Virtual reality in pediatrics, effects on pain and anxiety: A systematic review and meta-analysis update

Introduction: Medical procedures are often accompanied by pain and anxiety in pediatric patients. A relatively new technique to reduce pediatric pain and anxiety is virtualreality. Virtual reality is both applied as a distraction tool and as an exposure tool to prepare patients for medical procedures. Research into the application of virtual reality inmedical settings is rapidly evolving. This meta-analysis is an update of the meta-analysisof Eijlers et al. investigating the effectiveness of virtual reality as an intervention tool onpain and anxiety in pediatric patients undergoing medical procedures.Methods: We searched the databases Embase, Medline, Web of Science CoreCollection, Cochrane Central Register of Controlled Trials and PsycINFO. For eachof these databases, different search strategies were developed. The search periodfrom the meta-analysis from Eijlers et al., reaching until April 2018, was extended toDecember 2020. Pain and anxiety outcomes during medical procedures were compared for virtual reality and standard care conditions for various medical procedures.Results: The search yielded 1824 articles, of which 13 met our inclusion criteria.Combined with 13 articles of Eijlers' review study, this resulted in 26 articles. Virtualreality was applied as distraction (n = 23) during medical procedures or as exposure(n = 4) before medical procedures. The effect of virtual reality distraction was mostlystudied in patients during venous access (n = 10). The overall weighted standardizedmean difference for virtual reality distraction was −0.67 (95% CI, −0.89 to −0.45;p< .001) on patient-reported pain (based on 21 studies) and −0.74 (95% CI, −1.00to −0.48; p< .001) on patient-reported anxiety (based on 10 studies). The effect ofvirtual reality as an exposure tool on patient-reported anxiety was significant too(standardized mean difference = −0.58; 95% CI, −1.15 to −0.01; p< .05).Discussion: The current updated systematic review and meta-analysis indicates thatvirtual reality is a useful tool to reduce pain and anxiety in pediatric patients undergoing a range of medical procedures as it significantly decreases pain and anxietyoutcomes when compared to care as usual

Apparent Lack of BRAFV600E Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8+ T Cells in Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAFV600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from a

Increased Hepatic Insulin Action in Diet-Induced Obese Mice Following Inhibition of Glucosylceramide Synthase

Obesity is characterized by the accumulation of fat in the liver and other tissues, leading to insulin resistance. We have previously shown that a specific inhibitor of glucosylceramide synthase, which inhibits the initial step in the synthesis of glycosphingolipids (GSLs), improved glucose metabolism and decreased hepatic steatosis in both ob/ob and diet-induced obese (DIO) mice. Here we have determined in the DIO mouse model the efficacy of a related small molecule compound, Genz-112638, which is currently being evaluated clinically for the treatment of Gaucher disease, a lysosomal storage disorder.DIO mice were treated with the Genz-112638 for 12 to 16 weeks by daily oral gavage. Genz-112638 lowered HbA1c levels and increased glucose tolerance. Whole body adiposity was not affected in normal mice, but decreased in drug-treated obese mice. Drug treatment also significantly lowered liver triglyceride levels and reduced the development of hepatic steatosis. We performed hyperinsulinemic-euglycemic clamps on the DIO mice treated with Genz-112638 and showed that insulin-mediated suppression of hepatic glucose production increased significantly compared to the placebo treated mice, indicating a marked improvement in hepatic insulin sensitivity.These results indicate that GSL inhibition in obese mice primarily results in an increase in insulin action in the liver, and suggests that GSLs may have an important role in hepatic insulin resistance in conditions of obesity

Reducing Glycosphingolipid Content in Adipose Tissue of Obese Mice Restores Insulin Sensitivity, Adipogenesis and Reduces Inflammation

Adipose tissue is a critical mediator in obesity-induced insulin resistance. Previously we have demonstrated that pharmacological lowering of glycosphingolipids and subsequently GM3 by using the iminosugar AMP-DNM, strikingly improves glycemic control. Here we studied the effects of AMP-DNM on adipose tissue function and inflammation in detail to provide an explanation for the observed improved glucose homeostasis. Leptin-deficient obese (LepOb) mice were fed AMP-DNM and its effects on insulin signalling, adipogenesis and inflammation were monitored in fat tissue. We show that reduction of glycosphingolipid biosynthesis in adipose tissue of LepOb mice restores insulin signalling in isolated ex vivo insulin-stimulated adipocytes. We observed improved adipogenesis as the number of larger adipocytes was reduced and expression of genes like peroxisome proliferator-activated receptor (PPAR) γ, insulin responsive glucose transporter (GLUT)-4 and adipsin increased. In addition, we found that adiponectin gene expression and protein were increased by AMP-DNM. As a consequence of this improved function of fat tissue we observed less inflammation, which was characterized by reduced numbers of adipose tissue macrophages (crown-like structures) and reduced levels of the macrophage chemo attractants monocyte-chemoattractant protein-1 (Mcp-1/Ccl2) and osteopontin (OPN). In conclusion, pharmacological lowering of glycosphingolipids by inhibition of glucosylceramide biosynthesis improves adipocyte function and as a consequence reduces inflammation in adipose tissue of obese animals

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Virtual reality in pediatrics, effects on pain and anxiety: A systematic review and meta-analysis update

Introduction Medical procedures are often accompanied by pain and anxiety in pediatric patients. A relatively new technique to reduce pediatric pain and anxiety is virtual reality. Virtual reality is both applied as a distraction tool and as an exposure tool to prepare patients for medical procedures. Research into the application of virtual reality in medical settings is rapidly evolving. This meta-analysis is an update of the meta-analysis of Eijlers et al. investigating the effectiveness of virtual reality as an intervention tool on pain and anxiety in pediatric patients undergoing medical procedures. Methods We searched the databases Embase, Medline, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and PsycINFO. For each of these databases, different search strategies were developed. The search period from the meta-analysis from Eijlers et al., reaching until April 2018, was extended to December 2020. Pain and anxiety outcomes during medical procedures were compared for virtual reality and standard care conditions for various medical procedures. Results The search yielded 1824 articles, of which 13 met our inclusion criteria. Combined with 13 articles of Eijlers' review study, this resulted in 26 articles. Virtual reality was applied as distraction (n = 23) during medical procedures or as exposure (n = 4) before medical procedures. The effect of virtual reality distraction was mostly studied in patients during venous access (n = 10). The overall weighted standardized mean difference for virtual reality distraction was -0.67 (95% CI, -0.89 to -0.45; p < .001) on patient-reported pain (based on 21 studies) and -0.74 (95% CI, -1.00 to -0.48; p < .001) on patient-reported anxiety (based on 10 studies). The effect of virtual reality as an exposure tool on patient-reported anxiety was significant too (standardized mean difference = -0.58; 95% CI, -1.15 to -0.01; p < .05). Discussion The current updated systematic review and meta-analysis indicates that virtual reality is a useful tool to reduce pain and anxiety in pediatric patients undergoing a range of medical procedures as it significantly decreases pain and anxiety outcomes when compared to care as usual

Associations between polygenic risk score loading, psychosis liability, and clozapine use among individuals with schizophrenia

Importance: Predictors consistently associated with psychosis liability and course of illness in schizophrenia (SCZ) spectrum disorders (SSD), including the need for clozapine treatment, are lacking. Longitudinally ascertained medication use may empower studies examining associations between polygenic risk scores (PRSs) and pharmacotherapy choices. Objective: To examine associations between PRS-SCZ loading and groups with different liabilities to SSD: individuals with SSD on clozapine, individuals with SSD on other antipsychotics, their parents and siblings, and unrelated healthy controls; and between PRS-SCZ and the likelihood of receiving a prescription of clozapine relative to other antipsychotics. Design: Six-year follow-up and cross-sectional observational cohort study. Setting: Multi-center. Participants: Individuals diagnosed with SSD using clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Exposure: PRS-SCZ. Main Outcomes and Measures: We used multinomial logistic regression to examine possible differences between groups by computing risk ratios (RRs), i.e., ratios of the probability of pertaining to a particular group divided by the probability of healthy control status. We also computed PRS-informed odd ratios (ORs) for clozapine use relative to other antipsychotics. Results: PRSs-SCZ were generated for 2344 participants (mean age: 36.95 years; 42.4% female) remaining after quality control (557 individuals with SSD on clozapine, 350 individuals with SSD on other antipsychotics during six-year follow-up, 542 parents and 574 siblings of individuals with SSD, and 321 unrelated healthy controls). All RRs were significantly different from 1; RRs were highest for individuals with SSD on clozapine (RR=3.24 [95%CI 2.76-3.81], p=2.47x10-46), followed by individuals with SSD on other antipsychotics (RR=2.30 [95%CI 1.95-2.72], p=3.77x10-22), parents (RR=1.44 [95%CI 1.25-1.68], p=1.76x10-6), and siblings (RR=1.40 [95%CI 1.21-1.63], p=8.22x10-6). PRS-SCZ was positively associated with clozapine versus other antipsychotic use (OR=1.41 [95%CI 1.22-1.63], p=2.98x10-6), suggesting a higher likelihood of clozapine prescriptions in individuals with higher PRS-SCZ. Conclusions and Relevance: PRS-SCZ loading differs between groups of individuals with SSD, their relatives, and unrelated healthy controls, with clozapine users being at the far end of PRS-SCZ loading. Additionally, PRS-SCZ is associated with a higher likelihood of clozapine prescribing. Our findings may inform early intervention and prognostic studies into the value of PRS-SCZ for personalized antipsychotic treatment

Associations Between Polygenic Risk Score Loading, Psychosis Liability, and Clozapine Use Among Individuals With Schizophrenia

IMPORTANCE: Predictors consistently associated with psychosis liability and course of illness in schizophrenia (SCZ) spectrum disorders (SSD), including the need for clozapine treatment, are lacking. Longitudinally ascertained medication use may empower studies examining associations between polygenic risk scores (PRSs) and pharmacotherapy choices. OBJECTIVE: To examine associations between PRS-SCZ loading and groups with different liabilities to SSD (individuals with SSD taking clozapine, individuals with SSD taking other antipsychotics, their parents and siblings, and unrelated healthy controls) and between PRS-SCZ and the likelihood of receiving a prescription of clozapine relative to other antipsychotics. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was a multicenter, observational cohort study with 6 years of follow-up. Included were individuals diagnosed with SSD who were taking clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Data were collected from 2004 until 2021 and analyzed between October 2021 and September 2022. EXPOSURES: Polygenic risk scores for SCZ. MAIN OUTCOMES AND MEASURES: Multinomial logistic regression was used to examine possible differences between groups by computing risk ratios (RRs), ie, ratios of the probability of pertaining to a particular group divided by the probability of healthy control status. We also computed PRS-informed odd ratios (ORs) for clozapine use relative to other antipsychotics. RESULTS: Polygenic risk scores for SCZ were generated for 2344 participants (mean [SD] age, 36.95 years [14.38]; 994 female individuals [42.4%]) who remained after quality control screening (557 individuals with SSD taking clozapine, 350 individuals with SSD taking other antipsychotics during the 6-year follow-up, 542 parents and 574 siblings of individuals with SSD, and 321 unrelated healthy controls). All RRs were significantly different from 1; RRs were highest for individuals with SSD taking clozapine (RR, 3.24; 95% CI, 2.76-3.81; P = 2.47 × 10-46), followed by individuals with SSD taking other antipsychotics (RR, 2.30; 95% CI, 1.95-2.72; P = 3.77 × 10-22), parents (RR, 1.44; 95% CI, 1.25-1.68; P = 1.76 × 10-6), and siblings (RR, 1.40; 95% CI, 1.21-1.63; P = 8.22 × 10-6). Polygenic risk scores for SCZ were positively associated with clozapine vs other antipsychotic use (OR, 1.41; 95% CI, 1.22-1.63; P = 2.98 × 10-6), suggesting a higher likelihood of clozapine prescriptions among individuals with higher PRS-SCZ. CONCLUSIONS AND RELEVANCE: In this study, PRS-SCZ loading differed between groups of individuals with SSD, their relatives, and unrelated healthy controls, with patients taking clozapine at the far end of PRS-SCZ loading. Additionally, PRS-SCZ was associated with a higher likelihood of clozapine prescribing. Our findings may inform early intervention and prognostic studies of the value of using PRS-SCZ to personalize antipsychotic treatment

Apparent Lack of BRAFV600E Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8+ T Cells in Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAFV600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the HLA class I peptidomes of two distinct BRAFV600E transduced cell lines with confirmed expression of HLA-A*03:01 or HLA-A*11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAFV600E protein are not presented by HLA class I molecules. Given that the BRAFV600E mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH