The children anticoagulation and pharmacogenetics study (CAPS): Developing a dosing algorithm for acencocoumarol in paediatric patients

Background: Dosing of vitamin K antagonists (VKA) in paediatric patients is complex. The large variability in VKA dose requirement asks for elucidating the factors associated with this variability and taking these into account when defining the dose for a patient. For warfarin, paediatric dosing algorithms have been developed, but not for acenocoumarol. Objectives: To develop a dosing algorithm for acenocoumarol in pediatric patients with and without genetic information. Methods: This multicentre retrospective follow-up study was carried out in Dutch anticoagulation clinics and children's hospitals. Patients were selected when they used acenocoumarol for >1 month between January 1995 and December 2014 and were ≤18 years of age. The primary outcome was the mean daily dose during a stable period. A stable period was defined as ≥3 consecutive international normalized ratio measurements within therapeutic range over a period of ≥3 weeks. Clinical information (including height, weight and indication) and saliva samples for genotyping of CYP2C9 (∗2 and ∗3), VKORC1, CYP4F2, CYP2C18 and CYP3A4 (∗1B and ∗22) were collected. Linear regression was used to analyse their association with the log mean stable dose. Results: In total, 175 patients were included of whom 86 patients had a stable period and no missing clinical information (clinical algorithm cohort) and of 80 also genetic information was available (genetic algorithm cohort). The mean age at the stable period was 9 years. The most common indications were Fontan circulation, prosthetic heart valve, deep venous thrombosis and dilated cardiomyopathy. The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. By adding the genotypes of VKORC1, CYP2C18, and CYP2C9∗2/∗3, 61.8% of the variability was explained (genetic algorithm). Conclusions: Clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Including genetic factors in the algorithm, and especially VKORC1, increased this with 16.8%

Incidence of bleeding and thrombotic events in non-institutionalized paediatric patients using warfarin in the united kingdom

Background: Dosing of vitamin K antagonists (VKA) is complex with large inter- and intra-individual variability in patients' required VKA dose. Over- and underdosing can result in bleeding and thrombotic events. The incidence of these events in paediatric patients on warfarin therapy in a European population is unknown. Objectives: To estimate the incidence of bleeding and thrombotic events in warfarin using paediatric patients in the UK and to characterise patients who do or do not experience a bleeding or thrombotic event. Methods: Data were obtained from the UK CPRD in the period between January 1998 and November 2016. Using a cohort design, we identified all patients with ≥1 prescription for warfarin and who were ≤18 years. The date of the first prescription marked the start of the follow-up. Follow-up was classified into periods of warfarin use and non-use. Patients were followed until 19 years of age, death or departure from the practice. The incidence of non-fatal bleeding and thrombotic events was assessed using both information from CPRD and the linked Hospital Episode Statistics (HES). Fatal events were identified usings the linked mortality data from the Office for National Statistics (ONS). For calculating the incidence of thrombotic events only patients without a history of thrombosis were included. Results: In total, 685 patients were identified (median age 15 years, 45.4% female) of whom 372 could be linked to the HES and ONS databases. The incidence of bleeding and thrombotic events during warfarin use was 4.08 and 1.27/100 patient years, respectively. The incidence of bleeding events during non-use was 2.65/100 patient years (relative risk 1.58, 95% confidence interval [0.89-2.80]). Only 2 fatal events occurred, one bleeding and one thrombotic event. Patients with a bleeding event tended to have a higher percentage of INR measurements with a value above 4 (9.4 vs 3.9%) and a lower fraction below 2 (18.4 vs 39.1%) compared to patients without a bleeding event during the whole follow-up. Patients with a thrombotic event showed the opposite trend, a higher percentage of INRs below 2 (45.8 vs 29.5%) and a lower percentage of INRs above 4 (2.7 vs 5.3%). All differences were not statistically significant which maybe due to the small sample size. Conclusions: The incidence of bleeding events was higher than of thrombotic events. The trends in percentages of INRs under and above therapeutic range suggest that keeping the INR within range could decrease the occurence of these events

Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway

Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies

Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone

Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3-16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P3.4) from 8% to 85%(P</p

The pediatric acenocoumarol dosing algorithm:The Children Anticoagulation and Pharmacogenetics Study

Essentials: A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. Summary: Background: The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives: To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods: The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results: In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patien

Evaluation of the pharmacokinetics of prednisolone in paediatric patients with acute lymphoblastic leukaemia treated according to Dutch Childhood Oncology Group protocols and its relation to treatment response

Glucocorticoids form the backbone of paediatric acute lymphoblastic leukaemia (ALL) treatment. Many studies have been performed on steroid resistance; however, few studies have addressed the relationship between dose, concentration and clinical response. The aim of the present study was to evaluate the pharmacokinetics of prednisolone in the treatment of paediatric ALL and the correlation with clinical parameters. A total of 1028 bound and unbound prednisolone plasma concentrations were available from 124 children (aged 0–18 years) with newly diagnosed ALL enrolled in the Dutch Childhood Oncology Group studies. A population pharmacokinetic model was developed and post hoc area under the curve (AUC) was tested against treatment outcome parameters. The pharmacokinetics of unbound prednisolone in plasma was best described with allometric scaling and saturable binding to proteins. Plasma protein binding decreased with age. The AUC of unbound prednisolone was not associated with any of the disease parameters or treatment outcomes. Unbound prednisolone plasma concentrations correlated with age. No effect of exposure on clinical treatment outcome parameters was observed and does not substantiate individualised dosing. Poor responders, high-risk and relapsed patients showed a trend towards lower exposure compared to good responders. However, the group of poor responders was small and requires further research.</p

Excellent leukemia control after second hematopoietic cell transplants with unrelated cord blood grafts for post-transplant relapse in pediatric patients

BackgroundPatients with leukemia relapse after allogeneic hematopoietic cell transplant (HCT) have poor survival due to toxicity and disease progression. A second HCT often offers the only curative treatment.MethodsWe retrospectively reviewed our bi-institutional experience (MSKCC-USA; Utrecht-NL) with unrelated cord blood transplantation (CBT) for treatment of post-transplant relapse. Overall survival (OS) and event-free survival (EFS) were evaluated using the Kaplan-Meier method, treatment-related mortality (TRM) and relapse were evaluated using the competing risk method by Fine-Gray.ResultsTwenty-six patients age &lt; 21 years received a second (n=24) or third (n=2) HCT with CB grafts during the period 2009-2021. Median age at first HCT (HCT1) was 11.5 (range: 0.9-17.7) years and all patients received myeloablative cytoreduction. Median time from HCT1 to relapse was 12.8 (range 5.5-189) months. At CBT, median patient age was 13.5 (range 1.4-19.1) years. Diagnoses were AML: 13; ALL: 4, MDS: 5, JMML: 2; CML: 1; mixed phenotype acute leukemia: 1. Sixteen patients (62%) were in advanced stage, either CR&gt;2 or with active disease. Median time from HCT1 to CBT was 22.2 (range 7-63.2) months. All patients engrafted after CBT. Thirteen patients developed acute GvHD; 7 had grade III or IV. With a median survivor follow-up of 46.6 (range 17.4-155) months, 3-year OS was 69.2% (95% CI 53.6-89.5%) and 3-year EFS was 64.9% (95% CI 48.8-86.4%). Eight patients died, 3 of AML relapse and 5 due to toxicity (respiratory failure [n=4], GvHD [n=1]) at a median time of 7.7 (range 5.9-14.4) months after CBT. Cumulative incidence of TRM at 3 years was 19.2% (95% CI 4.1-34.4%). Notably, all TRM events occurred in patients transplanted up to 2015; no toxicity-related deaths were seen in the 16 patients who received CBT after 2015. Cumulative incidence of relapse was 15.9% (95% CI 1.6-30.2%) at 3 years, remarkably low for these very high-risk patients.ConclusionsSurvival was very encouraging following CB transplants in pediatric patients with recurrent leukemia after first HCT, and TRM has been low over the last decade. CBT needs to be strongly considered as a relatively safe salvage therapy option for post-transplant relapse

Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts

On the Early Digging of Peanut Fruits

1. The flowering period of peanut is about 100 days or more, which differentiates very much the respective maturity of each fruit of peanut, so it is difficult that growers catch its exact yielding time. 2. By the factors of climate, especially temperature, the flowering or maturing period is controlled, and the yielding period is from the middle of September to the end of October. 3. The effective flowering period was until the end of August, and the seeded plant at the beginning of July had its effective flowering period of only about one month, and so the July-seeded plant had only half of the product of the optimum seeded plant at the beginning of May. The seeded plant after July had the common pods, but brought no grain. 4. Immature grains decreased rapidly after about 90 days from the first flowering of each plant, or about 40 days from the maximum flowering time. 5. The plants harvested after the middle of October, which passed over the 110 days from the first flowering of each plant, produced many over-mature grains and germinating grains. 6. The early harvesting time is better than the customary time, and when the immature pods are many, the mature fruits should be harvested and the plants with immature pods should be gathered at the corner of the field and planted temporarily. After they were laid on till the frost time, the Secondly harvest should be done. 7. The optimum harvesting time was about after one month from the end of effective flowering period, or after one month and a half from the maximum of fertile percentage

Заболевание тазобедренного сустава у детей с наследственной предрасположенностью: концептуальная модель

На основе принципов интегративной медицины, системного подхода с использованием концептуально−логического моделирования разработана единая система представлений о заболеваниях тазобедренного сустава у детей с наследственной предрасположенностью. Показано, что предлагаемый интегративный подход может служить основой для разработки диагностических и прогностических критериев развития суставов и проведения патогенетического хирургического лечения, направленного на ликвидацию или существенное снижение частоты формирования диспластического коксартроза.Based on the principles of integrative medicine, systemic approach with the use of concept of logical modelling, a uniform system of concepts about the diseases of the hip joint in children with hereditary susceptibility was worked out. It was shown that the suggested integrative approach can be used for working out diagnostic and prognostic criteria of joint development and performing pathogenetic surgery aimed at elimination or reduction in the frequency of forming dysplastic coxarthrosis