Efficacy and safety of recombinant human thrombopoietin for the treatment of chronic primary immune thrombocytopenia in children and adolescents: A multicentre, randomized, double-blind, placebo-controlled phase III trial.

The efficacy and safety of recombinant human thrombopoietin (rhTPO) in children and adolescent patients with chronic primary immune thrombocytopenia (ITP) remains unclear. A multicentre, randomized, double-blind, placebo-controlled phase III trial was performed. Patients aged 6-17 years, diagnosed with ITP and resistant or relapsed to corticosteroid treatment were included. For the trial, part 1 was exploratory and part 2 was the main analysis, with part 1 determining whether part 2 was stratified by age. Patients in part 1 were treated with rhTPO (the 6- to 11-/12- to 17-year-old groups; 1:1). Patients in part 2 were randomized (3:1) to receive either rhTPO treatment or placebo. Patients received rhTPO or placebo at a dose of 300 U/kg once daily for up to 14 days. A total of 68 patients were included [part 1 (12 patients), part 2 (56 patients)]. The total response rate (TRR) in part 1 was 50.0% (95% CI: 21.09%-78.91%). For part 2, the TRR was 58.5% (95% CI: 42.11%-73.68%) and 13.3% (95% CI: 1.66%-40.46%) in the rhTPO and placebo groups (FAS) respectively. The difference in TRR between the rhTPO group and placebo group was 45.2% (95% CI: 22.33%-68.08%) and 44.6% (95% CI: 21.27%-67.85%) on the FAS and per-protocol set (PPS), respectively, which indicates the superiority of rhTPO treatment.

Haematopoietic stem cell transplantation after reduced intensity conditioning in children and adolescents with chronic myeloid leukaemia: A prospective multicentre trial of the I-BFM Study Group.

This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty-two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first- or second-generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1-guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second-year post-transplant. All patients engrafted. The 1-year transplant-related mortality was 3% (confidence interval [CI]: 0%-6%). After a median follow-up of 6.3 years, 5-year overall survival and event-free survival are 97% (CI: 93%-100%) and 91% (CI: 79%-100%) respectively. The current 5-year leukaemia-free survival with BCR::ABL1 <0.01% is 97% (CI: 88%-100%) and the current TKI- and DLI-free survival is 95% (CI: 85%-100%). The incidence of chronic graft-versus-host disease (GvHD) was 32%, being severe in four patients (13%). At last follow-up, 31 patients are GvHD-free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP-CML with an excellent disease-free and TKI-free survival.

The neural and genetic underpinnings of different developmental trajectories of Attention-Deficit/Hyperactivity Symptoms in children and adolescents.

BACKGROUND: The trajectory of attention-deficit hyperactivity disorder (ADHD) symptoms in children and adolescents, encompassing descending, stable, and ascending patterns, delineates their ADHD status as remission, persistence or late onset. However, the neural and genetic underpinnings governing the trajectory of ADHD remain inadequately elucidated. METHODS: In this study, we employed neuroimaging techniques, behavioral assessments, and genetic analyses on a cohort of 487 children aged 6-15 from the Children School Functions and Brain Development project at baseline and two follow-up tests for 1 year each (interval 1: 1.14 ± 0.32 years; interval 2: 1.14 ± 0.30 years). We applied a Latent class mixed model (LCMM) to identify the developmental trajectory of ADHD symptoms in children and adolescents, while investigating the neural correlates through gray matter volume (GMV) analysis and exploring the genetic underpinnings using polygenic risk scores (PRS). RESULTS: This study identified three distinct trajectories (ascending-high, stable-low, and descending-medium) of ADHD symptoms from childhood through adolescence. Utilizing the linear mixed-effects (LME) model, we discovered that attention hub regions served as the neural basis for these three developmental trajectories. These regions encompassed the left anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), responsible for inhibitory control; the right inferior parietal lobule (IPL), which facilitated conscious focus on exogenous stimuli; and the bilateral middle frontal gyrus/precentral gyrus (MFG/PCG), accountable for regulating both dorsal and ventral attention networks while playing a crucial role in flexible modulation of endogenous and extrinsic attention. Furthermore, our findings revealed that individuals in the ascending-high group exhibited the highest PRS for ADHD, followed by those in the descending-medium group, with individuals in the stable-low group displaying the lowest PRS. Notably, both ascending-high and descending-medium groups had significantly higher PRS compared to the stable-low group. CONCLUSIONS: The developmental trajectory of ADHD symptoms in the general population throughout childhood and adolescence can be reliably classified into ascending-high, stable-low, and descending-medium groups. The bilateral MFG/PCG, left ACC/mPFC, and right IPL may serve as crucial brain regions involved in attention processing, potentially determining these trajectories. Furthermore, the ascending-high pattern of ADHD symptoms exhibited the highest PRS for ADHD.

Evidence linking COVID-19 and the health/well-being of children and adolescents: an umbrella review.

BACKGROUND: Experiences during childhood and adolescence have enduring impacts on physical and mental well-being, overall quality of life, and socioeconomic status throughout one's lifetime. This underscores the importance of prioritizing the health of children and adolescents to establish an impactful healthcare system that benefits both individuals and society. It is crucial for healthcare providers and policymakers to examine the relationship between COVID-19 and the health of children and adolescents, as this understanding will guide the creation of interventions and policies for the long-term management of the virus. METHODS: In this umbrella review (PROSPERO ID: CRD42023401106), systematic reviews were identified from the Cochrane Database of Systematic Reviews; EMBASE (OvidSP); and MEDLINE (OvidSP) from December 2019 to February 2023. Pairwise and single-arm meta-analyses were extracted from the included systematic reviews. The methodological quality appraisal was completed using the AMSTAR-2 tool. Single-arm meta-analyses were re-presented under six domains associated with COVID-19 condition. Pairwise meta-analyses were classified into five domains according to the evidence classification criteria. Rosenberg's FSN was calculated for both binary and continuous measures. RESULTS: We identified 1551 single-arm and 301 pairwise meta-analyses from 124 systematic reviews that met our predefined criteria for inclusion. The focus of the meta-analytical evidence was predominantly on the physical outcomes of COVID-19, encompassing both single-arm and pairwise study designs. However, the quality of evidence and methodological rigor were suboptimal. Based on the evidence gathered from single-arm meta-analyses, we constructed an illustrative representation of the disease severity, clinical manifestations, laboratory and radiological findings, treatments, and outcomes from 2020 to 2022. Additionally, we discovered 17 instances of strong or highly suggestive pairwise meta-analytical evidence concerning long-COVID, pediatric comorbidity, COVID-19 vaccines, mental health, and depression. CONCLUSIONS: The findings of our study advocate for the implementation of surveillance systems to track health consequences associated with COVID-19 and the establishment of multidisciplinary collaborative rehabilitation programs for affected younger populations. In future research endeavors, it is important to prioritize the investigation of non-physical outcomes to bridge the gap between research findings and clinical application in this field.

More than a Nuisance: Implications of Food Marketing for Public Health Efforts to Curb Childhood Obesity.

Fifteen years ago, public health experts urged industry, governments, and advocates to take action to dramatically improve the unhealthy food-marketing environment surrounding children in order to address the global childhood obesity crisis. Since then, research has confirmed that food marketing to children has far-reaching negative effects on their diets and health, takes advantage of adolescent vulnerabilities, and contributes to health disparities. In addition, digital marketing has profoundly changed young people's engagement with brands. Moreover, reliance on industry self-regulation as a solution has proven ineffective. Government-led policies have been more successful, but they remain limited in scope and challenging to adopt and implement. New approaches are necessary to increase public and policy maker awareness that food marketing is more than a nuisance, that it threatens the long-term health of children and adolescents worldwide, and that meaningful governmental action is urgently required to curtail industry's negative impact on young people's well-being.

Long-term risk of mortality and loss to follow-up in children and adolescents on antiretroviral therapy in Asia.

OBJECTIVE: We described mortality and loss to follow-up (LTFU) in children and adolescents who were under care for more than 5 years following initiation of antiretroviral therapy (ART). METHODS: Patients were followed from 5 years after ART until the earlier of their 25th birthday, last visit, death, or LTFU. We used Cox regression to assess predictors of mortality and competing risk regression to assess factors associated with LTFU. RESULTS: In total, 4488 children and adolescents initiating ART between 1997 and 2016 were included in the analysis, with a median follow-up time of 5.2 years. Of these, 107 (2.2%) died and 271 (6.0%) were LTFU. Mortality rate was 4.35 and LTFU rate 11.01 per 1000 person-years. Increased mortality was associated with AIDS diagnosis (adjusted hazard ratio [aHR] 1.71; 95% confidence interval [CI] 1.24-2.37), current CD4 count <350 cells/mm3 compared with ≥500 (highest aHR 13.85; 95% CI 6.91-27.76 for CD4 <200), viral load ≥10 000 copies/mL compared with <400 (aHR 3.28; 95% CI 1.90-5.63), and exposure to more than one ART regimen (aHR 1.51; 95% CI 1.14-2.00). Factors associated with LTFU were male sex (adjusted subdistribution hazard ratio [asHR] 1.29; 95% CI 1.04-1.59), current viral load >1000 copies/mL compared with <400 (highest asHR 2.36; 95% CI 1.19-4.70 for viral load 1000-9999), and ART start after year 2005 compared with ≤2005 (highest asHR 5.96; 95% CI 1.98-17.91 for 2010-2016). CONCLUSION: For children and adolescents surviving 5 years on ART, both current CD4 and viral load remained strong indicators that help to keep track of their treatment outcomes. More effort should be made to monitor patients who switch treatments.

Psychotropic Medication Use and Polypharmacy Among Children and Adolescents Initiating Intensive Behavioral Therapy for Severe Challenging Behavior.

OBJECTIVE: To evaluate the prevalence, trends, and factors associated with psychotropic medication use and polypharmacy among children and adolescents initiating intensive behavioral therapy for severe challenging behavior over a 10-year period. STUDY DESIGN: In this retrospective observational study, we examined data from caregiver interviews and patient medical records on the number and types of psychotropic medications prescribed to patients initiating intensive behavioral therapy between January 1, 2013, and December 31, 2022. Trends in medication use and polypharmacy across the 10-year period were analyzed using regression analysis, while differences in demographics and clinical factors for patients with use and polypharmacy were analyzed using nonparametric statistical analysis with odds ratios presented for significant factors. RESULTS: Data from all 302 pediatric patients initiating intensive behavioral therapy across the 10-year period were analyzed. Among all patients and all years, 83.8% were taking at least 1 psychotropic medication and 68.2% experienced polypharmacy. There were no changes in the prevalence of use, mean number of medications taken, or polypharmacy across the 10-year period. Patients diagnosed with attention-deficit/hyperactivity disorder or anxiety disorder, as well as those exhibiting self-injurious behavior had higher use of psychotropic medication and polypharmacy and were taking more medications overall. CONCLUSIONS: Psychotropic medication use and polypharmacy were extremely high for children and adolescents with severe challenging behavior, but use and polypharmacy did not change over the 10-year period of data collection. Further research is needed to establish the generality of these findings to other regions of the US.

Breastfeeding Duration and Cardiometabolic Health during Adolescence: A Longitudinal Analysis.

OBJECTIVE: To investigate the longitudinal association between breastfeeding duration and cardiometabolic health, using repeated measures study design among children and adolescents. STUDY DESIGN: This study included 634 offsprings aged 10 to 21 years (52% female) from the Early Life Exposure in Mexico to Environmental Toxicants birth cohort followed up to four time points during adolescence. Breastfeeding duration was prospectively quantified using questionnaires during early childhood. Cardiometabolic risk factors, body composition, and weight-related biomarkers were assessed as outcomes during adolescent follow-up visits. Sex-stratified linear mixed-effects models were used to model the association between quartiles of breastfeeding duration and outcomes, adjusting for age and additional covariates. RESULTS: Median breastfeeding duration was 7 months (minimum = 0, maximum = 36). Boys in the second quartile (median breastfeeding = 5 months) had lower total fat mass % (ß (SE) -3.2 (1.5) P = .037), and higher lean mass % (3.1 (1.6) P = .049) and skeletal muscle mass % (1.8 (0.8) P = .031) compared with the reference group (median breastfeeding = 2 months). A positive linear trend between breastfeeding duration and trunk lean mass % (0.1 (0.04) P = .035) was found among girls. No association was found with other cardiometabolic indicators. CONCLUSION: Despite sex-specific associations of breastfeeding duration with body composition, there was a lack of substantial evidence for the protective effects of breastfeeding against impaired cardiometabolic health during adolescence among Mexican youth. Further longitudinal studies with a robust assessment of breastfeeding are recommended.

International disease burden of acute viral hepatitis among adolescents and young adults: An observational study.

Adolescents and young adults are the driving force of social development, and the prevalence of acute viral hepatitis (AVH) in this population cannot be ignored. At present, there are few studies on the disease burden of AVH in this age group, and most studies focus on chronic liver disease. In this study, we identified global trends in the burden of AVH among adolescents and young adults (15-29) to help policymakers implement precise disease interventions. In this observational study of disease trends, we collected data exclusively from the Global Burden of Disease (GBD) 2019 study. This study examined the trends in the prevalence, incidence and mortality of AVH among adolescents and young adults in 21 regions of the world from 2009 to 2019. Age-specific disease trends were analysed with a joinpoint regression model. The overall global disease burden of AVH declined. The prevalence rate per 100,000 people decreased from 316.13 in 2009 to 198.79 in 2019, the incidence rate decreased from 3245.52 in 2009 to 2091.93 in 2019, and the death rate decreased from 0.87 in 2009 to 0.43 in 2019. During the study period, the prevalence of hepatitis B virtues (HBV) in the young population decreased, but the downward trend of other types of hepatitis other than HBV was not obvious, especially HAV, which even showed an upward trend. Among adolescents and young adults aged 15-29 years, Western Saharan Africa had the highest prevalence of AVH in 2019. There were significant differences in mortality rates among different age groups; 20-24 was the age group with the highest mortality rate from 2009 to 2019, followed by the 15-19 and 25-29 age groups. Although the overall global AVH disease burden declined, some causes of AVH, such as HAV, showed an upward trend during the study period. In addition, the prevalence of AVH among adolescents and young adults in Asia and Africa was higher than that in other parts of the world and warrants more attention. Finally, more research should be conducted on mortality in the 20-24 age group.

Repeated Low-Level Red Light Therapy for Myopia Control in High Myopia Children and Adolescents: A Randomized Clinical Trial.

PURPOSE: To assess the effectiveness and safety of repeated low-level red light (RLRL), which is a newly available treatment for myopia control in children and adolescents with high myopia. DESIGN: Multicenter, randomized, parallel-group, single-blind clinical trial (randomized controlled trial; NCT05184621). PARTICIPANTS: Between February 2021 and April 2022, 192 children aged 6 to 16 years were enrolled. Each child had at least 1 eye with myopia of cycloplegic spherical equivalent refraction (SER) at least -4.0 diopters (D), astigmatism of ≤2.0 D, anisometropia of ≤3.0 D, and best-corrected visual acuity (BCVA) of 0.2 logarithm of the minimum angle of resolution or better. Follow-up was completed by April 2023. METHODS: Participants were randomly assigned at a 1:1 ratio to intervention (RLRL treatment plus single-vision spectacles) or control (single-vision spectacles) groups. The RLRL treatment was administered for 3 minutes per session, twice daily with a minimum interval of 4 hours, 7 days per week. MEAN OUTCOME MEASURES: The primary outcome and key secondary outcome were changes in axial length (AL) and cycloplegic SER measured at baseline and the 12-month follow-up visit. Participants who had at least 1 postrandomization follow-up visit were analyzed for treatment efficacy. RESULTS: Among 192 randomized participants, 188 (97.91%) were included in the analyses (96 in the RLRL group and 92 in the control group). After 12 months, the adjusted mean change in AL was -0.06 mm (95% confidence interval [CI], -0.10 to -0.02 mm) and 0.34 mm (95% CI, 0.30 to 0.39 mm) in the intervention and control groups, respectively. A total of 48 participants (53.3%) in the intervention group were still experiencing axial shortening >0.05 mm at the 12-month follow-up. The mean SER change after 12 months was 0.11 D (95% CI, 0.02to 0.19 D) and -0.75 D (95% CI, -0.88 to -0.62 D) in the intervention and control groups, respectively. CONCLUSIONS: Repeated low-level red light demonstrates stronger treatment efficacy among those with high myopia, with 53.3% experiencing substantial axial shortening. Repeated low-level red light provides an excellent solution for the management of high myopia progression, a significant challenge in ophthalmology practice. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Reference values for exhaled nitric oxide in healthy children aged 6-18 years in China: a cross-sectional, multicenter clinical study.

BACKGROUND: The reference values of eNO have certain differences among people of different countries and races. We aimed to obtain the reference value of eNO in healthy children and adolescents (6-18 years old) in China and to explore the associations between the reference values with ages, gender, heights, BMI, and regions. METHODS: We measured FeNO50 levels in 5949 healthy Chinese children and adolescents, FeNO200 and CaNO levels in 658 participants from 16 provinces of 7 administrative areas in China aged 6-18. All persons were studied after obtaining informed consent from children and their parents. RESULTS: The mean FeNO50 of 5949 Chinese children and adolescents aged 6-18 years was 14.1 ppb, with a 95% confidence interval of 1-38.1 ppb. The mean FeNO200 of 658 persons was 6.9 ppb with a 95% upper confidence interval of 15.0 ppb, and the mean CaNO was 3.0 ppb with a 95% upper confidence interval of 11.2 ppb. In the 6-11 age group, age and height were correlated with the logarithm of FeNO50 (P < 0.001, P < 0.05). There was no significant correlation between the logarithm of FeNO200 and gender, age, height and BMI (all P > 0.05). The logarithm of CaNO was correlated with gender (P < 0.05). In the 12-18 age group, gender, height, and region were correlated with the logarithm of FeNO50 (all P < 0.001). There was only a weak correlation between the logarithm of FeNO200 and height (P < 0.001). The logarithm of CaNO was negatively correlated with age (P < 0.05). CONCLUSIONS: Higher FeNO50, FeNO200 and CaNO values were found in healthy children and adolescents in China compared with foreign reports, and is affected by age, height, gender, and region. This study provides useful references for clinical application of eNO in children, especially Asian children.

Evaluation of the Prime Diet Quality Score from Early Childhood Through Mid-Adolescence.

BACKGROUND: Few diet quality indices have been developed and validated for use among children and adolescents. Additionally, many available indices require completion of burdensome dietary assessments. OBJECTIVES: We aimed to calculate and evaluate the performance of a modified version of the food-based Prime Diet Quality Score (PDQS) derived from different diet assessment methods conducted at 4 time points in a single study population from childhood through adolescence. METHODS: Among 1460 child participants in the Project Viva cohort, we calculated the PDQS in early and mid-childhood and early and mid-adolescence using dietary data obtained from food frequency questionnaire (early childhood: parent report), PrimeScreen (mid-childhood: parent report; early adolescence: self-report) and 24-h recall (mid-adolescence: self-report). We evaluated construct and relative validity and internal reliability of the score in each life stage. RESULTS: The PDQS showed a range of scores at all life stages and higher scores were associated with intake of many health-promoting macronutrients and micronutrients (e.g., protein, fiber, and vitamins) in early childhood and mid-adolescence. The PDQS performed similarly to the Youth Healthy Eating Index/Healthy Eating Index (Spearman r = 0.63-0.85) in various assessments. Higher PDQS was associated with expected characteristics including more frequent breakfast eating, family dinners, and vigorous physical activity; with less frequent TV viewing and fast food intake; and with more sleep and higher maternal diet scores during pregnancy. Cross-sectional associations of the PDQS with various anthropometric measurements and biomarkers were inconsistent but generally in the expected directions (e.g., higher PDQS associated with lower triglycerides and insulin and higher HDL cholesterol). Internal reliability was consistent with what has been found for other diet quality indices. CONCLUSIONS: The PDQS can be calculated from data collected using different and brief dietary assessment methods and appears to be a valid and useful measure of overall diet quality in children and adolescents. Project Viva was registered at clinicaltrials.gov as NCT02820402.

The significance and prognostic value of multifocal papillary thyroid carcinoma in children and adolescents.

INTRODUCTION: The prognostic value of multifocality in paediatric papillary thyroid carcinoma (PTC) patients remains a subject of debate. This study aimed to explore the clinical significance and prognostic value of multifocality in children and adolescents with PTC. METHODS: This study retrospectively analysed the clinicopathological characteristics and postoperative follow-up data of 338 PTC patients aged ≤ 20 years from May 2012 to July 2022. The clinical and pathological characteristics of 205 patients with unifocal lesions and 133 patients with multifocal lesions were compared. A logistic regression model evaluated the relationship between multifocal lesions and disease recurrence/persistence in children and adolescents with PTC. Based on the median follow-up time of children with multifocal PTC, 114 patients with multifocal PTC older than 20 years were added, and the clinicopathological characteristics were compared between the 133. paediatric/adolescent patients and 114 adult patients with multifocal PTC. RESULTS: Among the paediatric and adolescent patients, over a median follow-up time of 49 months, 133 had multifocal disease and 205 had unifocal disease. Multifocal PTC patients exhibited stronger invasiveness in the form of extrathyroidal extension, tumour diameter, lymph node metastasis, and distant metastasis. Multifocality (OR 2.68; p = 0.017), lateral lymph node metastasis (OR 2.85; p = 0.036), and distant metastasis (OR 4.28; p = 0.010) were identified as independent predictive factors for the recurrence/persistence of disease. Comparing the paediatric/adolescent vs. adult multifocal patients, the former demonstrated greater tumour invasiveness. Lateral lymph node metastasis (OR 6.36; P = 0.012) and distant metastasis (OR 3.70; P = 0.027) were independent predictive factors for recurrence/persistence of disease in multifocal patients, while age was not (OR 0.95; P = 0.455). CONCLUSION: Tumour multifocality independently predicts persistent/recurrent disease in paediatric and adolescent PTC patients.

Identification and Replication of Urine Metabolites Associated With Short-Term and Habitual Intake of Sweet and Fatty Snacks in European Children and Adolescents.

BACKGROUND: Intake of sweet and fatty snacks may partly contribute to the occurrence of obesity and other health conditions in childhood. Traditional dietary assessment methods may be limited in accurately assessing the intake of sweet and fatty snacks in children. Metabolite biomarkers may aid the objective assessment of children's food intake and support establishing diet-disease relationships. OBJECTIVES: The present study aimed to identify biomarkers of sweet and fatty snack intake in 2 independent cohorts of European children. METHODS: We used data from the IDEFICS/I.Family cohort from baseline (2007/2008) and 2 follow-up examination waves (2009/2010 and 2013/2014). In total, 1788 urine samples from 599 children were analyzed for untargeted metabolomics using high-resolution liquid chromatography-mass spectrometry. Short-term dietary intake was assessed by 24-h dietary recalls, and habitual dietary intake was calculated with the National Cancer Institute method. Data from the Dortmund Nutritional and Anthropometric Longitudinal Designed (DONALD) cohort of 24-h urine samples (n = 567) and 3-d weighted dietary records were used for external replication of results. Multivariate modeling with unbiased variable selection in R algorithms and linear mixed models were used to identify novel biomarkers. Metabolite features significantly associated with dietary intake were then annotated. RESULTS: In total, 66 metabolites were discovered and found to be statistically significant for chocolate candy; cakes, puddings, and cookies; candy and sweets; ice cream; and crisps. Most of the features (n = 62) could not be annotated. Short-term and habitual chocolate intake were positively associated with theobromine, xanthosine, and cyclo(L-prolyl-L-valyl). These results were replicated in the DONALD cohort. Short-term candy and sweet intake was negatively associated with octenoylcarnitine. CONCLUSIONS: Of the potential metabolite biomarkers of sweet and fatty snacks in children, 3 biomarkers of chocolate intake, namely theobromine, xanthosine, and cyclo(L-prolyl-L-valyl), are externally replicated. However, these potential biomarkers require further validation in children.

Immune and oxidative stress biomarkers in pediatric psychosis and psychosis-risk: Meta-analyses and systematic review.

OBJECTIVE: While genetic and cohort studies suggest immune and reduction/oxidation (redox) alterations occur in psychosis, less is known about potential alterations in children and adolescents. METHODS: We conducted a systematic review to identify immune and redox biomarker studies in children and adolescents (mean age ≤ 18 years old) across the psychosis spectrum: from psychotic like experiences, which are common in children, to threshold psychotic disorders like schizophrenia. We conducted meta-analyses when at least three studies measured the same biomarker. RESULTS: The systematic review includes 38 pediatric psychosis studies. The meta-analyses found that youth with threshold psychotic disorders had higher neutrophil/lymphocyte ratio (Hedge's g = 0.40, 95 % CI 0.17 - 0.64), tumor necrosis factor (Hedge's g = 0.38, 95 % CI 0.06 - 0.69), C-reactive protein (Hedge's g = 0.38, 95 % CI 0.05 - 0.70), interleukin-6 (Hedge's g = 0.35; 95 % CI 0.11 - 0.64), and total white blood cell count (Hedge's g = 0.29, 95 % CI 0.12 - 0.46) compared to youth without psychosis. Other immune and oxidative stress meta-analytic findings were very heterogeneous. CONCLUSION: Results from several studies are consistent with the hypothesis that signals often classified as "proinflammatory" are elevated in threshold pediatric psychotic disorders. Data are less clear for immune markers in subthreshold psychosis and redox markers across the subthreshold and threshold psychosis spectrum. Immune and redox biomarker intervention studies are lacking, and research investigating interventions targeting the immune system in threshold pediatric psychosis is especially warranted.

Unmasking the mental health scars of COVID-19: A longitudinal investigation of children and adolescents in post-lockdown China.

The long-term mental health consequences of COVID-19 in children and adolescents remain unclear. We investigated the impact of COVID-19 infection on mental health after China's zero-COVID policy relaxation, focusing on symptom-specific and social-family risk factors for mental health issues in children and adolescents. In a longitudinal study, 8348 youths (aged 10-18) were assessed twice (T1: September to October 2022 and T2: April to May 2023). Mental health changes (Δ=T1-T2) were compared between COVID-19-infected (COVID+, n = 4108) and non-infected (COVID-, n = 4240). After balancing social-family confounding factors at T1 with propensity score-based inverse probability weights, multivariable logistic regression was employed to assess associations between COVID-19 infection and the onset/worsening of mental health symptoms. Multivariable logistic regression was conducted to explore specific acute COVID-19 symptoms and social-family risk factors associated with the onset/worsening of mental health symptoms in COVID + group. Compared to COVID- group, COVID + group exhibited lower overall mental health improvement (Δ). COVID + group was associated with increased risks of depression worsening (OR 1.20, 95 % CI 1.04-1.39), anxiety worsening (OR 1.30, 95 % CI 1.15-1.47), stress worsening (OR 1.23, 95 % CI 1.03-1.46), insomnia worsening (OR 1.21, 95 % CI 1.05-1.39), and emotional symptoms worsening (OR 1.72, 95 % CI 1.27-2.33). Moderate-to-severe difficulty thinking, breathlessness, and gastrointestinal symptoms were specific COVID-19 symptoms associated with worsening of various mental health outcomes. Furthermore, academic difficulties, economic disadvantages, family conflicts, food addiction, and alcohol consumption were identified as social-family risk factors for worsening mental health symptoms in COVID + youths. COVID-19 infection leaves lasting mental health scars in youths, extending beyond the acute phase. Specific symptoms, particularly cognitive dysfunction and respiratory/gastrointestinal distress play a significant role in this vulnerability. Social-family factors further modulate these effects, highlighting the need for comprehensive interventions that address both biological and psychosocial aspects. This study provides valuable insights for tailoring mental health support to youths navigating the consequences of the COVID-19 pandemic.

Predictors of drug-resistant epilepsy in childhood epilepsy syndromes: A subgroup analysis from a prospective cohort study.

OBJECTIVE: Previous studies assessing factors associated with drug-resistant epilepsy (DRE) were constrained by their amalgamation of all epilepsy syndromes in their analyses and the absence of uniform criteria for defining DRE. Our objective was to identify predictors of DRE among the four primary childhood epilepsy syndrome groups within a cohort of children with new onset seizures, using the International League Against Epilepsy (ILAE) definition of DRE and the recent classification of epilepsies. METHODS: This is a prospective study of 676 children with new onset seizures initiated on antiseizure medication. Patients were monitored for the occurrence of DRE according to the ILAE criteria and were categorized into one of four epilepsy groups: self-limited focal epilepsies (SeLFEs), genetic generalized epilepsies (GGEs), developmental epileptic encephalopathies (DEEs), and focal epilepsies. Cox regression analysis was performed to identify predictors of DRE within each epilepsy group. RESULTS: Overall, 29.3% of children were classified as having DRE, with the highest incidence observed among children diagnosed with DEEs (77.7%), followed by focal epilepsies (31.5%). Across the entire cohort, predictors of DRE included the presence of an epileptogenic lesion, a higher pretreatment number of seizures, experiencing multiple seizure types, presence and severity of intellectual and developmental delay, myoclonus, and younger age at epilepsy onset. Within the GGEs, only a younger age at seizure onset and experiencing multiple seizure types predicted DRE. Among focal epilepsies, predictors of DRE included the presence of an epileptogenic lesion, experiencing multiple seizure types, and having a greater number of pretreatment seizures. Within the DEEs, predictors of DRE were the occurrence of tonic seizures. Predictors of DRE within SeLFEs could not be identified. SIGNIFICANCE: This study indicates that different epilepsy syndromes are associated with distinct predictors of drug resistance. Anticipation of drug resistance within various groups is feasible using accessible clinical variables throughout the disease course.

Recent trends in hospital admission due to bipolar disorder in 10-19-year-olds in Spain: A nationwide population-based study.

INTRODUCTION: Bipolar disorder (BD) hospitalization rates in children and adolescents vary greatly across place and over time. There are no population-based studies on youth BD hospitalizations in Spain. METHODS: We identified all patients aged 10-19 hospitalized due to BD in Spain between 2000 and 2021, examined their demographic and clinical characteristics, and assessed temporal trends in hospitalizations - overall and stratified by age and presence of additional psychiatric comorbidity. We used Joinpoint regressions to identify inflection points and quantify whole-period and annual percentage changes (APCs) in trends. RESULTS: Of 4770 BD hospitalizations in 10-19-year-olds between 2000 and 2021 (average annual rate: 4.8 per 100,000), over half indicated an additional psychiatric comorbidity, most frequently substance abuse (62.2%), mostly due to cannabis (72.4%). During the study period, admissions increased twofold with an inflection point: Rates increased annually only between 2000 and 2008, for APCs 34.0% (95% confidence interval: 20.0%, 71.1%) among 10-14-year-olds, 10.3% (6.4%, 14.3%) among 15-19-year-olds, and 15.5% (11.5%, 22.7%) among patients with additional psychiatric comorbidity. Between 2009 and 2021, rates decreased moderately among 10-14-year-olds - APC: -8.3% (-14.1%, -4.4%) and slightly among 15-19-year-olds without additional psychiatric comorbidity - APC: -2.6(-5.7, -1.0), remaining largely stable among 15-19-year-olds overall. CONCLUSIONS: Recent trends in hospitalization due to BD in 10-19-year-olds in Spain indicate salient increases in the early 2000s - especially among (i) patients aged 10-14 (decreasing moderately after 2009 among 10-14-year-olds and plateauing among 15-19-year-olds) and (ii) patients with additional psychiatric comorbidity (i.e., cannabis use disorder). These findings suggest links with recent changes in clinical practices for children and recent trends in substance use among Spanish youth.

Therapeutic drug monitoring in children and adolescents with schizophrenia-spectrum, affective, behavioural, tic and other psychiatric disorders treated with aripiprazole: results of the TDM-VIGIL pharmacovigilance study.

Aripiprazole is approved for various severe mental disorders in adults and adolescents. However, off-label prescribing is common, especially in children and adolescents (youth) in whom aripiprazole therapeutic serum level reference ranges are lacking for any disorders. The aim of the study was to evaluate the relationship between aripiprazole dose and serum concentrations and provide further knowledge on the use of aripiprazole in order to improve drug safety and effectiveness in the treatment of minors. The clinical course of youth treated with aripiprazole in the multicentre pharmacovigilance study TDM-VIGIL was systematically followed and serum concentrations measured. Sex, age, weight and comedications were analysed to identify possible effect modifiers. A preliminary therapeutic reference range was estimated for youth with schizophrenia-spectrum disorders, affective disorders and behavioural/emotional/tic disorders coded as treatment responders based on a Clinical-Global Impressions-Improvement (CGI-I) score of much or very much improved. In 93 youth (mean age = 15.2 ± 2.6, range = 7.4-18.2 years, females = 53%, CGI-Severity = 4.4 ± 1.1, responders = 64%), a positive, moderate correlation between the weight-normalized daily dose (WNDD) and aripiprazole serum concentration (=0.791, p < 0.0001) was found. The WNDD and co-medications that interact with CYP2D6 and CYP3A4 affected aripiprazole serum levels, explaining 64% of the variance. In patients within the preliminary therapeutic ranges determined by interquartile ranges (IQRs), slightly better outcomes and fewer adverse drug reactions were found versus patients within preliminary therapeutic ranges determined by the mean ± SD. The preliminary reference range for paediatric patients with schizophrenia-spectrum disorders calculated by the IQR showed an identical lower threshold (100-230 ng/ml) compared to adult schizophrenia-spectrum disorders patients (100-350 ng/ml). The preliminary therapeutic ranges for patients with affective disorders was: 60-160 ng/ml and for patients with behavioural/tic disorders 60-140 ng/ml. The therapeutic reference ranges for aripiprazole in youth estimated via the 25th and 75th IQRs may result in more clinically relevant therapeutic windows. Further studies need to confirm these results, especially in patients with affective and behavioural/tic disorder diagnoses.

Clinical characteristics and predictive factors of delayed diagnosis in patients with sellar germ cell tumors.

PURPOSE: To investigate the clinical characteristics and predictive factors associated with delayed diagnosis in patients with sellar germ cell tumors (GCTs), aiming for early diagnosis. METHODS: A total of 345 patients with sellar GCTs were retrospectively collected. Patients were classified into a delayed diagnosis group (> 6 months from onset to diagnosis) and a non-delayed diagnosis group (≤ 6 months). We compared general characteristics, clinical symptoms, diagnostic methods, treatment strategies, tumor prognosis, and pituitary function between the two groups. Predictive factors for delayed diagnosis were explored using multivariate logistic regression analysis. RESULTS: 225 patients (65.2%) experienced delayed diagnosis. Although there was no association between delayed diagnosis and survival rates or tumor recurrence rates, the delayed diagnosis group had a higher incidence of central diabetes insipidus, central adrenal insufficiency, central hypothyroidism, central hypogonadism, and growth hormone deficiency. Moreover, polyuria/polydipsia (OR 5.46; 95% CI 2.33-12.81), slow growth (OR 5.86; 95% CI 2.61-13.14), amenorrhea (OR 6.82; 95% CI 2.68-17.37), and germinoma (OR 4.99; 95% CI 1.08-3.61) were associated with a higher risk of delayed diagnosis, while older age of onset (OR 0.88; 95% CI 0.84-0.94) and nausea/vomiting (OR 0.31; 95% CI 0.15-0.63) contributed to earlier diagnosis. CONCLUSION: In patients with sellar GCTs, delayed diagnosis is common and linked to increased pituitary dysfunction. The initial symptoms of slow growth, polyuria/polydipsia, and amenorrhea, as well as germinoma with negative tumor markers, predict the possibility of a delayed diagnosis. Early diagnosis is crucial to minimize the impact of sellar GCTs on pituitary function.