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Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a rare genetic disorder caused by deleterious genetic variation in the prolyl endopeptidase-like (PREPL) gene. Previous reports have described patients with deletions and nonsense variants in PREPL, but nothing is known about the effect of missense variants in the pathology of CMS22. In this study, we have functionally characterized missense variants in PREPL from 3 patients with CMS22, all with hallmark phenotypes. Biochemical evaluation revealed that these missense variants do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria and disease mechanism. Structural analysis showed that the variants affect regions most likely involved in intraprotein or protein-protein interactions. Indeed, binding to a selected group of known interactors was differentially reduced for the 3 variants. The importance of nonhydrolytic functions of PREPL was investigated in catalytically inactive PREPL p.Ser559Ala cell lines, which showed that hydrolytic activity of PREPL is needed for normal mitochondrial function but not for regulating AP1-mediated transport in the transgolgi network. In conclusion, these studies showed that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense variants that do not necessarily result in a loss of hydrolytic activity of PREPL.

Psychoeducation programs may increase knowledge about stress and help adolescents cope with stress. However, research about the effectiveness of psychoeducation programs about stress for adolescents is limited. The present study aimed to fill this gap by evaluating the effect of a brief school-based universal psychoeducation program about stress, the Stress Lessons, in terms of knowledge and experienced stress. A total of 1613 adolescents (M = 13.41 years) from Dutch secondary schools participated. A cluster randomised controlled design was employed: classes were randomly assigned to an experimental or control condition. The experimental condition received three Stress Lessons between pre- and post-test. The Stress Lessons provided information about stress, how to recognize stress, and how to cope with and prevent stress. Questionnaires were used to assess knowledge about stress as well as experienced stress. Multilevel analyses were conducted to examine the effectiveness of the Stress Lessons and the moderating effect of gender, educational track, and ethnic background. Results showed that knowledge gain was significantly greater in the experimental than in the control condition. Experienced stress did not change due to the Stress Lessons. Moderator analyses revealed a larger effect of the Stress lessons in terms of knowledge about stress for girls compared to boys and for adolescents who followed academic compared to vocational education. Overall, the findings show that a brief psychoeducation program leads to a better understanding of stress. Therefore, it may be useful for schools to implement such programs to enhance adolescents' awareness.

Earlier work has explored spoken word production during irrelevant background speech such as intelligible and unintelligible word lists. The present study compared how different types of irrelevant background speech (word lists vs. sentences) influenced spoken word production relative to a quiet control condition, and whether the influence depended on the intelligibility of the background speech. Experiment 1 presented native Dutch speakers with Chinese word lists and sentences. Experiment 2 presented a similar group with Dutch word lists and sentences. In both experiments, the lexical selection demands in speech production were manipulated by varying name agreement (high vs. low) of the to-be-named pictures. Results showed that background speech, regardless of its intelligibility, disrupted spoken word production relative to a quiet condition, but no effects of word lists versus sentences in either language were found. Moreover, the disruption by intelligible background speech compared with the quiet condition was eliminated when planning low name agreement pictures. These findings suggest that any speech, even unintelligible speech, interferes with production, which implies that the disruption of spoken word production is mainly phonological in nature. The disruption by intelligible background speech can be reduced or eliminated via top-down attentional engagement.

Abstract Rare mutations in the gene encoding presenilin2 (PSEN2) are known to cause familial Alzheimer’s disease (FAD). Here, we explored how altered PSEN2 expression impacts on the amyloidosis, endolysosomal abnormalities, and synaptic dysfunction observed in female APP knock-in mice. We demonstrate that PSEN2 knockout (KO) as well as the FAD-associated N141IKI mutant accelerate AD-related pathologies in female mice. Both models showed significant deficits in working memory that linked to elevated PSEN2 expression in the hippocampal CA3 region. The mossy fiber circuit of APPxPSEN2KO and APPxFADPSEN2 mice had smaller pre-synaptic compartments, distinct changes in synaptic vesicle populations and significantly impaired long term potentiation compared to APPKI mice. At the cellular level, altered PSEN2 expression resulted in endolysosomal defects and lowered surface expression of synaptic proteins. As PSEN2/γ-secretase is restricted to late endosomes/lysosomes, we propose PSEN2 impacts endolysosomal homeostasis, affecting synaptic signaling in AD-relevant vulnerable brain circuits; which could explain how mutant PSEN2 accelerates AD pathogenesis.

Targeted school-based programs seem to be a promising approach to help adolescents in need. Nevertheless, successful implementation and evaluation of such programs is challenging. However, there is limited knowledge about (overcoming) the challenges of implementation and experimental evaluation of school-based programs. The goal of the present paper is, therefore, to improve future research by describing the challenges encountered and lessons learned during two randomized controlled trials (RCTs) to study the effectiveness of two skills-training programs reducing school or social stress. In this way, we aim to inform others who plan to implement and evaluate such programs in schools using an RCT design. Some of the challenges encountered apply to all effectiveness studies, such as the recruitment and retention of participants; others are more "intervention at school" specific, such as scheduling the programs and assessments. Our experiences show that it is possible to effectively implement and evaluate targeted programs promoting adolescent mental health in secondary schools with RCTs, even during a worldwide health pandemic, but that it requires investing sufficient time in keeping close and regular contact as well as clear communication between the involved parties. Moreover, high levels of flexibility are needed in adjusting scheduled meetings for intervention and research while keeping track of the entire process for each school and individual participant.

The present study aimed to identify overall stress and salient stressors experienced by adolescents from different education tracks and self-perceived ethnic backgrounds. A total of 1489 adolescents (M = 13.40 years; SD = 0.89 years) from nine Dutch secondary schools participated. Self-reported stressors were measured with the adapted version of the Adolescent Stress Questionnaire -- Short. After controlling for age, gender, country of birth, and school classes, results showed that overall stress did not differ for educational track nor for ethnic background subgroups. Adolescents in academic education reported more stress from school-related stressors than adolescents attending vocational education. Adolescents with a mixed ethnic background (i.e., Dutch and another ethnicity) reported more stress regarding school-related stressors than adolescents with a Dutch ethnic background. These differences between adolescents of different educational tracks and ethnic backgrounds have implications for intervention programs targeting specific stressors.

Abstract Background The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity. Methods Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. Results Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 − 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41–11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10−8), however, five variants were suggestive of association (P

Abstract Background Depression is a common mental disorder. Detecting (sub)clinical depressive symptoms in adolescents at an early stage and offering a low-threshold early intervention can minimize the risk of serious and/or long-term depression. As such, a digital intervention can be a low-threshold preventive and early intervention. This study aims to examine whether the Boost My Mood (BMM)-app is a suitable preventive early intervention for adolescents with (sub)clinical depressive symptoms. Methods This naturalistic single-arm evaluation study (N = 50) was conducted in adolescents aged 16–21 with (sub)clinical depressive symptoms. Furthermore, the BMM-app was studied in relation to anxiety, worrying, stress, and sleeping problems. An exploratory objective was to determine whether positive expectations and social support are related to app use. Results The study showed a significant decrease in not only depressive symptoms, but also anxiety, worrying and stress while using the BMM-app. Sleeping problems did not significantly decrease over time while using the BMM-app. The degree of use of the BMM-app and telling significant others about using the BMM-app were both not related to a decrease in depressive symptoms. The BMM-app was used significantly more when the adolescent had told relatives about their depressive symptoms. Conclusions A digital intervention, such as the BMM-app, can be a low-threshold preventive and early intervention for adolescents with (sub)clinical depressive symptoms. Beneficial effects of the BMM-app were reported on depressive symptoms as well as other aspects of quality of life, such as anxiety, worrying, and stress. Whereas several factors may have played a role in the current findings on depressive symptoms, there are reasons to assume that part of the reduction in symptoms could be attributed to the BMM-app. Although no causality can be assumed, this study is a first step in the implementation of preventive apps in mental health care.

Abstract Quantum annealing emerges as a promising approach for tackling complex scheduling problems such as the resource-constrained project scheduling problem (RCPSP). This study represents the first application of quantum annealing to solve the RCPSP, analyzing 12 well-known mixed integer linear programming (MILP) formulations and converting the most qubit-efficient one into a quadratic unconstrained binary optimization (QUBO) model. We then solve this model using the D-wave advantage 6.3 quantum annealer, comparing its performance against classical computer solvers. Our results indicate significant potential, particularly for small to medium-sized instances. Further, we introduce time-to-target and Atos Q-score metrics to evaluate the effectiveness of quantum annealing and reverse quantum annealing. The paper also explores advanced quantum optimization techniques, such as customized anneal schedules, enhancing our understanding and application of quantum computing in operations research.

Background: Given that high levels of stress during adolescence are associated with negative consequences, it is important that adolescents with psychological needs are supported at an early stage, for instance with interventions at school. However, knowledge about the potential of school-based programs targeting adolescents with psychological needs, aimed at reducing school or social stress, is lacking. Objective: The current study aimed to investigate the effectiveness of two targeted school-based skills-training programs, addressing either skills to deal with performance anxiety or social skills. Methods: Two randomized controlled trials were performed with participants who self-selected to one of the programs. The sample comprised of N = 361 adolescents (M[subscript age] = 13.99 years, SD = 0.83) from various educational levels and ethnic identity backgrounds. The performance anxiety program included N = 196 participants (N = 95 in the experimental group), while the social skills program included N = 165 participants (N = 86 in the experimental group). MANCOVA's were performed. Results: The performance anxiety program had a small effect on reducing adolescents' test anxiety. Furthermore, for adolescents who attended more than half of the sessions, the program had small effects on reducing test anxiety and fear of failure. The program did not improve adolescents' coping skills or mental health. The social skills program was not effective in improving social skills, social anxiety, and mental health. Conclusions: A relatively short, targeted program addressing skills to deal with performance anxiety can have the potential to reduce adolescents' performance anxiety.

Intradiscal drug delivery is a promising strategy for treating intervertebral disk degeneration (IVDD). Local degenerative processes and intrinsically low fluid exchange are likely to influence drug retention. Understanding their connection will enable the optimization of IVDD therapeutics. Release and retention of an inactive hydrophilic fluorine-19 labeled peptide (19F-P) as model for regenerative peptides was studied in a whole IVD culture model by measuring the 19F-NMR (nuclear magnetic resonance) signal in culture media and IVD tissue extracts. In another set-up, noninvasive near-infrared imaging was used to visualize IR-780, as hydrophobic small molecular drug model, retention upon injection into healthy and degenerative caudal IVDs in a rat model of disk degeneration. Furthermore, IR-780-loaded degradable polyester amide microspheres (PEAM) were injected into healthy and needle pricked degenerative IVDs, subcutaneously, and in knee joints with and without surgically-induced osteoarthritis (OA). Most 19F-P was released from the IVD after 7 days. IR-780 signal intensity declined over a 14-week period after bolus injection, without a difference between healthy and degenerative disks. IR-780 signal declined faster in the skin and knee joints compared to the IVDs. IR-780 delivery by PEAMs enhanced disk retention beyond 16 weeks. Moreover, in degenerated IVDs the IR-780 signal was higher over time than in healthy IVDs while no difference between OA and healthy joints was noted. We conclude that the clearance of peptides and hydrophobic small molecules from the IVD is relatively fast. These results illustrate that development of controlled release formulations should take into account the target anatomical location and local (patho)biology.

Background: HER2 targeting in esophageal adenocarcinoma (EAC) has shown potential, but often fails to show durable response. Given the contributions of the tumor immune microenvironment (TIME) to therapeutic responses, we aimed to chart the TIME characteristics of HER2 positive tumors. Methods: 84 biopsies were taken from the TRAP cohort (neoadjuvant chemoradiotherapy (nCRT) according to CROSS with trastuzumab and pertuzumab; n = 40; HER2+ n = 40) and a control cohort with nCRT only (n = 44; HER2- n = 40, HER2+ n = 4) before treatment. Biopsies were analysed using targeted gene expression analysis (Nanostring immune-oncology panel, 750 genes). Differential gene expression was assessed between HER2 positive (n = 44) vs. negative biopsies (n = 40), and non-responders (n = 17) vs. responders (n = 23) to anti-HER2 treatment. Statistical significance was determined as p-value

ABSTRACT In many socially monogamous bird species with biparental care, occasional social polygyny has been detected. We provide information about a case of facultative polygyny in the European Nightjar (Caprimulgus europaeus). The male nightjar (I96) formed a pair with two females (I95: the presumed primary female with whom he already bred since 2018; M042: the presumed secondary female, an inexperienced yearling). GPS and accelerometer data demonstrate how the male only sang in proximity of the primary nest, while assisting both females during incubation, as well as during the nestling period. When the male came to the nest, the primary and/or secondary female went foraging, but the secondary female received less assistance during incubation than the primary female, and her eggs were often left unattended. However, once the chicks of the secondary female hatched, male assistance suddenly increased, presumably at a cost to the primary female. Being only the second record of social polygyny in the European Nightjar, we do not have a direct explication for the occurrence of this polygynous event. We note that male density at the study site was lower than that observed in previous seasons. The male may have taken over the female that was initially paired to a neighbouring territory holder that then died. Alternatively, the inexperienced female might have mated with an already paired male, either because she was not aware of the mating status of the male, or because she could not find an unpaired male, or because mating with this paired male was better than mating with another unpaired male. In any case, the breeding ecology and mating behaviour of this crepuscular bird species remains little understood.

Noggin (NOG) is an antagonist of bone morphogenetic proteins (BMPs), which regulates development and homeostasis of bone and cartilage. NOG has also been discovered to be an antagonist of transforming growth factor-β1 (TGF-β1). However, the effect of NOG on chondrogenesis induced by TGF-β1 remains unknown. Interestingly, in previous work NOG did not appear to influence TGF-β3-driven chondrogenesis, implying isoform specificity. In our study, the impact of exogenous NOG on TGF-β-induced chondrogenesis of bone marrow derived mesenchymal stromal cells (MSCs) was further investigated. Both TGF-β1 and TGF-β3 supplementation increased NOG expression at day 7, 14, 21 and 28 in MSC pellet culture. Addition of NOG during chondrogenic differentiation in vitro reduced sGAG release into the medium and retention within the pellet induced by TGF-β1 or TGF-β3. This was further confirmed by Safranin O/Fast Green staining. Gene downregulation including ACAN, COL2A1 and SOX9, was also observed downregulated by NOG at day 7. The same inhibitory role of NOG in TGF-β1 or TGF-β3-induced chondrogenesis suggests that the effect is not isoform-specific. We also observed differences mediated by NOG between the TGF-β1 and TGF-β3 groups. NOG suppresses cell proliferation during TGF-β1-induced chondrogenesis, whereas no significant alteration was observed in the TGF-β3 group. The effect of NOG on hypertrophy at day 7 was also investigated. In the TGF-β1 group, NOG resulted in alleviation of hypertrophy by downregulating COL10A1 and IHH expression. In the TGF-β3 group, NOG reduced hypertrophy through downregulation of COL10A1 and RUNX2.

Abstract Background Despite the advent of neoadjuvant chemoradiotherapy (CRT), overall survival rates of esophageal adenocarcinoma (EAC) remain low. A readily induced mesenchymal transition of EAC cells contributes to resistance to CRT. Methods In this study, we aimed to chart the heterogeneity in cell state transition after CRT and to identify its underpinnings. A panel of 12 esophageal cultures were treated with CRT and ranked by their relative epithelial-mesenchymal plasticity. RNA-sequencing was performed on 100 pre-treatment biopsies. After RNA-sequencing, Ridge regression analysis was applied to correlate gene expression to ranked plasticity, and models were developed to predict mesenchymal transitions in patients. Plasticity score predictions of the three highest significant predictive models were projected on the pre-treatment biopsies and related to clinical outcome data. Motif enrichment analysis of the genes associated with all three models was performed. Results This study reveals NANOG as the key associated transcription factor predicting mesenchymal plasticity in EAC. Expression of NANOG in pre-treatment biopsies is highly associated with poor response to neoadjuvant chemoradiation, the occurrence of recurrences, and median overall survival difference in EAC patients (>48 months). Perturbation of NANOG reduces plasticity and resensitizes cell lines, organoid cultures, and patient-derived in vivo grafts. Conclusions In conclusion, NANOG is a key transcription factor in mesenchymal plasticity in EAC and a promising predictive marker for outcome.

Youth-initiated mentoring is an innovative youth care approach in which youth recruit supportive adults from their social networks as a mentor for youth and a partner for parents and professionals. This qualitative interview study documents what youth (n = 15) and parents (n = 13) from multi-problem families look for in a mentor, what mentors (n = 8) believe they have to offer, and whether what mentors believe to offer matches youth's and parents' needs. Youth and parents indicated that a strong connection and trust were most important, or even prerequisites, as youth who were unable to find mentors did not have strong relationships of trust. Youth and parents also voiced preferences for an understanding, sensitive mentor who offered youth perspective by providing support and advice and (according to some) setting rules. What mentors believed to offer matched youth's and parents' needs, suggesting that most youth successfully recruited suitable mentors.

Abstract Chronic low back pain caused by intervertebral disc (IVD) degeneration, also termed chronic discogenic low back pain (CD‐LBP), is one of the most prevalent musculoskeletal diseases. Degenerative processes in the IVD, such as inflammation and extra‐cellular matrix breakdown, result in neurotrophin release. Local elevated neurotrophin levels will stimulate sprouting and innervation of sensory neurons. Furthermore, sprouted sensory nerves that are directly connected to adjacent dorsal root ganglia have shown to increase microglia activation, contributing to the maintenance and chronification of pain. Current pain treatments have shown to be insufficient or inadequate for long‐term usage. Furthermore, most therapeutic approaches aimed to target the underlying pathogenesis of disc degeneration focus on repair and regeneration and neglect chronic pain. How biomolecular therapies influence the degenerative IVD environment, pain signaling cascades, and innervation and excitability of the sensory neurons often remains unclear. This review addresses the relatively underexplored area of chronic pain treatment for CD‐LBP and summarizes effects of therapies aimed for CD‐LBP with special emphasis on chronic pain. Approaches based on blocking pro‐inflammatory mediators or neurotrophin activity have been shown to hamper neuronal ingrowth into the disc. Furthermore, the tissue regenerative and neuro inhibitory properties of extracellular matrix components or transplanted mesenchymal stem cells are potentially interesting biomolecular approaches to not only block IVD degeneration but also impede pain sensitization. At present, most biomolecular therapies are based on acute IVD degeneration models and thus do not reflect the real clinical chronic pain situation in CD‐LBP patients. Future studies should aim at investigating the effects of therapeutic interventions applied in chronic degenerated discs containing established sensory nerve ingrowth. The in‐depth understanding of the ramifications from biomolecular therapies on pain (chronification) pathways and pain relief in CD‐LBP could help narrow the gap between the pre‐clinical bench and clinical bedside for novel CD‐LBP therapeutics and optimize pain treatment.

This paper explores recently emerging challenges in Medical Assistance in Dying on Psychiatric Grounds (MAID-PG), focusing on ethical, clinical, and societal perspectives. Two themes are explored. First, the growing number of young MAID-PG requestors and the public platform given to MAID-PG requests. Ethically, media portrayal, particularly of young patients’ testimonials, requires scrutiny for oversimplification, acknowledging the potential for a Werther effect alongside the absence of a Papageno effect. This highlights the need for better communication policies for media purposes. Second, cautionary considerations regarding psychiatric care adequacy are addressed. In MAID-PG this includes reasons underlying psychiatrist reluctance to engage in MAID-PG trajectories, leading to growing waiting lists at end-of-life-care centers. Addressing current shortages in psychiatric care adequacy is crucial, necessitating less narrow focus on short-term care trajectories and recovery beside transdiagnostic treatment approaches, expanded palliative care strategies, and integrated MAID-PG care.

Abstract Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88−1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73−2.38; p = 0.44). Grade 3−4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p

Abstract Background Railway suicide has profound implications for the victims and their family, and affects train drivers, railway personnel, emergency services and witnesses. To inform a multilevel prevention strategy, more knowledge is required about psychosocial and precipitating risk factors of railway suicide. Methods Data from Statistics Netherlands of all suicides between 2017 and 2021 (n = 9.241) of whom 986 died by railway suicide and interview data from a psychosocial autopsy of railway suicide decedents (n = 39) were integrated. We performed logistic regression analyses to identify sociodemographic predictors of railway suicide compared to other methods of suicide. The Constant Comparative Method was subsequently employed on interview data from the psychosocial autopsy to identify patterns in psychosocial risk factors for railway suicide. Results The strongest predictors of railway suicide compared to other suicide methods were young age ( 150.000 euros. Several subgroups emerged in the psychosocial autopsy interviews, which specifically reflect populations at risk of railway suicide. These subgroups were [1] young adult males with autism spectrum disorder who strived for more autonomy and an independent life, [2] young adult females with persistent suicidal thoughts and behaviours, [3] middle-aged males with a persistent mood disorder who lived with family and who faced stressors proximal to the suicide in personal and professional settings, [4] male out-of-the-blue suicides and [5] persons with psychotic symptoms and a rapid deterioration. Conclusions based on our findings we propose and discuss several recommendations to prevent railway suicide. We must continue to invest in a safe railway environment by training personnel and installing barriers. Additionally, we should adopt prevention strategies that align the needs of subgroups at increased risk, including young females who have attempted other methods of suicide and young males with autism spectrum disorder. Future research should determine the cost-effectiveness and feasibility of low-maintenance, automated interventions near crossings and psychiatric facilities.

Abstract Background Children from multi-problem families have an increased risk for experiencing mental health problems. These families face problems in several domains that are often found to be chronic and intergenerational. Yet, the effects of mental health care for youths from multi-problem families are small at best, urging research on new treatment programs. The InConnection approach is an integrated care program to improve resilience of youths with mental health needs from multi-problem families by connecting professional expertise from multiple disciplines with the informal social network of the youth. Youths are asked to nominate a youth-initiated mentor (YIM) from the supportive adults in their network. Methods This quasi-experimental study compared the effectiveness of the InConnection approach to treatment as usual in a sample of 107 families (n = 66 intervention group, n = 41 control group) with n = 115 youths receiving treatment (cases). Youths (n = 102 reports, M age = 15.59 years), parents (n = 85 reports) and case managers (n = 107 reports) responded to questionnaires four times over 15 months. Using these data, we measured youth resilience as the primary outcome, seven secondary outcomes, and three intermediate outcomes. Results Latent growth models showed only one significant change in outcomes over time across conditions, namely a decrease in case manager-reported child unsafety, and only two condition effects, which were both parent-reported. Parents in the InConnection group reported improvements over time in youth’s emotional and behavioral problems and their own positive parenting, whereas control parents reported no changes (ps ≤ 0.013). Discussion The treatment conditions were not effective in improving most of the youth and parental outcomes over time, except for child safety reported by the case manager. The InConnection approach only outperformed care as usual on two parent-reported outcomes. Future research should examine for whom and under what circumstances the InConnection approach works more convincingly. Trial registration Netherlands Trial Register NL7565. Retrospectively registered on 05/03/2019.

IntroductionWithin the Dutch clinical field of specialized mental health care for youth, an increasing subgroup of female adolescents with severe chronic suicidal behavior is recognized. This group was also identified in a Dutch psychological autopsy study among 35 relatives of adolescents (aged 10–19 years old) who died by suicide. There seems to be a lack of knowledge and consensus how to treat this severe chronic suicidal behavior, resulting in stagnation of care and growing demoralization among patients, parents, and mental health care providers. The aim of this paper is to describe characteristics of the suicidal process, to identify challenges experienced in providing mental health care for this subgroup, and to formulate preliminary recommendations.MethodA case description from the psychological autopsy study and a review of the relevant literature.ResultsThe persistent suicidal threat and the resulting despair of the patient and their parents are forcing the mental health care provider into an impasse: the primary focus of treatment slowly moves to guarantee the patient's safety, which leaves the treatment of underlying problems underexposed. Due to the chronicity of the suicidal ideation and behavior in a phase in which identity formation and developing cognitive and emotional regulation skills are important developmental tasks, we identify a risk of developing a suicidal identity.DiscussionBased on expert knowledge, we make recommendations on (1) treating suicidality as a transdiagnostic phenomenon with its own meaning and function, (2) implementing treatment considerations promoting the autonomy, (3) aiming at continuity of care and prevention of repeated patient referrals by creating a multidisciplinary network of care providers, and (4) making chronic suicidality tolerable for the care provider.ConclusionWe propose preliminary practical recommendations in our quest for optimal mental health care for chronically suicidal adolescents.

Strong Teens and Resilient Minds (STORM) is a multimodal, school-based approach for depression and suicide prevention in adolescents that is currently implemented in a region in the Netherlands. The STORM approach will be implemented in new regions in the coming years. This study used the implementation mapping protocol to report on the development of the STORM implementation plan. First, a needs assessment was conducted through semi-structured interviews with stakeholders and brainstorming sessions with regional programme leaders in the two regions that started implementing STORM in 2023. This led to the identification of six main barriers to implementation: high level of demands for schools, insufficient understanding of the programme content, insufficient network collaboration, no perceived relative advantage of STORM by stakeholders, lack of attention to sustainability, and high work pressure. Second, performance and change objectives were formulated based on these barriers. For example, a performance objective for potential providers was that they felt supported by STORM. Third, implementation strategies were selected from theory and translated into practical applications through brainstorming sessions with programme leaders. The following strategies were included in the implementation plan: collaborate with similar initiatives within the region, free up time for STORM tasks, tailor strategies, identify and prepare STORM champions, and promote network weaving. Last, a plan to evaluate the implementation of STORM and the application of the STORM implementation plan was formulated. Planned evaluation research will provide more insight into the usefulness and impact of the STORM implementation plan.

Previous studies on the processing of ambiguous pronominal reference have led to contradictory results: some suggested that ambiguity may hinder processing (Stewart, Holler, & Kidd, 2007), while others showed an ambiguity advantage (Grant, Sloggett, & Dillon, 2020) similar to what has been reported for structural ambiguities. This study provides a conceptual replication of Stewart et al. (2007, Experiment 1), to examine whether the discrepancy in earlier results is caused by the processing depth that participants engage in (cf. Swets, Desmet, Clifton, & Ferreira, 2008). We present the results from a word-by-word self-paced reading experiment with Dutch sentences that contained a personal pronoun in an embedded clause that was either ambiguous or disambiguated through gender features. Depth of processing of the embedded clause was manipulated through offline comprehension questions. The results showed that the difference in reading times for ambiguous versus unambiguous sentences depends on the processing depth: a significant ambiguity penalty was found under deep processing but not under shallow processing. No significant ambiguity advantage was found, regardless of processing depth. This replicates the results in Stewart et al. (2007) using a different methodology and a larger sample size for appropriate statistical power. These findings provide further evidence that ambiguous pronominal reference resolution is a flexible process, such that the way in which ambiguous sentences are processed depends on the depth of processing of the relevant information. Theoretical and methodological implications of these findings are discussed.

Chronic low back pain is often caused by intervertebral disc (IVD) degeneration. Preceding this degenerative process, the main cellular phenotype in the nucleus pulposus shifts from notochordal cells (NCs) to nucleus pulposus cells (NPCs). In previous studies, porcine NC-derived matrix (NCM), containing NC-secreted factors, induced matrix anabolic effects and inhibited pro-inflammatory mediators in NPCs in vitro and in degenerated canine IVDs in vivo. As the underlying mechanisms remained elusive, this study aimed to explore this with targeted gene expression and proteomic (DigiWest technology) analysis focused on inflammatory signaling pathways. After 6 hours, NCM (10 mg/mL) treatment initially stimulated pro-inflammatory mediators in canine and human NPCs in vitro and increased signaling in a chondrosarcoma derived Nuclear factor-κB reporter cell line. At protein level, NCM mainly induced changes in the Mitogen-activated protein kinase (MAPK) pathway after 72 hours. Expression of inhibitory Dual-specificity phosphatase (DUSP) proteins was increased in NCM-treated NPCs, whereas the expression of the three main pillars of the MAPK pathway (extracellular signal-regulated kinase (ERK)/cJun N-terminal kinase (JNK)/protein kinase C (PKC)) was inhibited. In follow-up validation, in vivo degenerated canine IVDs treated with an intradiscal NCM injection demonstrated increased DUSP5 and healthy nucleus pulposus marker (cytokeratin 19, Paired box 1 (PAX1), Forkhead Box F1 (FOXF1)) immunopositivity after 6 months of treatment. Altogether, NCM initially stimulated pro-inflammatory mediators in vitro, but thereafter exerts its prolonged effects by inhibiting the MAPK pathway. These findings provide insights in the underlying mechanisms involved in the instructive capacity of this naturally-derived biomaterial with the potential to serve as a cell-free NC-based therapy to treat intervertebral disc degeneration.