Internet-delivered parent-led intervention for anxiety in children and adolescents: a review of the literature.

The purpose of this study was to investigate whether there are elevated symptoms of anxiety or depression in children and adolescents (aged 2-18 years) who stutter, and to identify potential moderators of increased symptom severity. We conducted a preregistered systematic review of databases and gray literature; 13 articles met criteria for inclusion. A meta-analysis using robust variance estimation was conducted with 11 cohort studies comparing symptoms of anxiety in children and adolescents who do and do not stutter. Twenty-six effect sizes from 11 studies contributed to the summary effect size for anxiety symptoms (851 participants). Meta-analysis of depression outcomes was not possible due to the small number of studies. The summary effect size indicates that children and adolescents who stutter present with increased anxiety symptoms (g = 0.42) compared with nonstuttering peers. There were insufficient studies to robustly analyze depression symptoms, and qualitative review is provided. No significant between-groups differences were reported in any of the depression studies. Preliminary evidence indicates elevated symptoms of anxiety in some children and adolescents who stutter relative to peers. There was a tendency toward higher depression scores in this population, although reported between-groups differences did not reach statistical significance. These findings require replication in larger, preferably longitudinal studies that consider factors that may moderate risk. Nevertheless, our findings highlight a need for careful monitoring of mental health and well-being in young people who stutter. Supplemental Materials: http://osf.io/5m6zv.

Depression and anxiety are prevalent and rising in children and adolescents, prompting interest in exercise as a potential therapeutic intervention. The aim of this systematic umbrella review and meta-meta-analysis (a meta-analysis of meta-analyses) was to evaluate the effects of exercise on depression and anxiety symptoms in children and adolescents and to identify the most promising exercise-based approaches. This systematic umbrella review was preregistered (PROSPERO ID: CRD42024533558) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Preferred Reporting Items for Overviews of Reviews (PRIOR) guidelines. A search of 11 databases identified systematic reviews and meta-analyses of randomized controlled trials (RCTs) evaluating the effects of exercise (aerobic, resistance, mind-body exercise) on depression and anxiety symptoms in children and adolescents. Risk of bias was assessed using the A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) tool, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. Meta-analyses were conducted to combine effect sizes, using random effects models. Subgroup analyses were performed to examine participant and intervention characteristics. A total of 21 systematic reviews (n = 375 RCTs, n = 38,117 participants 5-18 years of age) were included. Participants included those with various clinical conditions, including depression, psychosocial disorders, obesity, and cancer, as well as healthy individuals. The pooled analysis found moderate effect sizes favoring exercise for symptoms of depression (standardized mean difference [SMD] = -0.45, 95% CI = -0.59 to -0.31, I2 = 71.37%, p < .01, 180 RCTs, n = 34,490 participants) and anxiety (SMD = -0.39, 95% CI = -0.61 to -0.17, I2 = 68.1%, p < .01, n = 55 RCTs, n = 24,797 participants). Mixed exercise modes and moderate-intensity exercise had the largest effects on depression, whereas resistance exercise was most effective for symptoms of anxiety. Interventions that were <12 weeks were more effective for depression compared with those that were ≥12 weeks. Benefits were generally consistent across populations. The certainty of evidence was moderate for depression and low to moderate for anxiety. This meta-meta-analysis finds that exercise reduces depression and anxiety symptoms in children and adolescents. These results suggest that structured exercise programs should be considered as part of comprehensive care approaches. This study reviewed evidence from 21 review articles, consisting of 375 randomized controlled trials involving over 38,000 children and adolescents, to examine the effects of exercise on symptoms of anxiety and depression. Results show that exercise significantly reduces symptoms of depression and anxiety, with moderate-intensity and resistance exercises being particularly effective. Shorter interventions (less than 12 weeks) had greater benefits for depression. These results highlight the potential of structured exercise programs as a valuable tool for improving youth mental health. • Clinicians should consider incorporating structured exercise programs, particularly moderate-intensity and resistance training, as part of a comprehensive approach to managing depression and anxiety in children and adolescents. • Shorter exercise interventions (<12 weeks) may provide greater benefits for depression and could be a practical starting point for integrating exercise into treatment plans. • Given the broad effectiveness of exercise across various populations, healthcare providers can recommend physical activity interventions regardless of a child's clinical condition, tailoring programs to individual needs and preferences. Effectiveness of physical activity in improving depression and anxiety in children and adolescents: a systematic umbrella review; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024533558.

To assess the contribution of caregiver and child depressive and anxiety symptoms severity to child asthma-related quality of life (QoL), apart from explanation by demographics and asthma control to QoL.The study population consisted of 205 caregiver-child pairs from Dallas, Texas, and Buffalo, New York, from June 2016 to December 2020. The study included children aged 7 to 17 years with a diagnosis of persistent asthma (classified by either of the following criteria: [1] requirement for treatment with daily controller medication or [2] symptoms of persistent asthma in children not on a daily controller medication with any of the following: [1] daytime symptoms 2 or more days per week; [2] rescue bronchodilator use 2 or more times per week; [3] nocturnal symptoms 2 or more nights per month; or [4] 2 or more oral steroid bursts in the past year). The study also included primary caregivers of the children under study. All caregivers met the criteria for major depressive disorder (MDD) based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria and diagnosed using a structured clinical interview.Participants of the study were observed every 4 weeks for a year. Child asthma-related quality of life was assessed with Pediatric Asthma Quality of Life Questionnaire (PAQLQ) total scores. Asthma control was measured with Asthma Control Test (ACT) or Childhood ACT (cACT). Caregiver depressive symptoms were measured by Hamilton Rating Scale for Depression (HRSD); caregiver anxiety symptoms were measured by State-Trait Anxiety Inventory (STAI). Child depressive symptoms were measured with Children’s Depression Inventory (CDI); child anxiety symptoms were measured with Screen for Child Anxiety Related Emotional Disorders Inventory (SCARED). A 3-stage hierarchical linear regression analysis was performed with PAQLQ total scores as the outcome of child asthma-related QoL. The following predictors were included for the 3 stages of linear regression: demographic characteristics for stage 1; asthma control (ACT, cACT) for stage 2; and caregiver depression (HRSD), caregiver anxiety (STAI), child depression (CDI), child anxiety (SCARED) for stage 3.The study analyzed data from a total of 205 child-caregiver pairs. The average age for children was 11 (±3) years, and 38 (±8) years for caregivers. Most participants were female (caregiver 98%, child 54.1%) and of Black race (caregiver 52.2%, child 56.6%). For the first stage of the hierarchical linear regression, demographic variables (child sex, age, caregiver educational level, caregiver race, caregiver ethnicity) contributed to 5.5% of variance in QoL. It was found that only child sex had a significant association with QoL, where males reported a higher QoL. For the second stage, asthma control (ACT/cACT) was included in the regression, which significantly increased explained variance to 32.6%. Asthma control was thus found to be a strong predictor of QoL, with better asthma control indicating a better QoL. For the third stage, the inclusion of child and caregiver anxiety and depression scores significantly increased explained variance to 42.6%. Child anxiety (SCARED scores) was found to be the only statistically significant mood-related predictor (P < .001, β = −0.332). This finding indicated that higher child anxiety scores were associated with lower asthma-related QoL. Asthma control had the most significant contribution to QoL variance as it was seen by a squared structure coefficients (rs2) score of 0.702, then child anxiety (rs2 score = 0.584), and lastly child depression (rs2 score = 0.343).Child and caregiver depression and anxiety have a pertinent influence on child asthma-related QoL after adjusting for demographic characteristics and asthma control. Specifically, child anxiety scores were found to be statistically significant predictors of diminished QoL.The study addresses the contribution of caregiver and child mood symptoms, specifically depression and anxiety, to pediatric asthma-related QoL. The finding of a significant and unique contribution of child anxiety to asthma-related quality of life adds to the necessity of addressing mental well-being in addition to physical health in pediatric asthma management. This study adds to the literature supporting the need for integrated medical and behavioral models of asthma management to improve asthma-related QoL in the pediatric population with asthma. This can include the addition of routine screening and treatment of anxiety and depression in both children with asthma and their primary caregivers into asthma management guidance. Further study should also focus on the implementation of integrated medical-psychological models for pediatric asthma management and explore barriers to application, access, and quality of model implementation, especially in high-risk, underserved, and underresourced populations.

Physical activity (PA) is associated with symptoms of depression and anxiety in children and adolescents. Using accelerometers to measure PA can provide more accurate and detailed data to investigate this relationship. However, no study has systematically reviewed and pooled the effects of accelerometer-measured PA on mental health. Therefore, this meta-analysis examined the association between accelerometer-measured PA and symptoms of depression and anxiety in children and adolescents and determined whether the strength of this relationship varied by accelerometery methodology. A systematic review conducted up to May 2025 using the following databases: Medline, PsycINFO, Embase, Web of Science, and SPORTDiscus, following the PRISMA guidelines, and using terms relating to children, PA, depression/anxiety and observational design. Meta-analyses were performed separately for 12 studies with continuous outcomes (Partial r) and 7 studies with binary outcomes (Odds Ratio). Subgroup analysis tested the moderating effects of accelerometer data collection and processing methods (e.g., epoch length, wear location, valid days, valid hours). Thirty studies met the inclusion criteria (n = 15 cross-sectional, n = 15 prospective) including 40,334 youth aged 5-18years. There was a small negative association of moderate-to-vigorous physical activity (MVPA) with depression (partial r = -0.17, 95%CI [-0.28, -0.06], p < 0.001) and anxiety (partial r = -0.21, 95%CI [-0.34, -0.09], p < 0.001). Total physical activity (TPA) (OR = 0.98, 95%CI [0.96,1.00], p = 0.05) and light intensity PA (OR = 0.95, 95%CI [0.92,0.98], p < 0.001) were associated with reduced risk of depression. The association between MVPA and depression appeared to vary by epoch length (≤ 15s partial r = -0.32, 95% [-0.49, -0.15]; > 15s partial r = -0.08, 95% [-0.19, 0.03]; difference p = 0.02). Sensitivity and publication bias analyses supported the overall robustness and reliability of the associations between PA and depression or anxiety. This review highlights that while PA was associated with reduced depression and anxiety in youth, substantial methodological heterogeneity, particularly in accelerometer protocols, may influence effect sizes. Improved and standardised accelerometry methodologies and developed innovative PA metrics are needed to better assess these relationships. The protocol for the present review was registered on PROSPERO (CRD42022320410) on 23rd March 2022. •This systematic review included 30 studies involving 40,334 children and adolescents aged 5-18years and revealed substantial variability in accelerometer data collection and processing methods across studies, including 11 different device models, 4 wear locations, 6 epoch lengths, 4 intensity thresholds units, 5 valid day definitions, and 7 non-wear criteria, as well as 17 questionnaires used to assess depression and anxiety. •Meta-analysis results showed that moderate-to-vigorous, total, and light physical activity were associated with reduced depression and anxiety in youth, while epoch length and accelerometer wear location may affect the magnitude of this relationship. The findings remained consistent across sensitivity analyses, and no evidence of publication bias was detected. •Of the 30 studies assessed for risk of bias, 2 were rated as good quality, 22 as fair quality, and 6 as poor quality. The main quality problems were the lack of sample size justification, or insufficient reporting of uniform selection criteria.

The current study used an eye-movement remote distractor paradigm (RDP) to examine the relationship between self-reported symptoms of social anxiety in children (9–11-year-olds), young adolescents (12–14-year-olds) and adults (18–43-year-olds) on saccade latencies to identify a target and saccadic errors to task irrelevant distractor (angry, neutral and happy faces). Distractors were presented simultaneously, either at the centre of the display, or at a contralateral parafoveal or peripheral location to the target. Symptoms of social anxiety in children were associated with increased saccade latencies in the presence of angry and neutral faces suggesting avoidance of these emotion expressions in this age group. Symptoms of social anxiety in adolescents and adults were respectively linked with longer latencies for neutral faces, indicating that neutral faces represent ambiguous and potentially negative stimuli for individuals with elevated social anxiety, and fit with research that has questioned the role of neutral faces as non-emotional control stimuli in attention research and anxiety.

Symptoms of depression and anxiety in youth with type 1 diabetes: A systematic review and meta-analysis

Anxiety and depression affect about 6.5% and 2.6% of young people and often occur together, worsening over time. Exercise increases mood-boosting chemicals like dopamine and endorphins, and research shows it can relieve these symptoms. However, most studies focus on ages 6-18 and test only one type of exercise, overlooking older adolescents (up to 24) and comparisons among different activities. This study addresses these gaps by examining 10-24-year-olds and using a network meta-analysis to compare various exercise programs-such as aerobic, resistance, mind-body, and mixed routines-to determine which best reduces anxiety and depression in this age group. A comprehensive search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library to identify randomized controlled trials assessing the impact of exercise interventions on children with anxiety and depression. The search spanned all available records from the inception of each database up to May 2024. Literature screening, data extraction, and quality evaluation were independently managed by two reviewers. Subsequently, Stata version 15.1 was utilized to perform a network meta-analysis. We included 26 randomized controlled trials and conducted a network meta-analysis to compare the effects of different exercise interventions on anxiety and depression symptoms in children and adolescents. For depressive symptoms, both aerobic exercise (SMD = - 3.66, 95% CI [- 6.62, - 0.69]) and medium-low intensity training (SMD = - 3.61, 95% CI [- 6.10, - 1.13]) were significantly more effective than no intervention. Resistance training showed the highest effect size (SMD = - 4.14, 95% CI [- 9.08, 0.79]), although this result did not reach statistical significance. According to SUCRA rankings, the interventions were ordered as follows in terms of efficacy for reducing depressive symptoms: resistance training (78.2%) > medium low intensity training (77.4%)= aerobic exercise (77.4%) > mind body exercise (55.7%) > group training (27.0%) > cognitive behavioral therapy (20.2%) > no intervention (14.7%). Regarding anxiety symptoms, none of the exercise interventions showed a statistically significant advantage compared to no intervention. However, aerobic exercise had the largest effect size (SMD = 3.10, 95% CI [- 0.85, 7.05]), followed by medium-low intensity training (SMD = 2.37, 95% CI [- 0.21, 4.95]) and mind-body exercise (SMD = 1.75, 95% CI [- 1.75, 5.25]), all of which showed favorable trends. Based on SUCRA rankings, the interventions were ordered as follows for reducing anxiety: aerobic exercise (79.2%) > mind body exercise (72.8%) > medium low intensity training (60.2%) > cognitive behavioral therapy (51.0%) > no intervention (26.5%) > group training (10.4%). Results should be interpreted with caution because the included trials were heterogeneous, only English-language studies were analyzed, outcome scales varied, and long-term follow-up data-especially for resistance training-were scarce. Exercise interventions may help alleviate anxiety and depressive symptoms in children and adolescents. Resistance training ranked relatively high for depression, while aerobic exercise showed favorable effects for anxiety. However, the current evidence remains limited, and further high-quality studies are needed to confirm these conclusions.

This study examined anxiety in preschool children within a South-African context. The parents and teachers of 101 South African children aged 2 to 6 years completed measures of children's anxiety-prone temperament (behavioral inhibition) and anxiety disorders symptoms. Parents and teachers of 59 children could be re-approached one year later, with the request to fill in both scales again, while parents at that time also completed a measure of parental overprotection. Results indicated that, compared with normative scores collected in Western countries, young South African children displayed relatively high levels of anxiety-proneness and anxiety disorders symptoms, although this cultural difference could only be demonstrated when using the parentreport data. Further, on both occasions there were substantial and positive correlations between children's behavioral inhibition and anxiety symptoms. Behavioral inhibition and anxiety symptoms, in particular when assessed by parent report, appeared to be fairly stable during the one-year period, and we found only tentative support for the idea that behavioral inhibition on time 1 increased the risk for anxiety symptoms on time 2. Finally, a cross-sectional analysis of the data collected on time 2 revealed a positive correlation between overprotection and children's anxiety symptoms as well as a marginally significant interaction of behavioral inhibition and overprotection on children's anxiety symptoms, indicating that in particular the combination of high behavioral inhibition and high overprotection tended to be associated with the highest anxiety levels.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition typified by inattention, hyperactivity, and impulsivity. Comorbid psychiatric disorders are common among children and adolescents with ADHD. In this study, it was aimed to examine anxiety and somatic symptoms in children and adolescents with ADHD and the effect of methylphenidate treatment on these symptoms. Three groups were formed, consisting of 37 children and adolescents diagnosed with ADHD and received methylphenidate treatment, 37 newly diagnosed, treatment-naive children and adolescents with ADHD diagnosis, and 37 children and adolescents without the diagnosis of ADHD. The symptoms of ADHD in children were examined by using the DSM-IV-based child and adolescent behavior disorders screening and rating scale, the symptoms of anxiety were examined by using the screen for child anxiety-related disorders (SCARED), and somatic symptoms were examined by using the DSM-5 level 2 somatic symptom scale. In the newly diagnosed, treatment-naive with ADHD group, anxiety and somatic symptoms were found to be significantly higher compared to the ADHD group with methylphenidate treatment and the non-ADHD group. It was shown that the symptoms of panic disorder, generalized anxiety, and social phobia were observed more in the newly diagnosed, treatment-naive with ADHD group compared to the treatment group with ADHD. It was determined that children and adolescents diagnosed with ADHD had more anxiety and somatic symptoms. Anxiety and somatic symptoms increased as the severity of ADHD symptoms increased. Anxiety and somatic symptoms were lower than in ADHD children receiving methylphenidate treatment. Clinicians should keep in mind to evaluate anxiety and somatic symptoms in children and adolescents with ADHD before the treatment.

Anemia is associated with adverse outcome in a severity-dependent fashion, commencing with slight deviations from normal hemoglobin levels.1, 2 At a certain degree of anemia, known as the transfusion threshold or trigger, allogeneic red cell transfusions are administered with the purpose of reducing the increased morbidity and mortality observed. Over the past 20 years, there has been growing interest in patient outcomes following allogeneic transfusions, particularly in identifying which patients are most likely to benefit from red cell transfusions and at which hemoglobin threshold. To achieve this, numerous randomized controlled trials have compared restrictive and liberal hemoglobin thresholds for red cell transfusion.3 These clinical trials shed some light on patient outcomes in hemoglobin ranges between 70 and 100 g/L. However, they do not reveal outcomes following transfusion below these hemoglobin values nor do they inform about the effects of treatments aimed at preventing patients from reaching the hemoglobin threshold for transfusion,4 an approach taken by patient blood management (PBM). PBM is "the science of optimizing patient outcomes through the judicious use of the patient's own blood as a patient-centered, multidisciplinary and multimodal approach to patient care. The core business of this newly developing specialty consists of managing anaemia, bleeding and coagulopathy".5 There are few data published on outcomes of patients with hemoglobin levels below 70 g/L.6, 7 What is known on the topic is often based on extrapolations from non-comparative studies assessing the relationship of anemia and mortality in the absence of transfusion.8, 9 However, while these studies provide some useful insights, they do not indicate whether transfusion would have modified outcomes. With the advent and growth of PBM programs and initiatives, anemia is increasingly avoided whenever possible and treated even at hemoglobin levels below those considered transfusion thresholds. In these settings, the effects of allogeneic transfusion have to be assessed against an even more complex background, comparing the impact of PBM as a bundle of care in relation to allogeneic transfusions. Such comparisons are difficult to make since the net effect of allogeneic transfusion on outcome is still ill-defined. Having or not having the option to administer allogeneic transfusions usually alters not only the transfusion behavior of clinicians, but also many other aspects of a patient's management. This includes the timing of an elective procedure, the likelihood of providing PBM measures, the order and speed with which hemostasis is attempted in bleeding patients, the extent of surgical hemostasis aimed for, and the extent of laboratory testing. We therefore undertook an effort to search the medical literature for the best available evidence, comparing outcomes of patients that cannot be transfused if deemed necessary (non-transfusable) with those that can be transfused (transfusable). Though the difference may be subtle, this is in contrast to studies comparing patients transfused to patients not transfused as part of their usual course of treatment. Our objective was to systemically review and summarize the literature to investigate whether adult hospitalized patients treated without the possibility of receiving allogeneic blood experience higher mortality or morbidity compared to patients able to receive allogeneic blood transfusions. We registered our protocol on PROSPERO (CRD42020196673) prior to commencing our review. We based our study methodology on recommendations from the Cochrane Handbook10 and reported our results in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.11 Formal ethics approval was not required for this systematic review and meta-analysis as we only analyzed published literature. It is challenging to involve patients or the public in this work as it involved a summary of research already conducted. However, we attempted to involve relevant consumer groups by mapping out potential stakeholders specific to the review question and by contacting patient representatives for populations not wishing to receive transfusions or with exceedingly rare blood types or complex antibody patterns. These and other stakeholders were asked by mail or in form of personal interviews to contribute to the body of relevant literature, to refine the research question, and to add detail to potential subgroup analyses and other relevant questions in the design of the review. Studies were eligible for inclusion if they investigated hospitalized adult patients or mature minors (>14 years) declining or unable to receive blood transfusions. The comparator group selected was patients able to receive allogeneic transfusions. The studies identified needed to measure at least one of the pre-defined outcomes of interest (mortality, morbidity, length of stay), and included more than three patients in the intervention group. To maximize the generalizability of our results, we included all studies irrespective of the setting, country, year of publication, publication status, or language. Our study group of interest was participants considered non-transfusable. We defined non-transfusable as: patients declining allogeneic transfusions (regardless of reason); patients treated under conditions where transfusions were not available (pandemics, disasters, combat settings, resource limited countries); patients with rare blood types or complex antibody patterns for whom no transfusions are available. We defined transfusable patients as those able to receive transfusions regardless of whether they were or were not administered a transfusion. Essentially our intervention of interest compared different bundles of care, namely the treatment non-transfusable and transfusable patients received. We started our search on July 12,020, searching MEDLINE, Embase, PubMed, and The Cochrane Registry. We contacted study authors and experts in the field to ensure relevant articles were not missing. In addition, we searched the reference lists of identified studies, reviews based on similar topics, conference abstracts from the Society for the Advancement of Blood Management (SABM) and the Network for the Advancement of Patient Blood Management, Hemostasis and Thrombosis (NATA), and ongoing trials registered in clinicaltrials.gov. We did not restrict our literature search by date. Our search string included terms and combination of terms like bloodless, Jehovah's Witnesses, blood conservation, blood management, transfusion free, refuse, deny, decline, reject, transfusion, blood, red cells, and mapped these to MESH terms where available. Details of our search strategy can be found in the Data S1 (pages 2–4). Two authors (PS, ML) independently screened titles and abstracts returned by the literature search. Studies not meeting the pre-defined eligibility criteria were excluded from our review. More details on the reason for exclusion are available in the Data S1. Disagreements were first resolved through discussion, followed by resolution with a third independent party. Using pre-defined data extraction sheets, two authors (PS, ML) independently extracted data from included studies. All disagreements in data extraction were resolved by discussion. We contacted 14 study authors for additional information but did not receive any data (Table S24, Data S1). For each study, we collected information on author details, year of publication, clinical setting, inclusion criteria, intervention group definition, comparator group definition, statistical methodology, number of patients transfused, number of units transfused, and blood management strategies implemented (management of anemia, bleeding, and coagulation). In addition, we collected information needed to assess the risk of bias. In terms of outcomes our primary outcome of interest was short-term mortality, defined as in-hospital, or where lacking, within 30-days. Therefore, we collected information on the number of deaths in each group and the time-period for mortality. Our pre-defined secondary outcomes included one-year mortality, hospital and ICU length of stay, infection, ventilator time, readmissions, stroke, acute myocardial infarction or other cardiac ischemia, renal complications, re-operation for bleeding, thromboembolism, acute respiratory distress, dementia, and disseminated intravascular coagulation (DIC). Renal outcomes were defined as the highest degree of kidney injury reported, irrespective of the measurement used. More detailed information on the other variables collected and their definitions are available from Table S8, Data S1. In accordance with the Cochrane Handbook, we assessed the risk of bias of individual studies in duplicate using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool.12 Studies with critical risk of bias were excluded from our systematic review, leaving only non-critical studies for analysis. Where more than one study of low to moderate risk of bias presented the results of an outcome of interest, and we judged these studies to be homogenous, we pooled these measures in meta-analyses.10 Dichotomous outcomes were reported as odds ratios (95% confidence intervals), with continuous outcomes reported as mean differences (95% confidence intervals). We examined heterogeneity among pooled studies using the I2 statistic and the Chi2 test, and as a rough guide considered Chi2 test p-value above .10 and an I2 statistic under 30% to suggest heterogeneity may not be important. All pooled data were analyzed using a random-effects model. We included studies that applied matching techniques to their study design as well as studies adjusting for confounders using multivariable regression techniques. To ensure results from non-randomized studies adjusted for confounders, we only collected numerators and denominators for dichotomous outcomes, or means and standard errors for continuous outcomes, from studies using matching techniques in their design. Where studies presented unadjusted and adjusted intervention effects from univariable and multivariable regression analyses we extracted the adjusted effect estimate and calculated its standard error for inclusion in our meta-analyses. Statistical analyses were performed using Review Manager 5.4.1 (RevMan, The Cochrane Collaboration, 2020).13 We planned to present results comparing non-transfusable to transfusable patients, therefore, any studies presenting estimates and 95% confidence intervals comparing transfusable to non-transfusable were inversed. To assess potential publication bias we presented a funnel plot for the primary outcome of short-term mortality. Deviations from the study protocol included adding hospital costs as an outcome measure and presenting a subgroup analysis of mortality in patients with severe anemia or hemorrhagic shock. Figure 1 summarizes the number of studies identified, screened for eligibility, and included in our systematic review. After duplicates were removed, our literature search returned 2848 article titles and abstracts, of which 2501 were excluded. Following this, 347 full-text articles were retrieved and assessed for eligibility and 306 excluded for not meeting our inclusion criteria. More details on exclusion reason are available from Table S9, Data S1. This left 41 studies published in 42 reports meeting the criteria for inclusion in our review.14-55 Study characteristics are presented in Table 1. Our literature search did not identify any randomized controlled trials meeting the eligibility criteria. Of the 41 included studies, all were retrospective cohort studies by design, and seven were abstracts.16, 22, 23, 34, 39, 45, 46 In the majority of studies, the non-transfusable cohort referred to those declining transfusions for personal or religious reasons.14, 16-54 We identified one study where patients did not receive an option for transfusion, potentially due to limited resources.15 We did not identify any studies that investigated patients who were non-transfusable due to rare blood types, or because of combat or disaster settings. We contacted 14 study authors for additional information but did not receive any data (Table S24, Data S1). We collected information on the individual PBM strategies applied to manage anemia, bleeding, and coagulopathy (Table S5 to S7, Data S1). Of the 41 studies included, 26 described the application of strategies to manage anemia,14, 18, 19, 21, 24-28, 30, 32-39, 43-45, 47, 49, 50, 53, 54 with a median of two strategies applied per study; 23 studies described the application of strategies to minimize bleeding,14, 17-20, 24-30, 33, 37, 38, 40, 43, 44, 47-49, 52, 54 with a median of two strategies per study; 15 studies described applying strategies for coagulopathy,14, 18, 22, 26, 30, 33, 36-38, 43, 44, 48, 49, 52, 54 with a median of one strategy per study (Table S18, Data S1). The number of patients in the non-transfusable cohort ranged from four to 322, and from 14 to 136,326 in the transfusable cohort. The most common clinical setting studied was cardiac surgery (n = 16),14, 18, 22, 25, 29, 34, 37, 38, 42-45, 48-50, 52 followed by orthopedic surgery (n = 8)17, 20, 27, 28, 33, 40, 53, 54 and urology (n = 4).16, 26, 31, 35 Other disciplines included in our systematic review were obstetrics and gynecology, hematology, critical care, internal medicine, cardiology, and trauma. Non-transfusable patients had more comorbidities, and were more likely to be female. Twelve out of 15 studies provided sufficient information on baseline hemoglobin and showed lower hemoglobin levels for non-transfusable patients at baseline.14, 16, 23, 24, 26, 28, 32, 35, 44, 45, 53, 54 We assessed the risk of bias within studies using the ROBINS-I tool,12 and present results in Table 1. Using the seven domains of the ROBINS-I tool, no studies were judged the low risk of bias, 11 studies were of moderate risk of bias,18, 24, 25, 29, 33, 38, 42, 47, 48, 51, 52 and 30 were serious risk of bias.14-17, 19-23, 26-28, 30-32, 34-37, 39-41, 43-46, 49, 50, 53, 54 Five of the 11 moderate risk of bias studies reported the nadir hemoglobin levels in non-transfusable and transfusable groups.24, 29, 33, 47, 52 Of these the mean nadir hemoglobin levels ranged from 53 to 102 g/L in the non-transfusable group and from 64 to 102 g/L in the transfusable group. Data on short-term mortality were provided in 35 of the 41 studies included in our review.,14, 15, 17-34, 37-42, 44, 46-53 with 32 reporting in-hospital mortality, and three 30-day mortality. Of these, 12 reported zero deaths in both groups,17, 19, 20, 25-28, 30, 33, 40, 49, 53 and the remaining 23 reported no significant differences between groups.14, 15, 18, 21-24, 29, 31, 32, 34, 37-39, 41, 42, 44, 46-48, 50-52 Eleven moderate risk of bias studies were included in the meta-analysis of short-term mortality (Figure 2).18, 24, 25, 29, 33, 38, 42, 47, 48, 51, 52 The odds ratio for mortality was 0.87 (95% confidence interval 0.61 to 1.25; p = .45; I2 = 0%) when comparing non-transfusable patients to transfusable patients. Four studies reported one-year mortality outcomes.16, 31, 34, 42 One study, of moderate risk of bias, reported significantly lower one-year mortality in non-transfusable patients when compared to transfusable patients (odds ratio = 0.43, 95% confidence interval, 0.23 to 0.79; p = .007).42 Three studies of serious risk of bias16, 31, 34 reported no statistically significant differences in one-year mortality. The funnel plot for short-term mortality indicates that the odds ratio is symmetrically distributed, suggesting publication bias is not likely (Figure 3). In addition, we assessed the direction of residual bias of studies which pointed to the assumption that the review is biased towards the transfused group (Table S17, Data S1). Table 2 presents random-effects meta-analyses of secondary outcomes in non-transfusable patients when compared to transfusable patients. Eighteen studies presented data on infections.14, 15, 19, 21-28, 37, 38, 41, 42, 45, 47, 54 Of these, two studies reported significantly fewer infections in non-transfusable patients,15, 42 with the remaining 16 reporting no statistically significant differences between groups.14, 19, 21-28, 37, 38, 41, 45, 47, 54 Five studies of moderate risk of bias were included in the meta-analysis for infection.24, 25, 38, 42, 47 The odds ratio for infection was 0.59 (95% confidence interval 0.34 to 1.03; p = .07; I2 = 23%) times lower in non-transfusable patients when compared to transfusable patients (Figure S20, Data S1). Odds ratio (M-H, Random, 95% CI) 0.59 [0.34, 1.03] p = .07; I2 = 23% Odds ratio (M-H, Random, 95% CI) 0.79 [0.38, 1.66] p = .54; I2 = 0% Odds ratio (M-H, Random, 95% CI) 0.55 [0.30, 1.01] p = .05; I2 = 28% Odds ratio (M-H, Random, 95% CI) 0.74 [0.51, 1.06] p = .10; I2 = 0% Odds ratio (M-H, Random, 95% CI) 0.71 [0.41, 1.23] p = .22; I2 = 0% Odds Ratio (M-H, Random, 95% CI) 0.57 [0.32, 1.01] p = .06; I2 = 0% Mean difference (IV, Random, 95% CI) 0.24 [−0.86, 1.33] p = .67; I2 = 0% Mean difference (IV, Random, 95% CI) −0.16 [−0.28, −0.04] p = .01; I2 = 0% Odds Ratio (M-H, Random, 95% CI) 1.16 [0.70, 1.93] p = .56; I2 = 0% Fifteen studies reported data on stroke outcomes,14, 18, 22, 23, 25, 29, 34, 37, 38, 42-44, 49, 50, 52 with three reporting zero stroke events in both groups.37, 38, 49 Of the remaining 12 studies, reported statistically significant differences between groups.14, 18, 22, 23, 25, 29, 34, 42-44, 50, 52 moderate risk of bias studies reported stroke 25, 29, 38, 42, 52 the odds ratio for stroke was 0.79 (95% confidence interval to p = .54; I2 = 0%) when comparing non-transfusable patients to transfusable patients (Figure Data S1). Data on acute myocardial infarction were available from 16 18, 23, 24, 26, 29, 37, 38, 42, 44, 47, 49, 50, 52, 54 Two studies reported significantly lower acute myocardial infarction events in non-transfusable 47 The remaining 14 reported no statistically significant differences between groups.14, 18, 23, 24, 26, 29, 37, 38, 44, 49, 50, 52, 54 studies of moderate risk of bias were included in the meta-analysis for acute myocardial 24, 29, 38, 42, 47, 52 The pooled odds for acute myocardial infarction was 0.55 (95% confidence interval p = .05; I2 = times lower in non-transfusable patients when compared to transfusable patients (Figure Data S1). studies reported 18, 30, 37, 42, 49, 54 with reporting statistically significant differences between groups Two studies of moderate risk of bias were included in the meta-analysis for 42 The pooled odds ratio for was 0.74 (95% confidence interval, to p = .10; I2 = 0%) times lower in the non-transfusable patients when compared to the transfusable patients (Figure Data S1). Data were available on renal from 29, 35, 37, 38, 42, 44, 50, 52 with all studies reporting no statistically significant differences between studies of moderate risk of bias were included in the meta-analysis for renal 24, 25, 29, 38, 42, 52 The pooled odds ratio for renal was 0.71 (95% confidence interval to p = .22; I2 = 0%) when comparing non-transfusable patients to transfusable patients (Figure S24, Data S1). Eleven studies presented the number of between study 18, 19, 34, 37, 38, 42, 49, 50, 52, 54 with one study reporting zero events in both of the studies included reported statistically significant differences in between The pooled odds for was 0.57 (95% confidence interval, to p = .06; I2 = 0%) times lower in non-transfusable patients when compared to transfusable patients. This was from the four studies of moderate risk of bias (Figure Data 38, 42, 52 studies reported length of hospital outcomes as means or 21, 30, 33, 35, 38, 39, 41, 45, 49, 50, 54 Of these data were available for mean and standard length of hospital from 38, 41, 45, 54 Two studies of serious risk of bias reported mean length of in non-transfusable 54 with the remaining reporting no statistically significant 38, 45, 46 Three studies of moderate risk of bias were included in the 25, The pooled mean difference for length of was 0.24 lower (95% confidence interval, to p = .67; I2 = 0%) when comparing non-transfusable patients to transfusable patients (Figure Data S1). Four studies reported mean care 25, 38, In the pooled analysis the mean difference in care was (95% confidence interval, to p = .01; I2 = 0%) lower in non-transfusable patients when compared to transfusable patients. These results were from three studies of moderate risk of bias (Figure Data 25, We were unable to results for events and as both these outcomes were only by one study of moderate risk of study reported statistically significant differences between There was no low or moderate risk of bias studies identified for bleeding, or outcomes. Five studies of serious risk of bias collected bleeding 30, 32, 41, 46 with one reporting significantly more bleeding events in non-transfusable patients when compared to transfusable Two studies of serious risk of bias reported 54 with reporting statistically significant differences between One study of serious risk of bias reported as an and reported study found statistically significant differences between We did not any studies reporting on acute respiratory or Two studies of moderate risk of bias reported hospital We were unable to the results of these studies as one reported median the other The study reporting found costs were significantly lower among non-transfusable the study reporting means found no significant differences between Four studies reporting short-term mortality were in patients with severe anemia or hemorrhagic 21, 29, 47 with reporting statistically significant differences between Two moderate risk of bias studies were included in the 47 The odds ratio for mortality was 1.16 (95% confidence interval to p = .56; I2 = 0%) when comparing non-transfusable patients to transfusable patients (Figure Data S1). Our systematic review included 41 studies, with 11 studies of moderate risk of bias pooled in our analysis. In the meta-analysis of short-term mortality non-transfusable patients were not more likely to have increased mortality when compared to transfusable patients. This the in our subgroup analysis of patients with severe anemia or hemorrhagic shock. considered non-transfusable were more likely to have a in the care There were no statistically significant differences between non-transfusable and transfusable patients in terms of other pre-defined morbidity outcomes, non-transfusable patients to have fewer acute myocardial and and data on hospital costs suggest similar or even lower hospital To our this is the first systematic review and meta-analysis comparing outcomes in non-transfusable and transfusable patients. The of our review, not our literature search by or study design, is a We applied the Cochrane methodology, registered our protocol prior to commencing our review, and performed study data and data in Our study has a number of For as there were no randomized controlled trials identified, our meta-analyses pooled the results of studies. It is possible there is residual that contribute to the results observed. To minimize any potential bias, we only included studies for confounders in their study and we did not studies of serious or critical risk of bias. In addition, we assessed the direction of residual bias of studies, which pointed to the assumption that the review is biased towards the transfused group. the of studies are well these data can be in a number of settings, where randomized trials cannot be performed due to a our meta-analysis of studies necessary data to a research question for which randomized is not available. potential of our meta-analysis is the of blood the non-transfusable patients did not receive any allogeneic blood the transfusable patients, when transfused, This is likely to between clinical settings, and therefore any this In addition, seven of the 11 studies judged the moderate risk of bias therefore included in our were in the cardiac surgery setting, with the other four studies in critical care, and trauma. This may the generalizability of our to other patient However, while the majority of studies were in the cardiac surgery setting, of participants pooled were from other settings, with the study the most included patients from a of surgical and In addition, the of morbidity outcomes is a as it is likely to in and in from study to study and is therefore more in when compared to mortality and length of outcomes. To there are two of studies transfusion in adult hospitalized studies comparing transfused with patients as well as randomized controlled trials comparing liberal and restrictive transfusion Systematic reviews and meta-analyses of studies comparing transfused patients to patients transfusion is associated with increased mortality and of randomized trials comparing restrictive and liberal hemoglobin thresholds no differences in mortality between in some lower mortality is reported in patients to restrictive thresholds. For meta-analyses from 53 randomized controlled trials and found of meta-analyses as to moderate reported no statistically significant difference in mortality, while reported lower mortality with restrictive transfusion Our review a third of study to the literature on this comparing different bundles of care, namely the treatment non-transfusable and transfusable patients in results between these three of studies For not statistically significant we found a fewer infection events among non-transfusable patients. This is with a systematic review and meta-analysis of randomized controlled trials which reported that restrictive transfusion thresholds in a of severe There are three patient groups identified as patients who a red cell and have the and blood is patients declining to and patients in where blood is not available combat settings, due to or We compared patients that may have have a transfusion as part of their usual care, to similar patients who were able to receive transfusions but may or may not have been Our also included patients not at risk of receiving a transfusion who still a bundle of care to their own blood anemia, bleeding, and to similar patients who may not have had their blood to the Our review patients, clinicians, and to make a the of transfusion and The results of our systematic review and meta-analysis the that comparing outcomes in non-transfusable and transfusable patients. The results may that studies of low to moderate risk of bias indicate patients unable to receive allogeneic blood transfusions have similar clinical outcomes, and in some may have outcomes than patients able to receive transfusions. The results of our meta-analysis may also provide to more aspects of PBM to transfusable patients. the results from studies of moderate risk of bias indicate that no difference in mortality or morbidity between non-transfusable and transfusable patients. However, patients considered non-transfusable were treated at similar or hospital We and the of the for their in relevant All authors have the form at and no from any for the no with any that have an interest in the work in the no other or that to have the the study searched for with other independently screened found articles for eligibility, data data of the article the study independently screened found articles for eligibility, data data the publication public publication of the and and the statistical and at the of and the and the work and detail to the All authors the data for the All authors were involved in the All authors the to be Data S1. The is not for the or of any information by the than be to the author for the

BackgroundAnxiety disorders emerge during childhood and adolescence and are frequently preceded by subsyndromal anxiety symptoms. Environmental toxicants, including gestational polybrominated diphenyl ether (PBDE) exposure, are associated with neuropsychiatric sequelae; however, the role of PBDEs as risk factors for anxiety in adolescence is unclear.MethodsUsing data from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort enrolled from 2003 to 2006, we investigated the relationship between gestational serum PBDE concentrations and anxiety symptoms in adolescents (N = 236). We measured five PBDE congeners (PBDE‐28, −47, −99, −100, and −153) at 16 ± 3 weeks of gestation and calculated their sum (∑PBDE). We assessed self‐reported anxiety symptoms using the Screen for Child Anxiety Related Emotional Disorders (SCARED) and depressive symptoms using the Children's Depression Inventory (CDI‐2) at age 12 years. We estimated the associations of maternal PBDE concentrations with child anxiety and depressive symptoms using multivariable linear regression and modified Poisson regression. Covariates included child sex, maternal race, maternal age at delivery, maternal marital status, maternal education, and household income at the 12‐year study visit as well as maternal depressive and anxiety symptoms. Sensitivity analyses were performed to control for maternal lead and mercury at delivery.ResultsAfter adjusting for predetermined covariates, each doubling in maternal PBDE concentrations was associated with increased SCARED scores (e.g., for ∑PBDE, SCARED total score, β = 1.6 95% confidence interval [CI]: 0.3–2.9, p = .019) and a nonsignificant increase in depressive symptoms (e.g., for CDI total score, β = .8, 95% CI: −0.2–1.8, p = .11).ConclusionsGestational serum PBDE concentrations just before mid‐pregnancy and during a period of active cortical and limbic neurogenesis, synaptogenesis and myelogenesis may be a risk factor for developing anxiety symptoms in early adolescence.

BackgroundIn the clinical setting, a large proportion of children with an autism spectrum disorder (ASD) experience anxiety symptoms. Because anxiety is an important cause of impairment for children with an ASD, it is necessary that effective anxiety interventions are implemented for these children. Recently, a serious game called Mindlight has been developed that is focused on decreasing anxiety in children. This approach is based on recent research suggesting that video games might be suitable as an intervention vehicle to enhance mental health in children. In the present study it will be investigated whether Mindlight is effective in decreasing (sub) clinical anxiety symptoms in children who are diagnosed with an ASD.Methods/DesignThe present study involves a randomized controlled trial (RCT) with two conditions (experimental versus control), in which it is investigated whether Mindlight is effective in decreasing (sub) clinical anxiety symptoms in children with an ASD. For this study, children of 8–16 years old with a diagnosis of an ASD and (sub) clinical anxiety symptoms will be randomly assigned to the experimental (N = 60) or the control (N = 60) condition. Children in the experimental condition will play Mindlight for one hour per week, for six consecutive weeks. Children in the control condition will play the puzzle game Triple Town, also for one hour per week and for six consecutive weeks. All children will complete assessments at baseline, post-intervention and 3-months follow-up. Furthermore, parents and teachers will also complete assessments at the same time points. The primary outcome will be child report of anxiety symptoms. Secondary outcomes will be parent report of child anxiety, child/parent report of depressive symptoms, and parent/teacher report of social functioning and behavior problems.DiscussionThis paper aims to describe a study that will examine the effect of the serious game Mindlight on (sub) clinical anxiety symptoms of children with an ASD in the age of 8–16 years old. It is expected that children in the experimental condition will show lower levels of anxiety symptoms at 3-months follow-up, compared to children in the control condition. If Mindlight turns out to be effective, it could be an important contribution to the already existing interventions for anxiety in children with an ASD. Mindlight could then be implemented as an evidence-based treatment for anxiety symptoms in children with an ASD in mental health institutes and special education schools.Trial registrationDutch Trial Register NTR5069. Registered 20 April 2015.

Anxiety disorders are among the most common youth mental health disorders. Early intervention can reduce elevated anxiety symptoms. School-based interventions exist but it is unclear how effective targeted approaches are for reducing symptoms of anxiety. This review and meta-analysis aimed to determine the effectiveness of school-based indicated interventions for symptomatic children and adolescents. The study was registered with PROSPERO [CRD42018087628]. We searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Library for randomised-controlled trials comparing indicated programs for child and adolescent (5–18 years) anxiety to active or inactive control groups. Data were extracted from papers up to December 2019. The primary outcome was efficacy (mean change in anxiety symptom scores). Sub-group and sensitivity analyses explored intervention intensity and control type. We identified 20 studies with 2076 participants. Eighteen studies were suitable for meta-analysis. A small positive effect was found for indicated programs compared to controls on self-reported anxiety symptoms at post-test (g = − 0.28, CI = − 0.50, − 0.05, k = 18). This benefit was maintained at 6 (g = − 0.35, CI = − 0.58, − 0.13, k = 9) and 12 months (g = − 0.24, CI = − 0.48, 0.00, k = 4). Based on two studies, > 12 month effects were very small (g = − 0.01, CI = − 0.38, 0.36). No differences were found based on intervention intensity or control type. Risk of bias and variability between studies was high (I2 = 78%). Findings show that school-based indicated programs for child and adolescent anxiety can produce small beneficial effects, enduring for up to 12 months. Future studies should include long-term diagnostic assessments.

Depression and anxiety are among the most common mental health problems affecting children and adolescents worldwide. Exercise is a widely used and potentially cost-effective non-pharmacological approach that may improve mood and mental health. However, the optimal exercise modalities and doses for alleviating depressive and anxiety symptoms in children and adolescents remain uncertain. Previous evidence has primarily relied on pairwise meta-analyses or conventional network meta-analyses: the former are unable to compare multiple exercise formats simultaneously, while the latter, although capable of integrating different interventions, have not quantified dose characteristics such as intensity, frequency, and duration. Consequently, systematic dose-response evidence regarding depressive and anxiety symptoms in children and adolescents is lacking. This study aims to examine the quantitative relationship between exercise dose and changes in depressive and anxiety symptoms. This protocol outlines a systematic review and Bayesian model-based dose-response network meta-analysis. A systematic search will be conducted of PubMed, Embase, Web of Science, the Cochrane Library, Scopus, PsycINFO, SPORTDiscus, and the China National Knowledge Infrastructure databases through May 2026. Randomized controlled trials enrolling children and adolescents aged 6-18years with depressive or anxiety symptoms and comparing different types and doses of exercise training will be eligible for inclusion. Study quality will be appraised using the Cochrane Risk of Bias 2.0 tool. Exercise interventions will be categorized by type (e.g., aerobic, resistance, mind-body, and combined exercise-only) prior to dose-response modeling. A Bayesian model-based dose-response network meta-analysis will be performed, with exercise dose quantified as weekly metabolic equivalent of task (MET) minutes (MET-min/week) by integrating intensity, session duration, and frequency. Nonlinear dose-response curves will be fitted for distinct exercise modalities. Meta-classification and regression tree (meta-CART) analysis will be employed to identify potential effect modifiers. This study will systematically evaluate the nonlinear dose-response relationships between exercise dose and changes in depressive and anxiety symptoms in children and adolescents, and estimate dose ranges associated with symptom change across exercise modalities. The findings may help inform future evidence-based recommendations and provide methodological guidance for dose-response research in child and adolescent mental health. This protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD420251174947.

To identify and describe current internet-based prevention and treatment programs for anxiety and depression in children and adolescents. Systematic search of the Cochrane Library, PsycINFO and PubMed databases conducted in June 2009. Studies of internet-based programs that addressed anxiety or depression in children and adolescents. No restrictions were placed on study quality. Eight studies of four intervention programs were identified. Programs were delivered via schools, in primary care, through mental health clinics or open access websites. Two were treatment programs, three offered universal prevention, two were indicated prevention programs, and one was a selective prevention program. Study quality was mixed, with three randomised controlled trials in which participants were randomly allocated to the intervention or control condition, one randomised uncontrolled trial, two controlled trials in which participants were not randomly assigned to conditions, and two uncontrolled pre-post evaluations. Two studies targeted anxiety in children, while the remainder addressed depression, or anxiety and depression, in adolescents. All the interventions were based on cognitive behaviour therapy, and six of the eight studies reported post-intervention reductions in symptoms of anxiety and/or depression or improvements in diagnostic ratings. Three of these studies also reported improvements at follow-up. Our findings provide early support for the effectiveness of internet-based programs for child and adolescent anxiety and depression. More extensive and rigorous research is needed to further establish the conditions through which effectiveness is enhanced, as well as to develop additional programs to address gaps in the field.