Exploring Risk Factors for Adverse Reactions in Children with an Acute Psychotic Episode Using the Global Trigger Tool: Does Age Matter?

Aim: To establish significant risk factors for the development of adverse drug effects (ADEs) in children and adolescents with an acute psychotic episode taking antipsychotics. Materials and Methods: The research team randomly selected 15 patient records each month for 3 years (2016-2018). Overall, 450 patient records were included (223 boys and 227 girls, mean age was 14.52 ± 2.21 years). Adverse effects were identified using the standard algorithm of the Global Trigger Tool method. A "trigger" is an indication that an adverse reaction is likely to occur, e.g., an antihistamine prescription on a prescribing list. When a trigger was detected, the case history was studied in further detail to confirm the occurrence of ADEs. We divided patients into two groups: the "children" group (under 12 years old) and the "adolescents" group (13 years and older). Data were analyzed using the statistical package IBM SPSS Statistics 23.0. Results: Of the 450 patient records, 402 (89.3%) had at least one trigger detected. In total, 126 case histories contained evidence of ADE (28%). The total number of ADEs per 1000 patient days was 5.39 and the number of ADEs per 100 admissions was 32.0. Among adolescents, two or more triggers per patient were significantly more frequently identified (61.3% vs. 44.6%; p = 0.001). ADEs were rare in "Children" compared with "Adolescents" (13.8% vs. 30.4%; p = 0.006). The logistic regression analysis confirmed high predictive role of "Adolescence" (odds ratio [OR] = 2.58; 95% confidence interval [CI] 1.22-5.4; p = 0.013), "Polypharmacy" (OR = 1.96; 95% CI 1.23-3.1; p = 0.004), and "First-life hospitalization" (OR = 2.17; 95% CI 1.34-3.48; p = 0.001) for ADE fact in patient records. Conclusion: We found that significant risk factors for ADEs to antipsychotics in patients with acute psychotic episode were adolescence (13 years and older), polypharmacy, and first-life hospitalization. The fact that children (i.e., younger than 13 years of age) are less likely to experience ADEs was not associated with high-risk drugs or higher doses in our study.

Immobilizing Interstitial Cardiac Fibrosis.

Background: The alterations in the endomysium and perimysium might cause compaction and gradual mechanical compression of cardiomyocytes resulting in their immobilization. This process finally leads to severe stiffening, so that the newly formed frame around individual cardiomyocytes and their clusters hinders normal diastole, and later systole. This phenomenon is referred to as immobilizing interstitial cardiac fibrosis (IICF). Deciphering the molecular and structural elements of myocardial changes is the key to understanding the pathogenetic foundations of heart failure development. Methods: The study included 69 patients. Group I (n = 32) included patients with IICF; group II (n = 37) was comparison group. We evaluated the clinical picture, anamnesis of the disease, the results of physical examination, laboratory and instrumental examination of patients and autopsy data. Results: In the anamnesis, patients with IICF were more likely to have diseases than patients in the control group: arrhythmia and impaired conductivity (88% vs. 19%, odds ratio (OR): 30.0; 95% confidence interval (CI): 7.918 - 113.7, P < 0.001), systemic connective tissue diseases (78% vs. 5%, OR: 62.5; 95% CI: 11.9 - 326.5, P < 0.001), viral infections (including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) (53% vs. 19%, OR: 4.86; 95% CI: 1.66 - 14.25, P = 0.003), type 2 diabetes mellitus (47% vs. 8%, OR: 10.0; 95% CI: 2.54 - 39.34, P < 0.001), radiation therapy for mediastinal lymphoma and other oncological diseases (19% vs. 0%, P = 0.008), focal infections (sinusitis, osteomyelitis, periodontitis, nephritis, cystitis, pyelonephritis, pleurisy, etc.) within 12 months (31% vs. 11%, P = 0.069), chronic kidney disease (25% vs. 8%, P = 0.097), and tuberculosis (9% vs. 0%, P = 0.095). We have identified a statistically significant difference between the groups: the volume of the fibrosis zone (17.5±9.2% vs. 4.9±2.3%, P = 0.001), the expression of type I collagen (5,182 ± 1,301 vs. 2,189 ± 754 in 1 mm2, P = 0.0001), type III collagen (7,562 ± 1,405 vs. 2,320 ± 541 in 1 mm2, P = 0.0001), matrix metalloproteinase (MMP)-2 (12,850 ± 6,200 vs. 9,501 ± 7,145 in 1 mm2, P = 0.005), MMP-9 (15,745 ± 5,695 vs. 6,920 ± 3,125 in 1 mm2, P = 0.0001), connexin-43 (25,689 ± 14,871 vs. 37,523 ± 12,561 in 1 mm2, P = 0.001), fibronectin (3,448 ± 720 vs. 1,544 ± 610 in 1 mm2, P = 0.0001), and transforming growth factor ß (TGF-ß) (5,121 ± 1,243 vs. 2,531 ± 1,489 in 1 mm2, P = 0.001). Conclusion: IICF is a separate pathological condition and one of the main causes of chronic heart failure. It is induced by changes in the myocardial connective tissue that prevent normal functioning of the myocardium.

Order and disorder, crossovers, and phase transitions in dipolar artificial spin ice on the Cairo lattice.

We study the thermodynamic properties of the magnetic dipolar spin ice on a 2D pentagonal Cairo lattice by using the numerical Metropolis and the complete enumeration methods. We use the model of point Ising-like dipoles considering long-range interactions with up to 100 nearest neighbors and with periodic boundary conditions. There are two explicit peaks both in the temperature behavior of the heat capacity and in the magnetic susceptibility. The low-temperature peak is caused only by long-range interactions and is not present in the model where each dipole interacts only with four nearest neighbors. The height of the peak depends logarithmically on the quantity of dipoles, which indicates a phase transition. The nature of the low-temperature phase transition is related to the transformation from order to disorder in orthogonal sublattices while maintaining the spin ice state and the spin ice rule in the sublattice of crosses. The high-temperature heat capacity peak is associated with the melting of spin ice, i.e., with the crossover from spin ice to paramagnetic chaos. Its height is constant and does not depend on the quantity of dipoles. It is shown that the choice of the radius of the dipole-dipole interaction has a significant effect on the statistical properties of the model. The model may even show the appearance of the long-range order and the phase transition in the case of long-range interaction or its absence in the case of short-range interaction.

CYP2D6 phenotype and ABCB1 haplotypes are associated with antipsychotic safety in adolescents experiencing acute psychotic episodes.

OBJECTIVES: To identify possible associations of CYP2D6, CYP3A4/5, and ABCB1 gene polymorphisms with the efficacy and safety of antipsychotics in adolescents with acute psychotic episodes. METHODS: We examined the associations of pharmacogenetic factors with the efficacy and safety of antipsychotics in 101 adolescents with acute psychotic episodes. The diagnosis on admission was "Brief psychotic disorder" (F23.0-23.9 by ICD-10). All patients were administered antipsychotics for 14 days. Treatment efficacy and safety were assessed using the PANSS, CGAS, CGI-S(I), UKU SERS, BARS, and SAS scales. Pharmacokinetic genotyping was performed for the CYP2D6*4, *10, ABCB1 1236C>T, 2677G>T, and 3435C>T genes. RESULTS: CYP2D6 intermediate metabolisers had "Micturition disturbances" more often than extensive metabolisers (24.2 vs. 7.4%; p=0.026). "Wild" homozygote ABCB1 3435C>T CC was associated with more prominent akathisia. Haplotype analysis of three ABCB1 polymorphisms revealed that the "wild" alleles "C-G-C" (ABCB1 1236-2677-3435) were associated with higher risk of "Reduced salivation" (OR=2.95; 95% CI=1.35-6.45; p=0.0078). CONCLUSIONS: CYP2D6 intermediate metabolism was associated with the risk of urinary difficulties under treatment with antipsychotics. We found that "wild" homozygotes ABCB1 1236C>T, 2677G>T, and 3435C>T were predictors of adverse drug effects caused by treatment with antipsychotics.

CYP2D6 phenotype and ABCB1 haplotypes are associated with antipsychotic safety in adolescents experiencing acute psychotic episodes.

OBJECTIVES: To identify possible associations of CYP2D6, CYP3A4/5, and ABCB1 gene polymorphisms with the efficacy and safety of antipsychotics in adolescents with acute psychotic episodes. METHODS: We examined the associations of pharmacogenetic factors with the efficacy and safety of antipsychotics in 101 adolescents with acute psychotic episodes. The diagnosis on admission was "Brief psychotic disorder" (F23.0-23.9 by ICD-10). All patients were administered antipsychotics for 14 days. Treatment efficacy and safety were assessed using the PANSS, CGAS, CGI-S(I), UKU SERS, BARS, and SAS scales. Pharmacokinetic genotyping was performed for the CYP2D6*4, *10, ABCB1 1236C>T, 2677G>T, and 3435C>T genes. RESULTS: CYP2D6 intermediate metabolisers had "Micturition disturbances" more often than extensive metabolisers (24.2 vs. 7.4%; p=0.026). "Wild" homozygote ABCB1 3435C>T CC was associated with more prominent akathisia. Haplotype analysis of three ABCB1 polymorphisms revealed that the "wild" alleles "C-G-C" (ABCB1 1236-2677-3435) were associated with higher risk of "Reduced salivation" (OR=2.95; 95% CI=1.35-6.45; p=0.0078). CONCLUSIONS: CYP2D6 intermediate metabolism was associated with the risk of urinary difficulties under treatment with antipsychotics. We found that "wild" homozygotes ABCB1 1236C>T, 2677G>T, and 3435C>T were predictors of adverse drug effects caused by treatment with antipsychotics.

Global trigger tool in child psychiatry: Treatment safety evaluation in adolescents with an acute psychotic episode.

OBJECTIVE: To analyse the frequency, structure and risk factors of adverse drug effects in adolescents with acute psychotic episode by the methods of global triggers - Paediatric All-Cause Harm Measurement Tool (PACHMT) and Global Assessment of Paediatric Patient Safety Tool (GAPPS). PATIENTS AND METHODS: We used 151 completed case histories of patients who were admitted to a psychiatric hospital with acute psychotic episode. We applied Global Trigger Tool algorithm to each case retrospectively: we developed a special trigger list for psychiatric patients based on PACHMT, GAPPS and general Global Trigger Tool. We also calculated the Medical Appropriateness Index (MAI) for each case. We applied trigger tool analysis for calculation of treatment safety parameters. Statistical analyses included Pearson's Chi-square, Mann-Whitney U, and Kruskal-Walles tests. RESULTS: We identified a total of 261 triggers among 151 analysed cases, 51 of which were accompanied by adverse drug effects (ADEs) (overall positive prediction value = 19.54%). The value of ADEs per 1000 bed days was 4.73, ADEs per 100 admissions was 33.77%. Extrapyramidal reactions to antipsychotics (58.8%) were the most common ADEs, followed by an abrupt medication stop of one or more drugs due to ADEs (25.5%). Significant predictors of antipsychotic-induced extrapyramidal symptoms were age, MAI score and total number of hospital admissions. CONCLUSION: We recommend three triggers, "Abrupt medication stop", "Prescribing of extrapyramidal symptoms corrector", and "Hospital readmission within 30 days", with reasonable positive predictive value for incorporation into routine systems for patient safety monitoring in adolescents with an acute psychotic episode. Antipsychotic-induced extrapyramidal symptoms were more prevalent in older adolescents and patients with fewer lifetime hospital admissions. These patients need to be carefully monitored to ensure patient safety.

Pharmacogenetics of antipsychotics in adolescents with acute psychotic episode during first 14 days after admission: effectiveness and safety evaluation.

OBJECTIVES: Prediction of the antipsychotic's effectiveness is a relevant topic in the field of personalized medicine. METHODS: The research design of this study is a prospective observation with posthoc analysis of associations of genetic polymorphisms with safety parameters and effectiveness of antipsychotic therapy. We observed 53 adolescents with an acute psychotic episode which were prescribed antipsychotics for 14 days. We evaluated the effectiveness of antipsychotics with the Positive and Negative Symptoms Scale and the safety with the UKU Side Effects Rating Scale, Simpson-Angus Scale, and Barnes Akathisia rating scale. We genotyped CYP3A4*22 (rs2740574), CYP3A5*3 (6986A>G, rs7767746), CYP2D6*4, *9, *10 (rs3892097, rs1065852), ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642), DRD2 (rs1800497), DRD4 (rs1800955), HTR2A (rs6313) by the real-time polymerase chain reaction method. RESULTS: We found significantly more frequent "increased dream activity" between CYP2D6 intermediate metabolizers and normal metabolizers (54 vs. 22%; p=0.043). The «increased duration of sleep¼ was more often observed in homozygotes TT of ABCB1 2677G>T/A (50 vs. 15.8%, p=0.006) and TT of 3435C>T (41.7 vs. 8.2%, p=0.007). CONCLUSIONS: We found that CYP2D6 and ABCB1 polymorphisms were associated with the safety of antipsychotics in adolescents with an acute psychotic episode.

Large peaks in the entropy of the diluted nearest-neighbor spin-ice model on the pyrochlore lattice in a [111] magnetic field.

We study the residual entropy of the nearest-neighbor spin-ice model in a magnetic field along the [111] direction using the Wang-Landau Monte Carlo method, with a special attention to dilution effects. For a diluted model, we observe a stepwise decrease of the residual entropy as a function of the magnetic field, which is consistent with the finding of the five magnetization plateaus in a previous replica-exchange Monte Carlo study by Peretyatko et al. [Phys. Rev. B 95, 144410 (2017)2469-995010.1103/PhysRevB.95.144410]. We find large peaks of the residual entropy due to the degeneracy at the crossover magnetic fields, h_{c}/J=0, 3, 6, 9, and 12, where h and J are the magnetic field and the exchange coupling, respectively. In addition, we also study the residual entropy of the diluted antiferromagnetic Ising models in a magnetic field on the kagome and triangular lattices. We again observe large peaks of the residual entropy, which are associated with multiple magnetization plateaus for the diluted model. Finally, we discuss the interplay of dilution and magnetic fields in terms of the residual entropy.

Entropy of diluted antiferromagnetic Ising models on frustrated lattices using the Wang-Landau method.

We use a Monte Carlo simulation to study the diluted antiferromagnetic Ising model on frustrated lattices including the pyrochlore lattice to show the dilution effects. Using the Wang-Landau algorithm, which directly calculates the energy density of states, we accurately calculate the entropy of the system. We discuss the nonmonotonic dilution concentration dependence of residual entropy for the antiferromagnetic Ising model on the pyrochlore lattice, and compare it to the generalized Pauling approximation proposed by Ke et al. [Phys. Rev. Lett. 99, 137203 (2007)PRLTAO0031-900710.1103/PhysRevLett.99.137203]. We also investigate other frustrated systems, the antiferromagnetic Ising model on the triangular lattice and the kagome lattice, demonstrating the difference in the dilution effects between the system on the pyrochlore lattice and that on other frustrated lattices.

Systematic sequencing of cDNA clones using the transposon Tn5.

In parallel with the production of genomic sequence data, attention is being focused on the generation of comprehensive cDNA-sequence resources. Such efforts are increasingly emphasizing the production of high-accuracy sequence corresponding to the entire insert of cDNA clones, especially those presumed to reflect the full-length mRNA. The complete sequencing of cDNA clones on a large scale presents unique challenges because of the generally small, yet heterogeneous, sizes of the cloned inserts. We have developed a strategy for high-throughput sequencing of cDNA clones using the transposon Tn5. This approach has been tailored for implementation within an existing large-scale 'shotgun-style' sequencing program, although it could be readily adapted for use in virtually any sequencing environment. In addition, we have developed a modified version of our strategy that can be applied to cDNA clones with large cloning vectors, thereby overcoming a potential limitation of transposon-based approaches. Here we describe the details of our cDNA-sequencing pipeline, including a summary of the experience in sequencing more than 4200 cDNA clones to produce more than 8 million base pairs of high-accuracy cDNA sequence. These data provide both convincing evidence that the insertion of Tn5 into cDNA clones is sufficiently random for its effective use in large-scale cDNA sequencing as well as interesting insight about the sequence context preferred for insertion by Tn5.

Clinical Versus Research Sequencing.

Historically, sequencing has been the key technology to assess variation in the genetic code, and has been widely accepted in clinical diagnostics of genetic disease. The advent of next-generation sequencing (NGS) methods increased the size of the analyzed target by several orders of magnitude, while at the same time drastically reducing the cost of sequencing. Current research allows sequencing of germline and tumor whole genomes. However, with the arrival of cutting-edge technology to the clinical diagnostic field, strict regulatory oversight is required to use the advances of the latest research when applied to routine clinical practice. We discuss the differences between sequencing in a research setting and sequencing in a clinical diagnostics setting, as applied to next-generation technology.

Oligonucleotide array CGH studies in myeloproliferative neoplasms: comparison with JAK2V617F mutational status and conventional chromosome analysis.

Comparative genomic hybridization (CGH), using oligo arrays with either 44,000 or 105,000 oligonucleotides, was performed on granulocyte-derived DNA from 71 patients with BCR-ABL-negative classic myeloproliferative neoplasms (MPNs): 32 primary myelofibrosis (PMF), 26 polycythemia vera (PV) and 13 essential thrombocythemia (ET). Copy number changes (CNCs) were detected in 44%, 35%, and 15% of the cases with PMF, PV and ET, respectively. In ET and PMF, CNCs were more frequently detected in the presence of JAK2V617F (50% vs. 19%; p=0.05). Conventional chromosome analysis was obtained in 57 patients either at diagnosis or within 1 year of the array CGH study; all 21 patients with PV and 11 with ET displayed normal cytogenetic findings despite the presence of CNCs in 29% and 18%, respectively. In PMF, the respective rates of CNCs and abnormal karyotype were 48% and 36%; karyotypic abnormalities, including unbalanced translocations, were often detected by array CGH as chromosomal gains or losses. This preliminary report suggests a potential value for array CGH in terms of both clinical diagnostics and genomic research in MPNs.