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This study examined the impact of the COVID-19-induced school lockdown on need satisfaction, well-being and motivation in both gifted and non-gifted primary school students in the Netherlands. A total of 312 parents (122 from gifted children) participated. The lockdown had mainly negative effects on students' need satisfaction, well-being and motivation. However, the impact of the lockdown was less negative for gifted students. There was also a levelling effect: Before the lockdown, gifted students had lower need satisfaction, well-being and motivation than their non-gifted peers, but these differences decreased during the lockdown due to (stronger) declines in the non-gifted. Changes in non-gifted students' well-being and motivation, because of the lockdown, were negatively mediated by autonomy and relatedness with classmates. Among the gifted, this was positively mediated by competence. Only before the lockdown, the effects of giftedness on well-being and motivation were mediated by autonomy and relatedness satisfaction.

Introduction Treating older adults with chemotherapy remains a challenge, given their under-representation in clinical trials and the lack of robust treatment guidelines for this population. Moreover, older patients, especially those with frailty, have an increased risk of developing chemotherapy-related toxicity, resulting in a decreased quality of life (QoL), increased hospitalisations and high healthcare costs. Phase II trials have suggested that upfront dose reduction of chemotherapy can reduce toxicity rates while maintaining efficacy, leading to fewer treatment discontinuations and an improved QoL. The DOSAGE aims to show that upfront dose-reduced chemotherapy in older patients with metastatic colorectal cancer is non-inferior to full-dose treatment in terms of progression-free survival (PFS), with adaption of the treatment plan (monotherapy or doublet chemotherapy) based on expected risk of treatment toxicity.Methods and analysis The DOSAGE study is an investigator-initiated phase III, open-label, non-inferiority, randomised controlled trial in patients aged≥70 years with metastatic colorectal cancer eligible for palliative chemotherapy. Based on toxicity risk, assessed using the Geriatric 8 (G8) tool, patients will be stratified to either doublet chemotherapy (fluoropyrimidine with oxaliplatin) or fluoropyrimidine monotherapy. Patients classified as low risk will be randomised between a fluoropyrimidine plus oxaliplatin in either full-dose or with an upfront dose reduction of 25%. Patients classified as high risk will be randomised between fluoropyrimidine monotherapy in either full-dose or with an upfront dose reduction. In the dose-reduced arm, dose escalation after two cycles is allowed. The primary outcome is PFS. Secondary endpoints include grade≥3 toxicity, QoL, physical functioning, number of treatment cycles, dose reductions, hospital admissions, overall survival, cumulative received dosage and cost-effectiveness. Considering a median PFS of 8 months and non-inferiority margin of 8 weeks, we shall include 587 patients. The study will be enrolled in 36 Dutch Hospitals, with enrolment scheduled to start in July 2024. This study will provide new evidence regarding the effect of dose-reduced chemotherapy on survival and treatment outcomes, as well as the use of the G8 to choose between doublet chemotherapy or monotherapy. Results will contribute to a more individualised approach in older patients with metastatic colorectal cancer, potentially leading to improved QoL while maintaining survival benefits.Ethics and dissemination This trial has received ethical approval by the ethical committee Leiden Den Haag Delft (P24.018) and will be approved by the Institutional Ethical Committee of the participating institutions. The results will be disseminated in peer-reviewed scientific journals.Trial registration number NCT06275958.

Soil organic carbon (SOC) in Arctic coastal polygonal tundra is vulnerable to climate change, especially in soils with occurrence of large amounts of ground ice. Pan-arctic studies of mapping SOC exist, yet they fail to describe the high spatial variability of SOC storage in permafrost landscapes. An important factor is the landscape history which determines landform development and consequently the spatial variability of SOC. Our aim was to map SOC stocks, and which environmental variables that determine SOC, in two adjacent coastal areas along Canadian Beaufort Sea coast with different glacial history. We used the machine learning technique random forest and environmental variables to map the spatial distribution of SOC stocks down to 1 m depth at a spatial resolution of 2 m for depth increments of 0–5, 5–15, 15–30, 30–60 and 60–100 cm.The results show that the two study areas had large differences in SOC stocks in the depth 60–100 cm due to high amounts of ground ice in one of the study areas. There are also differences in variable importance of the explanatory variables between the two areas. The area low in ground ice content had with 66.6 kg C/m−2 more stored SOC than the area rich in ground ice content with 40.0 kg C/m−2. However, this SOC stock could be potentially more vulnerable to climate change if ground ice melts and the ground subsides. The average N stock of the area low in ground ice is 3.77 kg m−2 and of the area rich in ground ice is 3.83 kg m−2.These findings support that there is a strong correlation between ground ice and SOC, with less SOC in ice-rich layers on a small scale. In addition to small scale studies of SOC mapping, detailed maps of ground ice content and distribution are needed for a validation of large-scale quantifications of SOC stocks and transferability of models.

The Arctic is rapidly changing. Outside the Arctic, large-sample catchment databases have transformed catchment science from focusing on local case studies to more systematic studies of watershed functioning. Here we present an integrated pan-ARctic CAtchments summary DatabasE (ARCADE) of > 40 000 catchments that drain into the Arctic Ocean and range in size from 1 to 3.1 × 106 km2. These watersheds, delineated at a 90 m resolution, are provided with 103 geospatial, environmental, climatic, and physiographic catchment properties. ARCADE is the first aggregated database of pan-Arctic river catchments that also includes numerous small watersheds at a high resolution. These small catchments are experiencing the greatest climatic warming while also storing large quantities of soil carbon in landscapes that are especially prone to degradation of permafrost (i.e., ice wedge polygon terrain) and associated hydrological regime shifts. ARCADE is a key step toward monitoring the pan-Arctic across scales and is publicly available: https://doi.org/10.34894/U9HSPV (Speetjens et al., 2022).

While over 99% of coastal arctic rivers drain small catchments, future projections of land-ocean fluxes are based on data from large rivers. We encourage inclusion of and increased focus on smaller catchments to support representative assessments of arctic ecosystem change.

Abstract Neo(adjuvant) systemic treatment regimens containing anthracyclines such as doxorubicin cause a significant risk of heart failure. These regimens are one of the corner stones of osteosarcoma treatment, and therefore several guidelines are in place to steer cardiotoxicity monitoring through baseline risk stratification and cardiac surveillance during and after completion of cancer therapy. Importantly, baseline risk stratification modules are dependent on age, prior cardiovascular disease and cardiovascular risk factors. Because the majority of osteosarcoma patients are below 30 years of age these criteria rarely apply and most patients are assigned to low or medium risk categories, whereas cardiovascular complications have profound impact on morbidity and mortality in this young population. Therefore, cardiac surveillance is very important in this group for timely detection of cardiotoxicity. Moreover, when severe cardiotoxicity that requires advanced heart failure treatment occurs, a cancer diagnosis has significant implications on treatment options, i.e. mechanical circulatory support and heart transplantation. These challenges are presented in this case of a patient without clinical risk factors admitted with cardiogenic shock requiring advanced heart failure treatment within 1 month after completion of doxorubicin containing chemotherapy for the treatment of high grade osteosarcoma.

Ongoing climate warming in the western Canadian Arctic is leading to thawing of permafrost soils and subsequent mobilization of its organic matter pool. Part of this mobilized terrestrial organic matter enters the aquatic system as dissolved organic matter (DOM) and is laterally transported from land to sea. Mobilized organic matter is an important source of nutrients for ecosystems, as it is available for microbial breakdown, and thus a source of greenhouse gases. We are beginning to understand spatial controls on the release of DOM as well as the quantities and fate of this material in large Arctic rivers. Yet, these processes remain systematically understudied in small, high-Arctic watersheds, despite the fact that these watersheds experience the strongest warming rates in comparison. Here, we sampled soil (active layer and permafrost) and water (porewater and stream water) from a small ice wedge polygon (IWP) catchment along the Yukon coast, Canada, during the summer of 2018. We assessed the organic carbon (OC) quantity (using dissolved (DOC) and particulate OC (POC) concentrations and soil OC content), quality (δ13C DOC, optical properties and source apportionment) and bioavailability (incubations; optical indices such as slope ratio, Sr; and humification index, HIX) along with stream water properties (temperature, T; pH; electrical conductivity, EC; and water isotopes). We classify and compare different landscape units and their soil horizons that differ in microtopography and hydrological connectivity, giving rise to differences in drainage capacity. Our results show that porewater DOC concentrations and yield reflect drainage patterns and waterlogged conditions in the watershed. DOC yield (in mg DOC g−1 soil OC) generally increases with depth but shows a large variability near the transition zone (around the permafrost table). Active-layer porewater DOC generally is more labile than permafrost DOC, due to various reasons (heterogeneity, presence of a paleo-active-layer and sampling strategies). Despite these differences, the very long transport times of porewater DOC indicate that substantial processing occurs in soils prior to release into streams. Within the stream, DOC strongly dominates over POC, illustrated by DOC/POC ratios around 50, yet storm events decrease that ratio to around 5. Source apportionment of stream DOC suggests a contribution of around 50 % from permafrost/deep-active-layer OC, which contrasts with patterns observed in large Arctic rivers (12 ± 8 %; Wild et al., 2019). Our 10 d monitoring period demonstrated temporal DOC patterns on multiple scales (i.e., diurnal patterns, storm events and longer-term trends), underlining the need for high-resolution long-term monitoring. First estimates of Black Creek annual DOC (8.2 ± 6.4 t DOC yr−1) and POC (0.21 ± 0.20 t yr−1) export allowed us to make a rough upscaling towards the entire Yukon Coastal Plain (34.51 ± 2.7 kt DOC yr−1 and 8.93 ± 8.5 kt POC yr−1). Rising Arctic temperatures, increases in runoff, soil organic matter (OM) leaching, permafrost thawing and primary production are likely to increase the net lateral OC flux. Consequently, altered lateral fluxes may have strong impacts on Arctic aquatic ecosystems and Arctic carbon cycling.

Abstract Background and purpose To gain insight into the treatment outcomes for anal cancer a retrospective analysis was performed with a special emphasis on trends in outcome and toxicities over time and on treatment of elderly patients. Materials and methods Medical records of 98 consecutive patients with squamous cell carcinoma of the anus of all stages treated with curative intent between 01-01-2009 and 31-12-2018 were analyzed with follow up until 31-12-2020. Standard tumor and pathological lymph node dose were 59.4 Gy (median 59.4 Gy, range 59.4–70 Gy) or 60 Gy (no deviation from intended dose), elective nodal regions were treated with 45 Gy (no deviations). Radiotherapy techniques in this period evolved from 3D-conformal to IMRT and VMAT. In 23 patients electron beams were used. Results Median age was 63 years (range 41–88), the majority of patients were female (60%). Twenty three patients were > 75 years old. The TNM stages were I, II, IIIA, and IIIB in 18%, 40%, 15% and 27%, 58% of patients had N0 status. Concurrent mitomycin C and 5-fluoruracil-based chemotherapy was given in 63 patients (64%). Five-year overall survival (OS), disease free survival (DFS), locoregional control (LRC) and colostomy free survival (CFS) were 71%, 80%, 82%, and 82% for the whole group. Results in patients > 75 years of age were not statistically different from those in younger patients. With the introduction of more conformal techniques DFS did not change and toxicities decreased. Conclusion Real word treatment outcomes per disease stage were in line with what is reported in literature. Older patients should also be offered treatment with curative intent.

Abstract Background While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease. Methods Open-label, single-center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first-line treatment, with or without the limited extrahepatic disease. The primary objective is to determine the safety, toxicity, and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at 1 year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, chi-square test). To study the association between risk factors and toxicity, a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves. Discussion This is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver. Trial Registration This trial was registered in the US National Library of Medicine with identifier NCT04283890 . Registered as per February 2020 - Retrospectively registered. EudraCT registration number: 2018-004248-49. Local MREC registration number: NL60508.058.19.

Total knee arthroplasty (TKA) failures are often attributed to unbalanced knee ligament loading. The current study aims to develop a probabilistic planning process to optimize implant component positioning that achieves a ligament-balanced TKA. This planning process accounts for both subject-specific uncertainty, in terms of ligament material properties and attachment sites, and surgical precision related to the TKA process typically used in clinical practice. The consequent uncertainty in the implant position parameters is quantified by means of a surrogate model in combination with a Monte Carlo simulation. The samples for the Monte Carlo simulation are generated through Bayesian parameter estimation on the native knee model in such a way that each sample is physiologically relevant. In this way, a subject-specific uncertainty is accounted for. A sensitivity analysis, using the delta-moment-independent sensitivity measure, is performed to identify the most critical ligament parameters. The designed process is capable of estimating the precision with which the targeted ligament-balanced TKA can be realized and converting this into a success probability. This study shows that without additional subject-specific information (e.g., knee kinematic measurements), a global success probability of only 12% is estimated. Furthermore, accurate measurement of reference strains and attachment sites critically improves the success probability of the pre-operative planning process. To allow more precise planning, more accurate identification of these ligament properties is required. This study underlines the relevance of investigating in vivo or intraoperative measurement techniques to minimize uncertainty in ligament-balanced pre-operative planning results, particularly prioritizing the measurement of ligament reference strains and attachment sites.

Transcatheter mitral valve replacement (TMVR) has emerged as a minimally invasive alternative for treating patients suffering from mitral valve disease. The number of TMVR procedures is expected to rise as devices currently in clinical trials obtain approval for commercialization. Automating the planning of such interventions becomes, therefore, more relevant in an attempt to decrease inter-subject discrepancies and time spent in patient assessment. This study evaluates the performance of an automated method for detection of anatomical landmarks and generation of relevant measurements for device selection and positioning. Cardiac CT scans of 70 patients were collected retrospectively. Fifty scans were used to generate a statistical shape model (SSM) of the left heart chambers at ten different timepoints, whereas the remaining 20 scans were used for validation of the automated method. The clinical measurements resulting from the anatomical landmarks generated automatically were compared against the measurements obtained through the manual indication of the corresponding landmarks by three observers, during systole and diastole. The automatically generated measurements were in close agreement with the user-driven analysis, with intraclass correlation coefficients (ICC) consistently lower for the saddle-shaped (ICCArea = 0.90, ICCPerimeter 2D = 0.95, ICCPerimeter 3D = 0.93, ICCAP-Diameter = 0.71, ICCML-Diameter = 0.90) compared to the D-shaped annulus (ICCArea = 0.94, ICCPerimeter 2D = 0.96, ICCPerimeter 3D = 0.96, ICCAP-Diameter = 0.95, ICCML-Diameter = 0.92). The larger differences observed for the saddle shape suggest that the main discrepancies occur in the aorto-mitral curtain. This is supported by the fact that statistically significant differences are observed between the two annulus configurations for area (p < 0.001), 3D perimeter (p = 0.009) and AP diameter (p < 0.001), whereas errors for 2D perimeter and ML diameter remained almost constant. The mitral valve center deviated in average 2.5 mm from the user-driven position, a value comparable to the inter-observer variability. The present study suggests that accurate mitral valve assessment can be achieved with a fully automated method, what could result in more consistent and shorter pre-interventional planning of TMVR procedures.

Background Amplivant is a molecularly optimized Toll-like receptor 2 ligand that can be covalently conjugated to tumor peptide antigens. In preclinical models, amplivant-adjuvanted synthetic long peptides (SLPs) strongly enhanced antigen presentation by dendritic cells, T cell priming and induction of effective antitumor responses. The current study is a first-in-human trial to investigate safety and immunogenicity of amplivant conjugated to human papillomavirus (HPV) 16-SLP.Methods A dose escalation phase I vaccination trial was performed in 25 patients treated for HPV16 positive (pre-)malignant lesions. Amplivant was conjugated to two SLPs derived from the two most immunodominant regions of the HPV16 E6 oncoprotein. The vaccine, containing a mix of these two conjugates in watery solution without any other formulation, was injected intradermally three times with a 3-week interval in four dose groups (1, 5, 20 or 50 µg per conjugated peptide). Safety data were collected during the study. Peptide-specific T cell immune responses were determined in blood samples taken before, during and after vaccination using complementary immunological assays.Results Toxicity after three amplivant-conjugated HPV16-SLP vaccinations was limited to grade 1 or 2, observed as predominantly mild skin inflammation at the vaccination site and sometimes mild flu-like symptoms. Adverse events varied from none in the lowest dose group to mild/moderate vaccine-related inflammation in all patients and flu-like symptoms in three out of seven patients in the highest dose group, after at least one injection. In the lowest dose group, vaccine-induced T cell responses were observed in the blood of three out of six vaccinated persons. In the highest dose group, all patients displayed a strong HPV16-specific T cell response after vaccination. These HPV16-specific T cell responses lasted until the end of the trial.Conclusions Amplivant-conjugated SLPs can safely be used as an intradermal therapeutic vaccine to induce robust HPV16-specific T cell immunity in patients previously treated for HPV16 positive (pre-) malignancies. Increased vaccine dose was associated with a higher number of mild adverse events and with stronger systemic T cell immunity.Trial registration numbers NCT02821494 and 2014-000658-12.

Previous studies have shown that the manufacturer’s default preoperative plans for total knee arthroplasty with patient-specific guides require frequent, time-consuming changes by the surgeon. Currently, no research has been done on predicting preoperative plans for orthopedic surgery using machine learning. Therefore, this study aims to evaluate whether artificial intelligence (AI) driven planning tools can create surgeon and patient-specific preoperative plans that require fewer changes by the surgeon. A dataset of 5409 preoperative plans, including the manufacturer’s default and the plans corrected by 39 surgeons, was collected. Features were extracted from the preoperative plans that describe the implant sizes, position, and orientation in a surgeon- and patient-specific manner. Based on these features, non-linear regression models were employed to predict the surgeon’s corrected preoperative plan. The average number of corrections a surgeon has to make to the preoperative plan generated using AI was reduced by 39.7% compared to the manufacturer’s default plan. The femoral and tibial implant size in the manufacturer’s plan was correct in 68.4% and 73.1% of the cases, respectively, while the AI-based plan was correct in 82.2% and 85.0% of the cases, respectively, compared to the surgeon approved plan. Our method successfully demonstrated the use of machine learning to create preoperative plans in a surgeon- and patient-specific manner for total knee arthroplasty.

Preoperative determination of implant size for total knee arthroplasty surgery has numerous clinical and logistical benefits. Currently, surgeons use X-ray-based templating to estimate implant size, but this method has low accuracy. Our study aims to improve accuracy by developing a machine learning approach that predicts the required implant size based on a 3D femoral bone mesh, the key factor in determining the correct implant size. A linear regression framework imposing group sparsity on the 3D bone mesh vertex coordinates was proposed based on a dataset of 446 MRI scans. The group sparse regression method was further regularized based on the connectivity of the bone mesh to enforce neighbouring vertices to have similar importance to the model. Our hypergraph regularized group lasso had an accuracy of 70.1% in predicting femoral implant size while the initial implant size prediction provided by the instrumentation manufacturer to the surgeon has an accuracy of 23.1%. Furthermore, our method was capable of predicting the implant size up to one size smaller or larger with an accuracy of 99.1%, thereby surpassing other state-of-the-art methods. The hypergraph regularized group lasso was able to obtain a significantly higher accuracy compared to the implant size prediction provided by the instrumentation manufacturer.

Climate warming is accelerating erosion along permafrost-dominated Arctic coasts. This results in the additional supply of organic matter (OM) and nutrients into the coastal zone. In this study we investigate the impact of coastal erosion on the marine microbial community composition and growth rates in the coastal Beaufort Sea. Dissolved organic matter (DOM) derived from three representative glacial deposit types (fluvial, lacustrine, and moraine) along the Yukon coastal plain, Canada, were used as substrate to cultivate marine bacteria using a chemostat setup. Our results show that DOM composition (inferred from UV-Visible spectroscopy) and biodegradability (inferred from DOC concentration, bacterial production and respiration) significantly differ between the three glacial deposit types. DOM derived from fluvial and moraine types show clear terrestrial characteristics with low aromaticity (Sr: 0.63 ± 0.02 and SUVA254: 1.65 ± 0.06 L mg C−1 m−1 & Sr: 0.68 ± 0.01 and SUVA254: 1.17 ± 0.06 L mg C−1 m−1, respectively) compared to the lacustrine soil type (Sr: 0.71 ± 0.02 and SUVA254: 2.15 ± 0.05 L mg C−1 m−1). The difference in composition of DOM leads to the development of three different microbial communities. Whereas Alphaproteobacteria dominate in fluvial and lacustrine deposit types (67 and 87% relative abundance, respectively), Gammaproteobacteria is the most abundant class for moraine deposit type (88% relative abundance). Bacterial growth efficiency (BGE) is 66% for DOM from moraine deposit type, while 13 and 28% for DOM from fluvial and lacustrine deposit types, respectively. The three microbial communities therefore differ strongly in their net effect on DOM utilization depending on the eroded landscape type. The high BGE value for moraine-derived DOM is probably caused by a larger proportion of labile colorless DOM. These results indicate that the substrate controls marine microbial community composition and activities in coastal waters. This suggests that biogeochemical changes in the Arctic coastal zone will depend on the DOM character of adjacent deposit types, which determine the speed and extent of DOM mineralization and thereby carbon channeling into the microbial food web. We conclude that marine microbes strongly respond to the input of terrestrial DOM released by coastal erosion and that the landscape type differently influence marine microbes.

Background. With soft-tissue sarcoma of the extremity (ESTS) representing a heterogenous group of tumors, management decisions are often made in multidisciplinary team (MDT) meetings. To optimize outcome, nomograms are more commonly used to guide individualized treatment decision making. Purpose. To evaluate the influence of Personalised Sarcoma Care (PERSARC) on treatment decisions for patients with high-grade ESTS and the ability of the MDT to accurately predict overall survival (OS) and local recurrence (LR) rates. Methods. Two consecutive meetings were organised. During the first meeting, 36 cases were presented to the MDT. OS and LR rates without the use of PERSARC were estimated by consensus and preferred treatment was recorded for each case. During the second meeting, OS/LR rates calculated with PERSARC were presented to the MDT. Differences between estimated OS/LR rates and PERSARC OS/LR rates were calculated. Variations in preferred treatment protocols were noted. Results. The MDT underestimated OS when compared to PERSARC in 48.4% of cases. LR rates were overestimated in 41.9% of cases. With the use of PERSARC, the proposed treatment changed for 24 cases. Conclusion. PERSARC aids the MDT to optimize individualized predicted OS and LR rates, hereby guiding patient-centered care and shared decision making.

Introduction Treatment with anti-PD-1 immunotherapy does not lead to long-lasting clinical responses in approximately 60% of patients with metastatic melanoma. These refractory patients, however, can still respond to treatment with tumour infiltrating lymphocytes (TIL) and interferon-alpha (IFNa). A combination of TIL, pegylated-interferon-alpha (PEG-IFNa) and anti-PD-1 is expected to provide a safe, feasible and effective therapy for patients with metastatic melanoma, who are refractory to standard of care treatment options.Methods and analysis Patients are treated in two phases. In phase I, the safety of the combination TIL and anti-PD-1 is assessed (cohort 1) according to CTCAE 4.03 criteria. Subsequently, the safety of cotreatment with PEG-IFNa is tested in cohort 2. The efficacy will be evaluated in the second phase of the trial. Efficacy is evaluated according to RECIST 1.1 and immune-related response criteria. Clinical and immunological parameters will be evaluated for their relation with clinical responsiveness.Ethics and dissemination Ethical approval of the trial was obtained from the Central Committee on Research Involving Human Subjects in the Netherlands. The trial results will be shared with the scientific community at (inter)national conferences and by publication in a peer-reviewed journal.Trial registration number NCT03638375; Pre-results.

Triple P is a parenting program intended to prevent and to provide treatment for severe behavioral, emotional, and developmental problems in children. The aim of this meta-analysis was to assess the effectiveness of Triple P Level 4 interventions on parenting styles and parental competency. Level 4 is an intensive training program of 8-10 sessions for parents of children with more severe behavioral difficulties. The results indicated that the Triple P Level 4 interventions reduced dysfunctional parenting styles in parents and also improved parental competency. These effects were maintained well through time and appear to support the widespread adoption and implementation of Triple P Level 4 interventions that is taking place in an increasing number of countries around the world.

The Triple P Positive Parenting Program is a multilevel parenting program to prevent and offer treatment for severe behavioral, emotional, and developmental problems in children. The aim of this meta-analysis is to assess the effectiveness of Triple P Level 4 interventions in the management of behavioral problems in children by pooling the evidence from relevant literature that included Level 4 Triple P interventions. Level 4 intervention is indicated if the child has multiple behavior problems in a variety of settings and there are clear deficits in parenting skills. Results indicate that Level 4 of Triple P interventions reduced disruptive behaviors in children. These improvements were maintained well over time, with further improvements in long-term follow-up. These effects support the widespread adoption and implementation of Triple P that is taking place in an increasing number of countries in quite diverse cultural contexts around the world. (Contains 3 tables.)