration sérique en acide urique (tant absolue que corrigée en fonction de l'âge gestationnel [score Z]) et les issues indésirables (maternelles et périnatales). Des analyses ont été menées pour comparer des cohortes de femmes présentant une prééclampsie définie par l'hypertension et la protéinurie à des cohortes de femmes présentant une prééclampsie définie par l'hypertension et l'hyperuricémie. Résultats : Le score Z quant à l'acide urique était associé à des issues périnatales indésirables (RC, 1,5; IC à 95 %, 1,4 - 1,7) et comptait une estimation ponctuelle > 0,7 (surface sous la courbe de la fonction d'efficacité de l'observateur, 0,72; IC à 95 %, 0,69 - 0,74). Une association significative a également été constatée entre la concentration sérique en acide urique et des issues indésirables maternelles; toutefois, l'estimation ponctuelle était < 0,7. Aucune différence significative n'a été constatée entre les groupes « prééclampsie définie par l'hypertension et la protéinurie ¼ et « prééclampsie définie par l'hypertension et l'hyperuricémie ¼. Conclusion : Bien que la concentration sérique en acide urique (corrigée en fonction de l'âge gestationnel par l'intermédiaire d'un score Z) soit utile sur le plan clinique pour ce qui est de la prévision des issues indésirables périnatales chez les femmes hospitalisées présentant une prééclampsie, elle ne compte pas une utilité semblable en ce qui concerne les issues indésirables maternelles.

Synchronous T-lymphoblastic lymphoma and neuroblastoma in a 3-yr-old with novel germline SMARCA4 and EZH2 variants.

T-lymphoblastic lymphoma (T-LLy) is the most common lymphoblastic lymphoma in children and often presents with a mediastinal mass. Lymphomatous suprarenal masses are possible but rare. Here, we discuss the case of a previously healthy 3-yr-old male who presented with mediastinal T-LLy with bilateral suprarenal masses. Following initial treatment, surgical biopsy of persisting adrenal masses revealed bilateral neuroblastoma (NBL). A clinical genetics panel for germline cancer predisposition did not identify any pathogenic variants. Combination large panel (864 genes) profiling analysis in the context of a precision oncology study revealed two novel likely pathogenic heterozygous variants: SMARCA4 c.1420-1G > T p.? and EZH2 c.1943G > C p.(Ile631Phefs*44). Somatic analysis revealed potential second hits/somatic variants in EZH2 (in the T-LLy) and a segmental loss in Chromosome 19p encompassing SMARCA4 (in the NBL). Synchronous cancers, especially at a young age, warrant genetic evaluation for cancer predisposition; enrollment in a precision oncology program assessing germline and tumor DNA can fulfill that purpose, particularly when standard first-line genetic testing is negative and in the setting of tumors that are not classic for common cancer predisposition syndromes.

Herpes simplex virus type 1-encoded glycoprotein C contributes to direct coagulation factor X-virus binding.

The HSV1 (herpes simplex virus type 1) surface has been shown recently to initiate blood coagulation by FVIIa (activated Factor VII)-dependent proteolytic activation of FX (Factor X). At least two types of direct FX-HSV1 interactions were suggested by observing that host cell-encoded tissue factor and virus-encoded gC (glycoprotein C) independently enhance FVIIa function on the virus. Using differential sedimentation to separate bound from free 125I-ligand, we report in the present study that, in the presence of Ca2+, FX binds directly to purified wild-type HSV1 with an apparent dissociation constant (K(d)) of 1.5+/-0.4 muM and 206+/-24 sites per virus at saturation. The number of FX-binding sites on gC-deficient virus was reduced to 43+/-5, and the remaining binding had a lower K(d) (0.7+/-0.2 microM), demonstrating an involvement of gC. Engineering gC back into the deficient strain or addition of a truncated soluble recombinant form of gC (sgC), increased the K(d) and the number of binding sites. Consistent with a gC/FX stoichiometry of approximately 1:1, 121+/-6 125I-sgC molecules were found to bind per wild-type HSV1. In the absence of Ca2+, the number of FX-binding sites on the wild-type virus was similar to the gC-deficient strain in the presence of Ca2+. Furthermore, in the absence of Ca2+, direct sgC binding to HSV1 was insignificant, although sgC was observed to inhibit the FX-virus association, suggesting a Ca2+-independent solution-phase FX-sgC interaction. Cumulatively, these data demonstrate that gC constitutes one type of direct FX-HSV1 interaction, possibly providing a molecular basis for clinical correlations between recurrent infection and vascular pathology.

NeuroDevNet: Training the next generation of Canadian developmental neurobiologists.

Enhancing Canadian capacity in the research and treatment for neurodevelopmental disorders is central to NeuroDevNet's mission. Building on the notion that it takes a network of scientists, clinicians, and educators to train the next generation researchers, NeuroDevNet brings together the diversity of expertise from across Canada to provide multifaceted, cross-disciplinary training opportunities for our trainees. Our Program provides for a diverse training experience that fosters the development of active young researchers with a collaborative focus and an eye toward the bidirectional translation of knowledge between the bench and the bedside. With funding from the NCE of Canada, as well as public and private partnerships, we offer fellowship and internship opportunities to trainees that encourage collaborative interactions, interdisciplinary exchanges and knowledge translation. This program will enhance the development and integration of NeuroDevNet as well as the Canadian community caring for the health and wellbeing of its citizens with neurodevelopmental disorders.