Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs.

Interrupted lung angiogenesis is a hallmark of bronchopulmonary dysplasia (BPD); however, druggable targets that can rescue this phenotype remain elusive. Thus, our investigation focused on amphiregulin (Areg), a growth factor that mediates cellular proliferation, differentiation, migration, survival, and repair. While Areg promotes lung branching morphogenesis, its effect on endothelial cell (EC) homeostasis in developing lungs is understudied. Therefore, we hypothesized that Areg promotes the proangiogenic ability of the ECs in developing murine lungs exposed to hyperoxia. Lung tissues were harvested from neonatal mice exposed to normoxia or hyperoxia to determine Areg expression. Next, we performed genetic loss-of-function and pharmacological gain-of-function studies in normoxia- and hyperoxia-exposed fetal murine lung ECs. Hyperoxia increased Areg mRNA levels and Areg+ cells in whole lungs. While Areg expression was increased in lung ECs exposed to hyperoxia, the expression of its signaling receptor, epidermal growth factor receptor, was decreased, indicating that hyperoxia reduces Areg signaling in lung ECs. Areg deficiency potentiated hyperoxia-mediated anti-angiogenic effects. In contrast, Areg treatment increased extracellular signal-regulated kinase activation and exerted proangiogenic effects. In conclusion, Areg promotes EC tubule formation in developing murine lungs exposed to hyperoxia.

Attenuating effects of Azanza garckeana fractions on glycemo-impaired-associated dyslipidemia, hepatopathy, and nephropathy.

OBJECTIVES: The use of medicinal plants for diabetes treatment is increasing owing to their effectiveness and safety compared to synthetic drugs. Thus, the ameliorative effects of Azanza garckeana (F. Hoffm.) fractions in diabetes-induced dyslipidemia, hepatopathy, and nephropathy in rats were evaluated in this study. METHODS: Rats with alloxan (120 mg/kg body weight (BW))-induced diabetes were randomized into different groups (n=5) and treated with the crude methanolic extract, and fractions (n-hexane, ethyl acetate, and aqueous fractions) of A. garckeana each at 100, 200, and 400 mg/kg BW. Glibenclamide (5 mg/kg BW) was used as a reference drug, and all treatments were administered orally daily for 6 weeks. RESULTS: Our data revealed that treatment with the crude extract caused a dose-dependent hypoglycemic effect of 61.32±3.45%, 76.05±3.05%, and 78.59±5.90% at 100, 200, and 400 mg/kg BW, respectively and improved the BW of the animals. The extract also ameliorated the elevated cholesterol, triglyceride, low-density lipoprotein cholesterol, and increased serum levels of high-density lipoprotein cholesterol compared with untreated control animals. The extract also reversed serum biochemical alterations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, total and direct bilirubin, urea, and uric acid that were observed in untreated diabetic rats. Interestingly, the A. garckeana fraction also exhibited significant protection against diabetes-induced dyslipidemia, hepatopathy, and nephropathy in rats, with the ethyl acetate fraction exhibiting a remarkable protective effect. The LC-MS characterisation of the active fraction identified the presence of various phenolic and flavonoid compounds that could be responsible for the bioactivity of the fraction. CONCLUSION: Collectively, this study suggests the potential application of A. garckeana for effective treatment of diabetic nephropathy, with the ethyl acetate fraction of this plant representing a reserve of potential candidates for developing new drugs.

Apigetrin-enriched Pulmeria alba extract prevents assault of STZ on pancreatic ß-cells and neuronal oxidative stress with concomitant attenuation of tissue damage and suppression of inflammation in the brain of diabetic rats.

In the present study, in vitro, in vivo, and in silico models were used to evaluate the therapeutic potential of Pulmeria alba methanolic (PAm) extract, and we identified the major phytocompound, apigetrin. Our in vitro studies revealed dose-dependent increased glucose uptake and inhibition of α-amylase (50% inhibitory concentration (IC50)= 217.19 µg/mL), antioxidant (DPPH, ferric-reducing activity of plasma (FRAP), and lipid peroxidation (LPO) [IC50 = 103.23, 58.72, and 114.16 µg/mL respectively]), and anti-inflammatory potential (stabilizes human red blood cell (HRBC) membranes, and inhibits proteinase and protein denaturation [IC50 = 143.73, 131.63, and 198.57 µg/mL]) by the PAm extract. In an in vivo model, PAm treatment reversed hyperglycemia and attenuated insulin deficiency in rats with streptozotocin (STZ)-induced diabetes. A post-treatment tissue analysis revealed that PAm attenuated neuronal oxidative stress, neuronal inflammation, and neuro-cognitive deficiencies. This was evidenced by increased levels of antioxidants enzymes (superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)), and decreased malondialdehyde (MDA), proinflammatory markers (cyclooxygenase 2 (COX2), nuclear factor (NF)-κB and nitric oxide (NOx)), and acetylcholinesterase (AChE) activities in the brain of PAm-treated rats compared to the STZ-induced diabetic controls. However, no treatment-related changes were observed in levels of neurotransmitters, including serotonin and dopamine. Furthermore, STZ-induced dyslipidemia and alterations in serum biochemical markers of hepatorenal dysfunction were also reversed by PAm treatment. Extract characterization identified apigetrin (retention time: 21,227 s, 30.48%, m/z: 433.15) as the major bioactive compound in the PAm extract. Consequently, we provide in silico insights into the potential of apigetrin to target AChE/COX-2/NOX/NF-κB Altogether the present study provides preclinical evidence of the therapeutic potential of the apigetrin-enriched PAm extract for treating oxidative stress and neuro-inflammation associated with diabetes.

Biochemical and tissue physiopathological evaluation of the preclinical efficacy of Solanum torvum Swartz leaves for treating oxidative impairment in rats administered a ß-cell-toxicant (STZ).

The current study evaluated the protective role of Solanum torvum Swartz against diabetes-induced oxidative stress and tissue impairment in streptozotocin (STZ)-intoxicated rats. Rats with STZ (40 mg/kg intraperitoneally (i.p.))-induced diabetes were divided into five groups (n = 5) and treated with (i) normal saline, (ii) 150 mg/kg body weight (BW) of the ethanol extract of S. torvum leaf (EESTL), (ii) 300 mg/kg BW EESTL, (iv) 100 mg/kg BW metformin, and (v) 50 m/kg BW metformin + 100 mg/kg BW EESTL orally for 21 days. Our results revealed that the EESTL displayed dose-dependent ferric-reducing antioxidant power (FRAP) activity, scavenged DPPH radicals (IC50) = 13.52 ± 0.45 µg/mL), and inhibited lipid peroxidation in an in vitro models. In addition, the EESTL demonstrated dose-dependent inhibitory activity against α-amylase (IC50 =138.46 ± 3.97 µg/mL) and promoted glucose uptake across plasma membranes of yeast cells in a manner comparable to that of metformin. Interestingly, the extract demonstrated in vivo blood glucose normalization effects with concomitant increased activities of antioxidant parameters (superoxide dismutase (SOD), catalase, and reduced glutathione (GSH)) while decreasing malondialdehyde (MDA) levels when compared to untreated rats. Similarly, serum biochemical alterations, and tissues (liver, kidney, and pancreases) histopathological aberrations in untreated rats with STZ-induced diabetes were attenuated by treatment with the EESTL. Biometabolite characterization of the extract identified gallic acid (45.81 ppm), catechin (1.18 ppm), p-coumaric acid (1.43e-1 ppm), DL-proline 5-oxo-methyl ester (9.16 %, retention time (RT): 8.57 min), salicylic acid (3.26% and 7.61 min), and butylated hydroxytoluene (4.75%, RT: 10.18 min) as the major polyphenolic compounds in the plant extract. In conclusion, our study provides preclinical evidence of the antioxidant properties and oxidative stress-preventing role of S. torvum in STZ-dosed diabetic rats. Taken together, the EESTL represents a reserve of bioactive metabolites for managing diabetes and associated complications.

Preclinical anti-inflammatory and antioxidant effects of Azanza garckeana in STZ-induced glycemic-impaired rats, and pharmacoinformatics of it major phytoconstituents.

The quest for novel anti-diabetic medication from medicinal plants is very important since they contain bioactive phytochemicals that offer better activity and safety compared to conventional therapy. In the present study, in vitro, in vivo and in silico approaches were explored to evaluate the anti-inflammatory, antioxidants, and hypoglycemic activities of the crude methanol extract of Azanza garckeana pulp. Our in vitro analysis revealed that the extract contains total phenols (260.80 ±â€¯2.23 mg/100 g) and total flavonoids (10.28 ±â€¯1.29 mg/100 g) contents, and demonstrated dose-dependent in vitro antioxidants activities in; DPPH (IC50 =141.30 ±â€¯1.64 µg/mL), FRAP (IC50 =155.07 ±â€¯1.03 µg/mL), LPO (IC50 =184.96 ±â€¯2.01 µg/mL), and ABTS (IC50 =162.56 ±â€¯1.14 µg/mL) assays; anti-inflammatory activities in: membrane stabilization (IC50 =141.34 ±â€¯0.46 µg/mL), protein denaturation (IC50 =203.61 ±â€¯2.35 µg/mL) and proteinase activities (IC50=f 171.35 ±â€¯1.56 µg/mL) assays; and hypoglycemic activities in: α- amylase (IC50 277.85 ±â€¯2.51 µg/mL), and glucose uptake by yeast cells assays. In vivo analysis revealed that the extract exhibited dose-dependent anti-inflammatory, hypoglycemic activities and improved the weight gain in STZ-induced diabetic rats. In addition, the extract attenuated oxidative stress and increased the activities of SOD, catalase, GSH while depleting the level of LPO in STZ induced diabetic rats. Consequently, the liquid chromatography mass spectrometry (LC-MS) characterization of A. garckeana pulp, revealed the presence of 2-Hexadecen-1-ol,3,7,11,15-tetramethyl-,(2E,7 R,11 R)-, nonyl flavanone, testolactone and 6-(Benzyloxy)- 4,4-Dimethyl-2-Chromanone. These compounds were subjected to pharmacoinformatics analysis among which testolactone and 6-(Benzyloxy)- 4,4-Dimethyl-2-Chromanone demonstrated the best drug-likeness, pharmacokinetics, and also exhibited potential hypoglycemic and anti-inflammatory properties. Altogether, the present study provides preclinical evidence of the antioxidant, anti-inflammatory and antidiabetic activities of A. garckeana extract suggesting its potential applications for the development of alternative therapy for diabetes and its associated inflammatory condition.

Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome.

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.

A systematic review and meta-analysis of the associations between interparental and sibling relationships: Positive or negative?

According to family systems theory, a family is regarded as an organized whole and relations within this system are interconnected. However, it is not clear to date whether the interparental and the sibling relationship are associated and, if such an association exists, whether it is positive or negative. Previous findings on the associations between the interparental and sibling relationships are inconsistent and there is as yet no pertinent review or meta-analysis. Therefore, this systematic review and meta-analysis set out (1) to aggregate previous studies investigating the links between the interparental and sibling relationships and (2) to examine potential moderators in this link. Based on 47 studies reporting 234 effect sizes (N = 29,746 from six nations; 6-12 years; 49% boys), meta-analytic results suggest a small positive correlation between interparental and sibling relationship quality (r = .14). Only the percentage of male children in the sample moderated this effect. Sex composition of sibling dyad and source of publication affected whether positive or negative associations were found. The findings support a growing consensus that family relations do not function in isolation, but are mutually interdependent, which should be considered in clinical practice.

A Pilot Randomized Controlled Trial of Virtual Reality Distraction to Reduce Procedural Pain During Subcutaneous Port Access in Children and Adolescents With Cancer.

OBJECTIVES: We aimed to determine the feasibility of virtual reality (VR) distraction for children with cancer undergoing subcutaneous port (SCP) access. We also aimed to estimate preliminary treatment effects of VR compared with an active distraction control (iPad). MATERIALS AND METHODS: A single-site pilot randomized controlled trial comparing VR to iPad distraction was conducted. Eligible children and adolescents were aged 8 to 18 years undergoing treatment for cancer with upcoming SCP needle insertions. Intervention acceptability was evaluated by child, parent, and nurse self-report. Preliminary effectiveness outcomes included child-reported pain intensity, distress, and fear. Preliminary effectiveness was determined using logistic regression models with outcomes compared between groups using preprocedure scores as covariates. RESULTS: Twenty participants (mean age 12 y) were randomized to each group. The most common diagnosis was acute lymphocytic leukemia (n=23, 58%). Most eligible children and adolescents (62%) participated, and 1 withdrew after randomization to the iPad group. Nurses, parents, and children reported the interventions in both groups to be acceptable, with the VR participants reporting significantly higher immersion in the distraction environment (P=0.0318). Although not statistically significant, more VR group participants indicated no pain (65% vs. 45%) and no distress (80% vs. 47%) during the procedure compared with the iPad group. Fear was similar across groups, with ~60% of the sample indicating no fear. DISCUSSION: VR was feasible and acceptable to implement as an intervention during SCP access. Preliminary effectiveness results indicate that VR may reduce distress and distress compared with iPad distraction. These data will inform design of a future full-scale randomized controlled trial.

The iCanCope pain self-management application for adolescents with juvenile idiopathic arthritis: a pilot randomized controlled trial.

OBJECTIVES: To evaluate the feasibility and preliminary effectiveness of iCanCope with Pain (iCanCope), a smartphone-based pain self-management program, in adolescents with JIA. iCanCope featured symptom tracking, goal-setting, pain coping skills and social support. METHODS: A two-arm pilot randomized controlled trial was used to evaluate the iCanCope app compared with a version with symptom tracking only. Primary (feasibility) outcomes were: participant accrual/attrition rates, success of app deployment, acceptability and adherence. Secondary (preliminary effectiveness) outcomes were: pain intensity, pain-related activity limitations and health-related quality of life. Outcomes were assessed at baseline and 8 weeks. Adherence was defined as the proportion of completed symptom reports: 'low' (≤24%); 'low-moderate' (25-49%); 'high-moderate' (50-75%); or 'high' (76-100%). Linear mixed models were applied for preliminary effectiveness analyses as per intention-to-treat. RESULTS: Adolescents (N = 60) were recruited from three paediatric rheumatology centres. Rates of accrual and attrition were 82 and 13%, respectively. Both apps were deployed with high success (over 85%) and were rated as highly acceptable. Adherence was similar for both groups, with most participants demonstrating moderate-to-high adherence. Both groups exhibited a clinically meaningful reduction in pain intensity (≥1 point) that did not statistically differ between groups. There were no significant changes in activity limitations or health-related quality of life. CONCLUSION: The iCanCope pilot randomized controlled trial was feasible to implement in a paediatric rheumatology setting. Both apps were deployed successfully, with high acceptability, and were associated with moderate-to-high adherence. Preliminary reductions in pain intensity warrant a future trial to evaluate effectiveness of iCanCope in improving health outcomes in adolescents with JIA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02764346.

Teens Taking Charge: A Randomized Controlled Trial of a Web-Based Self-Management Program With Telephone Support for Adolescents With Juvenile Idiopathic Arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a serious and potentially debilitating pediatric illness. Improved disease self-management may help to improve health outcomes. OBJECTIVE: This study aimed to evaluate the effectiveness of the Teens Taking Charge Web-based self-management intervention in reducing symptoms and improving health-related quality of life (HRQL) in adolescents with JIA compared with a Web-based education control condition. METHODS: Adolescents with JIA aged 12 to 18 years were recruited from 11 Canadian pediatric rheumatology centers. Caregivers were invited to participate along with their child. In addition to standard medical care, participants were randomized to receive either (1) the Teens Taking Charge self-management intervention or (2) a Web-based education control condition for a period of 12 weeks. Adolescents in the intervention group completed website modules addressing cognitive behavioral coping skills, stress management, and other self-management topics, while also receiving monthly telephone calls from a trained health coach. Adolescents in the education control group were instructed to view a series of preselected public JIA educational websites and received monthly calls from a coach who asked about their own best efforts at managing JIA. Caregivers in the intervention group completed website modules related to promoting independence and disease self-management in their child. Caregivers in the education control group were instructed to view a series of preselected public JIA educational websites. Outcome assessment occurred at baseline, 12 weeks (posttreatment), and at 6 and 12 months postrandomization. The primary outcomes were pain intensity, pain interference, and HRQL. Secondary outcomes were emotional symptoms, adherence, coping, knowledge, and self-efficacy. RESULTS: In total, 333 adolescents and 306 caregivers were enrolled. Significant overall reductions in pain intensity (P=.02) and pain interference (P=.007) were observed for intervention group participants compared with those in the education control group, after adjusting for baseline levels. There was a significant overall improvement in HRQL related to problems with pain (P=.02) and problems with daily activities (P=.01). There was also a significant difference in the intervention group over time (P=.008) for HRQL related to treatment problems, with the intervention group participants demonstrating improved HRQL by 12 months compared with education control group participants. Both groups showed nonsignificant improvements compared with baseline in other primary outcomes. There were no significant differences between the groups in any secondary outcomes or caregiver-reported outcomes. CONCLUSIONS: The results of this randomized trial suggest that the Teens Taking Charge Web-based intervention is effective at reducing both pain intensity and pain interference, as well as improving HRQL in adolescents with JIA, compared with education control. These effects are sustained for up to 12 months following program completion. The Teens Taking Charge program is now publicly available at no cost. TRIAL REGISTRATION: ClinicalTrials.gov NCT01572896; https://clinicaltrials.gov/ct2/show/NCT01572896.

Atovaquone is active against AML by upregulating the integrated stress pathway and suppressing oxidative phosphorylation.

Atovaquone, a US Food and Drug Administration-approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 to 80 µM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 <30 µM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2α, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2α led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML.

Sustained remission with azacitidine monotherapy and an aberrant precursor B-lymphoblast population in juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) has a poor prognosis in general, with hematopoietic stem cell transplant (HSCT) remaining the standard of care for cure. The hypomethylating agent, azacitidine, has been used as a bridging therapy to transplant. However, no patients have been treated with azacitidine without an HSCT post azacitidine. We report on an infant with JMML with somatic KRAS G12A mutation and monosomy 7 who achieved sustained remission following azacitidine monotherapy. He also developed an aberrant B-lymphoblast population which declined with similar kinetics as his JMML-associated abnormalities, suggesting that a B-lymphoblast population in JMML does not always progress to acute leukemia.

A clinicopathologic study of the spectrum of systemic forms of EBV-associated T-cell lymphoproliferative disorders of childhood: A single tertiary care pediatric institution experience in North America.

BACKGROUND: Systemic forms of EBV-associated T-cell lymphoproliferative disorders of childhood (S-EBV-T-LPD) comprise three major forms: EBV-positive hemophagocytic lymphohistiocytosis (EBV-HLH), systemic EBV-positive T-cell lymphoma (S-EBV-TCL), and systemic chronic active EBV infection (S-CAEBV). These disorders occur rarely in children in Western countries. Here, we described eight children of such entities. DESIGN: Eight cases (six clinical and two autopsy) with S-EBV-T-LPD of childhood were retrospectively identified from 1990 to 2015. Clinicopathologic parameters including histomorphology, immunophenotype, EBV studies, and T-cell receptor gene rearrangement studies were recorded. RESULTS: Patients include five females and three males of Hispanic, Asian, and Caucasian origins with an age range of 14 months to 9 years. Fever, hepatosplenomegaly, cytopenias, abnormal EBV serologies, and very high EBV viral loads were common findings. Histologic findings showed EBV+ T-cell infiltrates with variable degrees of architectural distortion and cytologic atypia ranging from no to mild cytologic atypia to overt lymphoma and tissue hemophagocytosis. All showed aberrant CD4+ or CD8+ T cells with dim to absent CD5, CD7, and CD3, and bright CD2 and CD45 by flow cytometry or loss of CD5 by immunohistochemistry. TCR gene rearrangement studies showed monoclonal rearrangements in all clinical cases (6/6). Outcomes were poor with treatment consisting of chemotherapy per the HLH-94 or HLH-2004 protocols with or without bone marrow transplant. CONCLUSION: In this large pediatric clinicopathologic study of S-EBV-T-LPD of childhood in the United States, EBV-HLH, S-EBV-TCL, and S-CAEBV show many overlapping features. Diagnosis is challenging, and overall outcome is poor using current HLH-directed therapies.

Recommendations for selection of self-report pain intensity measures in children and adolescents: a systematic review and quality assessment of measurement properties.

In 2006, PAIN published a systematic review of the measurement properties of self-report pain intensity measures in children and adolescents (Stinson JN, Kavanagh T, Yamada J, Gill N, Stevens B. Systematic review of the psychometric properties, interpretability and feasibility of self-report pain intensity measures for use in clinical trials in children and adolescents. PAIN 2006;125:143-57). Key developments in pediatric pain necessitate an update of this work, most notably growing use of the 11-point numeric rating scale (NRS-11). Our aim was to review the measurement properties of single-item self-report pain intensity measures in children 3 to 18 years old. A secondary aim was to develop evidence-based recommendations for measurement of child and adolescent self-report of acute, postoperative, and chronic pain. Methodological quality and sufficiency of measurement properties for reliability, validity, responsiveness, and interpretability was assessed by at least 2 investigators using COnsensus based Standards for the selection of health Measurement INstruments (COSMIN). Searches identified 60 unique self-report measures, of which 8 (reported in 80 papers) met inclusion criteria. Well-established measures included the NRS-11, Color Analogue Scale (CAS), Faces Pain Scale-Revised (FPS-R; and original FPS), Pieces of Hurt, Oucher-Photographic and Numeric scales, Visual Analogue Scale, and Wong-Baker FACES Pain Rating Scale (FACES). Quality of studies ranged from poor to excellent and generally reported sufficient criterion and construct validity, and responsiveness, with variable reliability. Content and cross-cultural validity were minimally assessed. Based on available evidence, the NRS-11, FPS-R, and CAS were strongly recommended for self-report of acute pain. Only weak recommendations could be made for self-report measures for postoperative and chronic pain. No measures were recommended for children younger than 6 years, identifying a need for further measurement refinement in this age range. Clinical practice and future research implications are discussed.

iCanCope with Sickle Cell Pain: Design of a randomized controlled trial of a smartphone and web-based pain self-management program for youth with sickle cell disease.

Many adolescents with sickle cell disease (SCD) experience recurrent and chronic pain, which has a negative impact on their health-related quality of life (HRQL). Cognitive-behavioral therapy (CBT) interventions can lead to improvement in pain and HRQL, yet due to barriers to care, most youth with SCD will not receive these interventions. To address this need for innovative programs targeting youth with SCD pain, we developed iCanCope, a tailored smartphone and web-based program that delivers a pain self-management intervention to youth with SCD. We describe the rationale, design, and implementation of a three-site parallel group randomized controlled trial with a sample of 160 adolescents with SCD and their parent caregivers. The iCanCope program includes pain self-management skills training (personalized CBT-based coping skills such as deep breathing, relaxation, and cognitive skills), goal setting, and social support. The attention control group is provided with access to a self-guided website with education about SCD. Assessments will occur at baseline (T1), immediately after completion of the intervention (12 weeks; T2) and at 6 months post-intervention (T3). Primary outcomes include coping strategies and pain intensity; secondary outcomes include physical, social, and emotional functioning, treatment satisfaction, health service use and caregiver response to youth pain behavior. Potential mediators (goal setting, self-management, and perceptions of social support) and moderators (e.g., demographic factors) will also be tested. The objective is to offer an effective, convenient, and low-cost psychosocial intervention to youth with SCD to enhance their self-management of pain.

Social Media Content About Children's Pain and Sleep: Content and Network Analysis.

BACKGROUND: Social media is often used for health communication and can facilitate fast information exchange. Despite its increasing use, little is known about child health information sharing and engagement over social media. OBJECTIVE: The primary objectives of this study are to systematically describe the content of social media posts about child pain and sleep and identify the level of research evidence in these posts. The secondary objective is to examine user engagement with information shared over social media. METHODS: Twitter, Instagram, and Facebook were searched by members of the research team over a 2-week period using a comprehensive search strategy. Codes were used to categorize the content of posts to identify the frequency of content categories shared over social media platforms. Posts were evaluated by content experts to determine the frequency of posts consistent with existing research evidence. User engagement was analyzed using Netlytic, a social network analysis program, to examine visual networks illustrating the level of user engagement. RESULTS: From the 2-week period, nearly 1500 pain-related and 3800 sleep-related posts were identified and analyzed. Twitter was used most often to share knowledge about child pain (639/1133, 56.40% of posts), and personal experiences for child sleep (2255/3008, 75.00% of posts). For both topics, Instagram posts shared personal experiences (53/68, 78% pain; 413/478, 86.4% sleep), Facebook group posts shared personal experiences (30/49, 61% pain; 230/345, 66.7% sleep) and Facebook pages shared knowledge (68/198, 34.3% pain; 452/1026, 44.05% sleep). Across platforms, research evidence was shared in 21.96% (318/1448) of pain- and 9.16% (445/4857) of sleep-related posts; 5.38% (61/1133) of all pain posts and 2.82% (85/3008) of all sleep posts shared information inconsistent with the evidence, while the rest were absent of evidence. User interactions were indirect, with mostly one-way, rather than reciprocal conversations. CONCLUSIONS: Social media is commonly used to discuss child health, yet the majority of posts do not contain research evidence, and user engagement is primarily one-way. These findings represent an opportunity to expand engagement through open conversations with credible sources. Research and health care communities can benefit from incorporating specific information about evidence within social media posts to improve communication with the public and empower users to distinguish evidence-based content better. Together, these findings have identified potential gaps in social media communication that may be informative targets to guide future strategies for improving the translation of child health evidence over social media.

Development and Usability Evaluation of a Desktop Software Application for Pain Assessment in Infants.

BACKGROUND: Pain assessment is a key component of pain management and research in infants. We developed software to assist in coding of pain in infants called PAiN (Pain Assessment in Neonates). AIMS: The aims of this study were to evaluate the usability of PAiN in terms of effectiveness, efficiency, and satisfaction among novice and expert users and to compare the efficiency and satisfaction of PAiN to existing software for coding of infant pain among expert users. METHODS: A quantitative usability testing approach was conducted with two participant groups, representing novice and expert end-users. Testing included an observed session with each participant completing a pain assessment coding task, followed by administration of the Post Study System Usability Questionnaire and Desirability Toolkit. For comparison, the usability of existing coding software was also evaluated by the expert group. RESULTS: Twelve novice and six expert users participated. Novice users committed 14 noncritical navigational errors, and experts committed six. For experts, the median time for completing the coding task was 28.6 min in PAiN, compared to 46.5 min using the existing software. The mean Post Study System Usability Questionnaire score among novice (1.89) and expert users (1.40) was not significantly different (P = 0.0917). Among experts, the score for the existing software (4.83) was significantly (P = 0.0277) higher compared to PAiN (1.40). Lower scores indicate more positive responses. CONCLUSIONS: Users were highly satisfied with PAiN. Experts were more efficient with PAiN compared to the existing software. The study was critical to ensuring that PAiN is error free and easy to use prior to implementation.

Contexte: L'évaluation de la douleur est une composante clé de la prise en charge et de la recherche sur la douleur chez les nourrissons. Nous avons développé un logiciel pour aider à codifier la douleur chez les nourrissons appelé PaiN (Pain Assessment in Neonates).But: Évaluer l'utilisabilité de PaiN en termes d'efficacité, d'efficience et de satisfaction auprès d'utilisateurs novices et experts, et comparer l'efficacité de PaiN et la satisfaction d'utilisateurs experts au logiciel existant pour la codification de la douleur chez les nourrissons.Méthodes: Une étude quantitative pour tester l'utilisabilité a été menée auprès de deux groupes de participants, représentant des utilisateurs finaux novices et experts. Le test comprenait l'observation d'une session où chaque participant devait effectuer une tâche de codification de l'évaluation de la douleur, suivie de l'administration du Post Study System Usability Questionnaire et du Desirability Toolkit. À des fins de comparaison, l'utilisabilité d'un logiciel de codification existant a aussi été évaluée par le groupe expert.Résultats: Douze utilisateurs novices et six utilisateurs experts ont participé à l'étude. Les utilisateurs novices ont commis 14 erreurs de navigation non critiques, tandis que les experts en ont commis six. Pour les experts, le temps médian pour effectuer la tâche de codification a été de 28,6 minutes pour PaiN, comparativement à 46,5 minutes lorsque le logiciel existant était utilisé. Le score moyen obtenu pour le Post Study System Usability Questionnaire chez les utilisateurs novices (1,89) et les utilisateurs experts (1,40) n'était pas significativement différent (p=0,0917). Parmi les experts, le score pour le logiciel existant (4,83) était significativement (p=0,0277) plus élevé comparativement à PaiN (1,40). Les scores plus faibles indiquent davantage de réponses positives.Conclusions: Les utilisateurs étaient très satisfaits de PaiN. Les experts ont été plus efficaces avec PaiN qu'avec le logiciel existant. L'étude était d'importance priomordiale pour s'assurer que PaiN ne contienne aucune erreur et soit facile d'utilisation avant sa mise en oeuvre.

Stress and the Emerging Roles of Chromatin Remodeling in Signal Integration and Stable Transmission of Reversible Phenotypes.

The influence of early life experience and degree of parental-infant attachment on emotional development in children and adolescents has been comprehensively studied. Structural and mechanistic insight into the biological foundation and maintenance of mammalian defensive systems (metabolic, immune, nervous and behavioral) is slowly advancing through the emerging field of developmental molecular (epi)genetics. Initial evidence revealed that differential nurture early in life generates stable differences in offspring hypothalamic-pituitary-adrenal (HPA) regulation, in part, through chromatin remodeling and changes in DNA methylation of specific genes expressed in the brain, revealing physical, biochemical and molecular paths for the epidemiological concept of gene-environment interactions. Herein, a primary molecular mechanism underpinning the early developmental programming and lifelong maintenance of defensive (emotional) responses in the offspring is the alteration of chromatin domains of specific genomic regions from a condensed state (heterochromatin) to a transcriptionally accessible state (euchromatin). Conversely, DNA methylation promotes the formation of heterochromatin, which is essential for gene silencing, genomic integrity and chromosome segregation. Therefore, inter-individual differences in chromatin modifications and DNA methylation marks hold great potential for assessing the impact of both early life experience and effectiveness of intervention programs-from guided psychosocial strategies focused on changing behavior to pharmacological treatments that target chromatin remodeling and DNA methylation enzymes to dietary approaches that alter cellular pools of metabolic intermediates and methyl donors to affect nutrient bioavailability and metabolism. In this review article, we discuss the potential molecular mechanism(s) of gene regulation associated with chromatin modeling and programming of endocrine (e.g., HPA and metabolic or cardiovascular) and behavioral (e.g., fearfulness, vigilance) responses to stress, including alterations in DNA methylation and the role of DNA repair machinery. From parental history (e.g., drugs, housing, illness, nutrition, socialization) to maternal-offspring exchanges of nutrition, microbiota, antibodies and stimulation, the nature of nurture provides not only mechanistic insight into how experiences propagate from external to internal variables, but also identifies a composite therapeutic target, chromatin modeling, for gestational/prenatal stress, adolescent anxiety/depression and adult-onset neuropsychiatric disease.

Interleukin-6 levels predict event-free survival in pediatric AML and suggest a mechanism of chemotherapy resistance.

The tumor microenvironment can protect cancer cells from conventional anticancer therapies. Thus, targeting these protective mechanisms could eradicate therapy-resistant cancer cells and improve outcomes. Interleukin-6 (IL-6) provides extrinsic protection for several solid tumors and multiple myeloma. In pediatric acute myeloid leukemia (AML), IL-6-induced STAT3 signaling frequently becomes stronger at relapse, and increases in IL-6-induced STAT3 activity are associated with inferior survival after relapse. These findings suggested that the IL-6-induced STAT3 pathway may promote chemotherapy resistance and disease progression. Thus, we investigated the dysregulation of IL-6 levels in the bone marrow niche in pediatric patients with AML and the association between IL-6 levels and outcome. We measured levels of over 40 cytokines and growth factors in plasma from diagnostic bone marrow aspirates of 45 pediatric AML patients and 7 healthy sibling controls. Of the measured cytokines, only IL-6 levels were associated with event-free survival. Importantly, the effect of elevated IL-6 was most striking among children classified as having a low risk of relapse. In these patients, 5-year event-free survival was 82.5% ± 11% for patients with low IL-6 levels at diagnosis (n = 14) compared with 17.3% ± 11% for patients with elevated IL-6 (n = 13, log-rank P = .0003). In vitro, exogenous IL-6 reduced mitoxantrone-induced apoptosis in cell lines and primary pediatric AML samples. These results suggest that IL-6 levels at diagnosis could be used to help identify children at high risk of relapse, particularly those who are otherwise classified as low risk by current algorithms. Moreover, the IL-6 pathway could represent a target for overcoming environment-mediated chemotherapy resistance.