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Abstract Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that amyloid-like proteins are produced in a variety of human cell types, including stem cells, brain organoids and fully differentiated neurons by mistakes that occur in messenger RNA molecules. Some of these mistakes generate mutant proteins already known to cause disease, while others generate proteins that have not been observed before. Moreover, we show that these mistakes increase when cells are exposed to DNA damage, a major hallmark of human aging. When taken together, these experiments suggest a mechanistic link between the normal aging process and age-related diseases.

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.

Introduction: A depressive disorder during adolescence is a serious and disabling disorder, which has a high impact on the development of adolescents. Blended treatment, combining online and face-to-face sessions, is effective and can reduce some of the barriers for adolescents to use mental health care. There is a lack of knowledge about whether therapeutic alliance is established in blended treatment for adolescents and young adults suffering from a depressive disorder. This study examines whether the quality of the therapeutic alliance differs when cognitive behavior therapy (CBT) is delivered in combination with online intervention (b-CBT) compared to solely face-to-face (FtF-CBT) and the extent to which a stronger therapeutic alliance is associated with better treatment outcome. Methods: A pragmatic quasi-experimental design was used. Data collected within two separate studies were combined. A total of 85 participants (80 % female), aged 13–22 (mean = 16.63, SD = 1.92) were recruited within mental health care institutions and diagnosed with a depressive disorder (using K-SADS). Assessments were done at pre-treatment (T0), after five weeks (T1), after ten weeks (T2), post-treatment (T3) and one to four weeks after treatment (T4) and included measures of depressive symptomatology (CDI-2). The therapeutic alliance was measured at T1, T2 and T3 by the TASC. t-tests for independent samples were used to test differences in therapeutic alliance rates between b-CBT and FtF-CBT at post-treatment. A linear growth model for depressive symptoms based on five time points with Latent Growth Curve Analysis (LGCA) was used to test whether the therapeutic alliance is associated with depressive symptoms. Results: No differences in therapeutic alliance between b-CBT and FtF-CBT were found on either client-rated or therapist-rated therapeutic alliance. For both intervention groups, no significant association between the therapeutic alliance and depressive outcome was found. Discussion: This study shows that providing part of CBT using an online environment does not have a negative impact on the therapeutic alliance. In contrast to earlier research, no association was found between the therapeutic alliance and therapy outcome in neither the b-CBT nor the FtF-CBT intervention.

In this paper an advanced modulation strategy is proposed that generates the switch control signals of a power converter while inherently guaranteeing zero-voltage switching (ZVS) operation. The proposed modulator is based on a first-order $\Delta \Sigma$-modulator combined with a hold-off circuit. This hold-off circuit consists of a D-latch and maintains the converter's switching state until ZVS commutation can be achieved while an integrator ensures the correct average output. Furthermore, features are implemented to improve start-up and transient behavior. The operating principle and stability of the proposed modulator is discussed and simulation results are presented. Finally, the proposed modulator is validated on a $2 \,\mathrm{k}\mathrm{W}$ GaN-based synchronous buck converter. Results show that the converter naturally operates under ZVS conditions by continuously varying its switching frequency without having to compute switching times or frequencies. The proposed method is an interesting alternative to pulse-width modulation especially when operating at high switching frequencies or when the switching loss in the power converter is significant.

Abstract Background Substance use is highly prevalent among Dutch adolescents. The Healthy School and Drugs program is a nationally implemented school-based prevention program aimed at reducing early and excessive substance use among adolescents. Although the program's effectiveness was tested in a quasi-experimental design before, many program changes were made afterwards. The present study, therefore, aims to test the effects of this widely used, renewed universal prevention program. Methods/Design A randomized clustered trial will be conducted among 3,784 adolescents of 23 secondary schools in The Netherlands. The trial has three conditions; two intervention conditions (i.e., e-learning and integral) and a control condition. The e-learning condition consists of three digital learning modules (i.e., about alcohol, tobacco, and marijuana) that are sequentially offered over the course of three school years (i.e., grade 1, grade 2, and grade 3). The integral condition consists of parental participation in a parental meeting on substance use, regulation of substance use, and monitoring and counseling of students' substance use at school, over and above the three digital modules. The control condition is characterized as business as usual. Participating schools were randomly assigned to either an intervention or control condition. Participants filled out a digital questionnaire at baseline and will fill out the same questionnaire three more times at follow-up measurements (8, 20, and 32 months after baseline). Outcome variables included in the questionnaire are the percentage of binge drinking (more than five drinks per occasion), the average weekly number of drinks, and the percentage of adolescents who ever drunk a glass of alcohol and the percentage of adolescents who ever smoked a cigarette or a joint respectively for tobacco and marijuana. Discussion This study protocol describes the design of a randomized clustered trial that evaluates the effectiveness of a school-based prevention program. We expect that significantly fewer adolescents will engage in early or excessive substance use behaviors in the intervention conditions compared to the control condition as a direct result of the intervention. We expect that the integral condition will yield most positive results, compared with the e-learning condition and control condition. Trial registration The protocol for this study is registered with the Nederlands Trial Register NTR1516

Background: Pre-test genetic counseling of patients with breast cancer is increasingly being offered by non-genetic healthcare professionals. We aimed to evaluate the experiences of patients with breast cancer receiving pre-test genetic counseling from a non-genetic healthcare professional (i.e., surgeon or nurse). Methods: Patients who were diagnosed with breast cancer and received pre-test counseling from their surgeon or nurse (mainstream group), and patients who received pre-test counseling from a clinical geneticist (usual care group) were invited to participate in our multicenter study. Between September 2019 and December 2021, patients received a questionnaire after pre-test counseling (T0) and four weeks after receiving their test results (T1) to evaluate psychosocial outcomes, knowledge, discussed topics and satisfaction. Results: We included 191 patients in our mainstream and 183 patients in our usual care group and received, respectively 159 and 145 follow-up questionnaires. Levels of distress and decisional regret were comparable in both groups. Decisional conflict was higher in our mainstream group (p = 0.01), but only 7% had clinically relevant decisional conflict (vs 2% in usual care group). The possible implications of a genetic test on (secondary) breast or ovarian cancer risks were less frequently discussed in our mainstream group (p = 0.03 and p = 0.000, respectively). In both groups knowledge about genetics was comparable, satisfaction was high and the majority of patients in both groups preferred to give both verbal and written consent for genetic testing. Conclusion: Mainstreamed genetic care provides sufficient information for the majority of breast cancer patients to decide about genetic testing with minimal distress.

Abstract Background Measurement-Based Care (MBC) is the routine administration of measures, clinicians’ review of the feedback and discussion of the feedback with their clients, and collaborative evaluation of the treatment plan. Although MBC is a promising way to improve outcomes in clinical practice, the implementation of MBC faces many barriers, and its uptake by clinicians is low. The purpose of this study was to investigate whether implementation strategies that were developed with clinicians and aimed at clinicians had an effect on (a) clinicians’ uptake of MBC and (b) clients’ outcomes of MBC. Methods We used an effectiveness-implementation hybrid design based on Grol and Wensing’s implementation framework to assess the impact of clinician-focused implementation strategies on both clinicians’ uptake of MBC and outcomes obtained with MBC for clients in general mental health care. We hereby focused on the first and second parts of MBC, i.e., the administration of measures and use of feedback. Primary outcome measures were questionnaire completion rate and discussion of the feedback with clients. Secondary outcomes were treatment outcome, treatment length, and satisfaction with treatment. Results There was a significant effect of the MBC implementation strategies on questionnaire completion rate (one part of clinicians’ uptake), but no significant effect on the amount of discussion of the feedback (the other part of clinicians’ uptake). Neither was there a significant effect on clients’ outcomes (treatment outcome, treatment length, and satisfaction with treatment). Due to various study limitations, the results should be viewed as exploratory. Conclusions Establishing and sustaining MBC in real-world general mental health care is complex. This study helps to disentangle the effects of MBC implementation strategies on differential clinician uptake, but the effects of MBC implementation strategies on client outcomes need further examination.

The molecular mechanisms that ensure faithful transcription of genetic information are still unclear. Chung et al. identify various genes, alleles and processes that affect the fidelity of transcription multiple organisms, suggesting evolutionary conservation of fidelity factors, and compare the error rate of transcription among these species.

Adolescent depression is a major concern for public health and is associated with negative consequences and outcomes. Identifying adolescent characteristics that might relate to the risk for developing depression is crucial. This study investigated bidirectional associations between coping strategies and depressive symptoms over time. The participants were 1,341 secondary school students from the Netherlands (X-bar = 13.91, SD = 0.55, 47.5% girls) who completed self-report questionnaires at six waves over 2.5 years. Cross-lagged models were used to investigate the associations between coping strategies and depressive symptoms. Coping strategies did not predict depressive symptoms over time. However, there was an indication of the reverse relationship. When adolescents experienced elevated depressive symptoms, they used fewer adaptive techniques to target stress. Gender differences were found in the use of avoidance. The inconsistencies of these findings with earlier studies are discussed and provide new directions for future research on working mechanisms underlying depression prevention programs.

Background: Based on self-reported social capital, different typologies of family networks of people with intellectual disabilities were examined. Associations between behavioural and emotional problems or well-being and typologies were investigated. Method: 137 participants with mild intellectual disability were interviewed using the Family Network Method-Intellectual Disability to assess their emotionally supportive family relationships. Data on participants' well-being and behavioural and emotional problems were also gathered. Latent class analysis was used to identify family typologies based on social network measures. Results: Four distinguishable typologies were identified, two supportive and two less supportive. A small association was found with behavioural and emotional problems and one of the supportive typologies. Associations with constructs of well-being were found for both supportive and less supportive typologies. Conclusions: A variety of family types were found, with implications for sensitive professional support.

Numerous lines of evidence suggest that DNA damage contributes to the initiation, progression, and severity of neurodegenerative diseases. However, the molecular mechanisms responsible for this relationship remain unclear. This review integrates historical data with contemporary findings to propose that DNA damage exacerbates neurodegenerative diseases by inducing transcription errors. First, we describe the scientific rationale and basic biological concepts that underpin this hypothesis. Then, we provide epidemiological, cellular, and molecular data to support this idea, and we describe new and recently published observations that suggest that the former high incidence of neurodegenerative disease in Guam may have been driven by DNA damage-induced transcription errors. Finally, we explore the long-term implications of these findings on our understanding of the impact of genotoxic stress on human aging and disease. [ABSTRACT FROM AUTHOR]

This work presents a closed-form analytic approach to calculate the distortion introduced in resistive current measurements due to thermal properties of shunt resistors. As a shunt’s resistance varies with temperature, the sensed voltage becomes distorted. This non-linear effect depends on the thermal interface, dissipated power and material properties of the shunt resistor. It is presented, how to simplify the non-linear equation of the shunt temperature and calculate the resulting voltage spectrum, without the use of computationally extensive time-to-frequency-domain transforms. The results of the presented method match simulations including the non-linear behaviour, enabling a quick search through a solution space. The method is experimentally verified by use of a linear amplifier with an output distortion of −90 dB at low frequencies. In the experiment, a total harmonic distortion of up to −70 dB is observed in several shunt resistors covering a range of different thermal properties. Based on the presented method, shunt resistors can be chosen according to the minimum distortion required in a given application. Depending on the frequencies of interest, shunt resistors with a high temperature coefficient might still offer sufficient distortion performance.

Accurate calculation of semiconductor losses and temperature is the foundation of any design methodology for a power electronic converter. Computation accuracy and speed play a vital role if a large set of parameters needs to be considered. Averaged loss models often neglect the temperature dependence of transistors, leading to fast, but inaccurate results. In contrast, iterative methods and simulation tools, which can include temperature dependence, take significantly longer to compute, but yield more precise results. This paper presents a best of both worlds approach, by using the harmonic balance method to obtain the steady-state solution for any inverter topology including temperature dependent conduction and switching losses. The proposed method solves for the discrete Fourier series of the device temperature, by expressing the temperature dependence and operating parameters in the frequency domain. The set of equations for each coefficient is solved by a single matrix inversion, resulting in very fast computation for steady-state temperature cycles. The steady-state operation of over one thousand possible inverter designs is calculated within less than one minute, matching iterative simulation in device temperature, conduction and switching losses, at a fraction of the computation time. In addition, the method shows good agreement with temperature measurements of a three-phase silicon-carbide inverter.

Introduction: Identifying factors that contribute to the development of suicidal ideation (SI) is crucial for prevention and treatment. Perfectionistic Concerns (PC) represent the experience of external pressure to be perfect and have been consistently linked to SI, but it is unclear how PC and SI are associated in depressed adults. This study examined the association between PC and SI and whether self-esteem, loneliness and rumination (brooding, reflection and depression-related rumination) moderated this association in a clinical sample. Methods: This cross-sectional study used a psychiatric outpatient sample of depressed adults, selected for the presence of SI. In total 110 adults (mean age 33.54 (SD = 12.03) and 60% female) participated in this study. Associations were estimated by regression analyses. Results: PC was not associated with SI in the sample (r =.16, p =.087). However, high levels of PC in combination with low self-esteem (β = -.29, p =.007) or with high levels of depression-related rumination (β =.22, p =.017) were positively associated with SI. Loneliness, brooding and reflection did not moderate the PC-SI relationship. Discussion: These findings underline the importance of taking into account the individual characteristics in depressed, perfectionistic individuals when estimating SI severity and selecting the focus of intervention. Due to the cross-sectional design no causal inferences can be made. [ABSTRACT FROM AUTHOR]

Accurate transcription is required for the faithful expression of genetic information. However, little is known about the fidelity of RNA synthesis or the biological consequences of transcription errors in living cells. Here, we review recent developments in massively parallel sequencing technology that allow the fidelity of transcription to be measured with unprecedented accuracy and summarize new observations that provide insight into the role of transcription errors in aging and disease. Taken together, these developments have the potential to change our understanding of mutagenesis itself, and significantly enhance our understanding of the origins of human disease.

Our most recent RCT provides evidence that indicated depression prevention is effective in reducing depressive symptoms in adolescents when implemented in the school community. In the present study we further test the potential effects of this prevention approach on symptoms related to depression: anxiety, suicidality, somatic symptoms, and perfectionism. We conducted exploratory analyses in 130 adolescents with elevated depressive symptoms aged between 12 and 16 years old (M = 13.59; SD = 0.68; 63.8% girls) who were randomly assigned to the experimental (OVK 2.0) or active control condition (psycho-education). Self-reported anxiety, suicidality, somatic symptoms, and perfectionism were assessed at pretest, post intervention, as well as 6- and 12-months follow-up. Latent growth curve analyses revealed that there was a significant decrease in anxiety in both conditions and that this decrease was significantly larger in the intervention condition than in the control condition. Somatic symptoms and socially prescribed perfectionism decreased significantly in the intervention condition and suicidality decreased significantly in the control condition. Yet there was no difference in decrease in suicidality, somatic symptoms, and perfectionism between the two conditions. This study suggest that screening on depressive symptoms and providing a CBT depression prevention program for adolescents with elevated depressive symptoms, can decrease comorbid symptoms of anxiety and therefore ensure better outcomes. We discuss the clinical implications as well suggestions for future research.Clinical Trial Registration: The study is registered in the Dutch Trial Register for RCTs (NTR5725). Date registered: 11th of March 2016.

Background: The Multicenter Youth Flexible ACT Study is an ongoing observational prospective cohort study that examines the effects of Youth Flexible ACT (Assertive Community Treatment) on young people with complex care needs who are difficult to engage in traditional (office-based) mental health services. However, a clear and detailed description of this patient group is lacking. In the current paper, we present baseline characteristics and psychosocial outcomes of the Youth Flexible ACT target group and explore the existence of underlying specific patient subgroups.Methods: Sixteen Youth Flexible ACT teams from seven mental healthcare institutes in the Netherlands participated in the study. Research participants were monitored for 18 months and administered questionnaires measuring psychiatric- and social functioning every 6 months, yielding four measurements. Baseline data were obtained from 199 adolescents, their mental health workers, and parents/carers. Latent Class Analysis based on HoNOSCA scores (measuring psychosocial and daily functioning) was conducted to identify underlying subgroups.Results: The target group of Youth Flexible ACT mainly consisted of patients older than 15 years of age with a history of (specialized) mental healthcare. They face many complex problems, including trauma; developmental, mood, and anxiety disorders; and problems with school attendance, family life, and peer relationships. Other frequently reported difficulties were substance misuse, the involvement of the legal system or police, problems with intellectual functioning, and personal finance. Patients were classified into four distinct classes: the “internalizing,” “externalizing,” “non-specific,” and the “overly impulsive” subgroup. Each subgroup had its unique pattern of difficulties and focus, respectively, high levels of depression and anxiety, disruptive behavior, unspecific difficulties, and substance misuse.Conclusions: As expected, patients in Youth Flexible ACT experienced many severe problems, rendering them vulnerable to fragmented and, thus, ineffective care. Our findings underscore the need for an integrated care approach with a multidisciplinary team of skilled professionals that can bridge these wide-ranging psychosocial problems, as each class of participants experienced a different set of difficulties. Youth Flexible ACT teams need to adjust their care services accordingly.

Introduction When adolescents experience complex psychiatric and social problems, numerous healthcare services usually become involved. In these cases, fragmentation of care services is a risk that often results in both ineffective care and in patients disengaging from care services. To address these issues, Youth Flexible Assertive Community Treatment (Youth Flexible ACT) was developed in the Netherlands. This client-centred service delivery model aims to tackle the fragmented care system by providing psychiatric treatment and support in a flexible and integrated manner. While Youth Flexible ACT is gaining in popularity, the effectiveness of the care model remains largely unexamined.Methods and analysis Here, we present an observational prospective cohort (2017–2021) in which a broad range of treatment outcomes will be monitored. The primary aim of the study is to examine change in treatment outcomes over the course of the Flexible ACT care. The secondary aim is to examine the association between (elements of) Youth Flexible ACT model fidelity and treatment outcomes. An estimated total number of 200 adolescents who receive care from one of the 16 participating Youth Flexible ACT teams will be included in the study. Participants will be asked to complete assessments at four time points in 6-month intervals, resulting in a study duration of 18 months. Latent growth curve analysis will be conducted to examine change in psychosocial functioning over time and its relation to model fidelity.Ethics and dissemination This study received ethical approval from Trimbos Ethics Committee (201607_75-FACT2). This approval applies for all participating institutions. The results of the study will be reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology statement. Results will be disseminated via peer-reviewed academic journals and presentations at conferences. In addition, results will be made available for participating sites, funders and researchers.