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Abstract Background Depression and panic disorders have high prevalence rates in primary care. Given the crucial role of general practitioners in diagnosing and treating mental disorders, the two-arm cluster-randomized, controlled PREMA trial was designed. PREMA was aimed at investigating a new intervention combining cognitive behavioral therapy, case management and eHealth components for patients with depression and/or panic disorder with or without agoraphobia in primary care practices in Germany. This qualitative study, embedded in the PREMA trial, explores primary healthcare professionals’ lived experiences in using the new treatment program. Using a qualitative design, we conducted eleven interviews with general practitioners and medical assistants from Hesse, Germany, between July 2021 and March 2022. For both groups we relied on a semi-structured interview guide covering the following subjects: study procedures, implementation, practicality, and individual components of the treatment program. Interviews were audio-recorded, transcribed verbatim and analyzed by two researchers using content analysis. A deductive-inductive approach was used for the analysis according to Kuckartz. Results We narratively summarized the facilitators and barriers from two different stakeholders across five key themes regarding experiences of feasibility and practicability of the new treatment program: study instruction materials, individual components of the treatment program, practicality, target population, and benefits of the treatment program. Facilitators to become familiar with the study include study instruction materials that are easy to understand and not too complex, considering the limited time resources available; barriers included text-heavy instruction materials, lack of collegial exchange, and issues especially with digital materials also involved access and log-in difficulties on the online platform. Facilitators for using the treatment program include the combination of face-to-face consultations and the use of an online platform, enabling a structured approach and regularity; barriers included patients feeling unsupported in performing anxiety exercises independently at home. For practicality, the professional skills of medical assistants and their central role as points of contact for patients facilitated the implementation; barriers included time-intensive organization and planning of monitoring phone calls and consultations. Regarding the target population, general practitioners and medical assistants state that the treatment program would be most appropriate for patients with mild to moderate depression and for those waiting for psychotherapeutic treatment; it would be less suitable for older patients, and those with negative attitudes towards technological tools. For benefits of the program, facilitating factors included free and low-threshold access to the online platform and strengthening the relationship between medical assistants and patients; barriers included a preference for in-person conversations and the inability of some people to use online applications. Conclusions The complexity of the new treatment program and the associated high workload underline the need for further adjustments to the treatment approach. Team-based care and the expanded responsibilities of medical assistants demonstrated promising results. Trial registration The study was registered in the German Clinical Trials Register (DRKS00016622) on February 22, 2019.

Abstract Background Despite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy. Methods/Design ACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material. Discussion ACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment. Trial registration The study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024. Graphical Abstract

Background Short and rare episodes of atrial fibrillation (AF) are commonly detected using implanted devices (device‐detected AF) in patients with prior stroke or transient ischemic attack (TIA). The effectiveness and safety of oral anticoagulation in patients with prior stroke or TIA and device‐detected AF but with no ECG‐documented AF is unclear. Methods and Results This prespecified analysis of the NOAH‐AFNET 6 (Non‐Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes) trial with post hoc elements assessed the effect of oral anticoagulation in patients with device‐detected AF with and without a prior stroke or TIA in the randomized, double‐blind, double‐dummy NOAH‐AFNET 6 trial. Outcomes were stroke, systemic embolism, and cardiovascular death (primary outcome) and major bleeding and death (safety outcome). A prior stroke or TIA was found in 253 patients with device‐detected AF randomized in the NOAH‐AFNET 6 (mean age, 78 years; 36.4% women). There was no treatment interaction with prior stroke or TIA for any of the primary and secondary time‐to‐event outcomes. In patients with a prior stroke or TIA, 14 out of 122 patients experienced a primary outcome event with anticoagulation (5.7% per patient‐year). Without anticoagulation, there were 16 out of 131 patients with an event (6.3% per patient‐year). The rate of stroke was lower than expected (anticoagulation: 4 out of 122 [1.6% per patient‐year]; no anticoagulation: 6 out of 131 [2.3% per patient‐year]). Numerically, there were more major bleeding events with anticoagulation in patients with prior stroke or TIA (8 out of 122 patients) than without anticoagulation (2 out of 131 patients). Conclusions Anticoagulation appears to have ambiguous effects in patients with device‐detected AF and a prior stroke or TIA in this hypothesis‐generating analysis of the NOAH‐AFNET 6 in the absence of ECG‐documented AF, partially due to a low rate of stroke without anticoagulation.

Chemical recycling of plastic wastes through pyrolysis, gasification, or partial oxidation is a promising alternative to landfill disposal and incineration which must be applied in a future circular economy. These technologies enable the chemical industry, which currently heavily relies on crude oil, to obtain necessary chemical feedstock from postconsumer plastic waste. Kinetic models of pyrolysis and gasification reactions are required to dimension and design these processes on an industrial scale. The creation of detailed kinetic networks is often not feasible due to their complexity in this application, which is when the lumped kinetic modeling approach is used. This work develops and compares five lumped kinetic models for the co-pyrolysis of LDPE with a heavy petroleum fraction in a tubular reactor. A priori lumping is used for four models, and the fifth is created using a posteriori principle whereby in each model the product mixture is defined by eight lumps distinguished by their boiling point. The aim of this work is to compare different approaches for modeling reaction pathways in lumped kinetic models and to identify their impact on the predictive accuracy of the model. It was shown that all of the modeling approaches and the resulting models have similar prediction accuracies and deviations but with different kinetic parameters. Each model was used for a scale-up of an industrial-sized reactor to check whether the model had an influence on the design or predicted operation of the reactor.

Abstract To survive, cells must respond to changing environmental conditions. One way that eukaryotic cells react to harsh stimuli is by forming physiological, RNA-seeded subnuclear condensates, termed amyloid bodies (A-bodies). The molecular constituents of A-bodies induced by different stressors vary significantly, suggesting this pathway can tailor the cellular response by selectively aggregating a subset of proteins under a given condition. Here, we identify critical structural elements that regulate heat shock-specific amyloid aggregation. Our data demonstrates that manipulating structural pockets in constituent proteins can either induce or restrict their A-body targeting at elevated temperatures. We propose a model where selective aggregation within A-bodies is mediated by the thermal stability of a protein, with temperature-sensitive structural regions acting as an intrinsic form of post-translational regulation. This system would provide cells with a rapid and stress-specific response mechanism, to tightly control physiological amyloid aggregation or other cellular stress response pathways.

Abstract Βackground Children of parents with a mental illness have up to 50% chance of developing a mental illness themselves. Numerous studies have shown that preventive family-oriented interventions can decrease the risk by 40% and that professionals are a decisive factor influencing family-oriented practice. There are also substantial differences between professions in terms of their family-oriented practices. This study examines the level of family-oriented practice for different professional groups in Germany. Methods Data were used from the baseline assessment of the two-group randomized controlled multicenter trial ci-chimps as a subproject of CHIMPS-NET, which took place from January 2020 to May 2021 in 18 clinical centers in Germany. Child and adolescent mental health systems as well as adult mental health systems took part and every professional involved in the treatment was invited to participate. Data was used from 475 mental health professionals including physicians, psychologists, psychotherapists for adults and for children and adolescents, occupational/ music/ physio/ art therapists/ (social) education workers and nursing/ education service. Family-oriented mental health practice was examined using the translated version of the Family-Focused Mental Health Practice Questionnaire (FFMHPQ) with means and standard deviations calculated for each of the 18 FFMHPQ-GV subscales. ANOVAs were computed to compare professions and significant differences were examined via post hoc analyses (Scheffé). Additionally, effect sizes were calculated (Omega squared). Results Differences were seen between the professions in all aspects of family-oriented practice: Both regarding organizational policy and support aspects, issues concerning working with parent-clients, as well as professional skills and knowledge aspects. Psychotherapists for children and adolescents scored the highest family-oriented practices compared to all other professional groups on almost all subscales. Conclusion This study examines the level of family-oriented practice for different professional groups in Germany. Apart from skills and knowledge about the impact of mental illness and parenting, psychotherapists for children and adolescents had the highest scores and engaged most in family-oriented practice. Psychotherapists for adults got the least workplace support for family-oriented practice but were competent providing resources and referral information to the concerned families and feel confidence working with them. Due to these results, a training need exists to improve skills and knowledge about the impact of mental illness and parenting. Additionally, there is still potential for institutional support in promoting family-oriented work. Trial registration The CHIMPS-NET-study was registered with the German Clinical Trials Register on 2019–12-19 (DRKS00020380) and with Clinical Trials on 2020–4-30 (NCT04369625), the ci-chimps-study was registered with the German Clinical Trials Register (DRKS00026217) on 2021–08-27 and with Clinical Trials on 2021–11-04 (NCT05106673).

AbstractBackground Atrial fibrillation (AF) is a common treatable risk factor for stroke. Screening for paroxysmal AF in general practice is difficult, but biomarkers might help improve screening strategies.Objectives We investigated six blood biomarkers for predicting paroxysmal AF in general practice.Methods This was a pre-specified sub-study of the SCREEN-AF RCT done in Germany. Between 12/2017-03/2019, we enrolled ambulatory individuals aged 75 years or older with a history of hypertension but without known AF. Participants in the intervention group received active AF screening with a wearable patch, continuous ECG monitoring for 2x2 weeks and usual care in the control group. The primary endpoint was ECG-confirmed AF within six months after randomisation. High-sensitive Troponin I (hsTnI), brain natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), N-terminal pro atrial natriuretic peptide (NT-ANP), mid-regional pro atrial natriuretic peptide (MR-pro ANP) and C-reactive protein (CRP) plasma levels were investigated at randomisation for predicting AF within six months after randomisation.Results Blood samples were available for 291 of 301 (96.7%) participants, including 8 with AF (3%). Five biomarkers showed higher median results in AF-patients: BNP 78 vs. 41 ng/L (p = 0.012), NT-pro BNP 273 vs. 186 ng/L (p = 0.029), NT-proANP 4.4 vs. 3.5 nmol/L (p = 0.027), MR-pro ANP 164 vs. 125 pmol/L (p = 0.016) and hsTnI 7.4 vs. 3.9 ng/L (p = 0.012). CRP levels were not different between groups (2.8 vs 1.9 mg/L, p = 0.1706).Conclusion Natriuretic peptide levels and hsTnI are higher in patients with AF than without and may help select patients for AF screening, but larger trials are needed.

Abstract Background This systematic review addresses how adolescent‐rated parent‐child communication (PCC) quality is related to adolescent mental health. Methods We performed a systematic literature search in Medline and APA PsycInfo, including peer‐reviewed quantitative studies examining associations between adolescent‐rated dyadic PCC quality and general as well as specific measures of adolescent mental health. Qualitative and case studies were excluded, as were studies reporting only parent‐rated communication quality or instruments assessing other constructs than dyadic PCC. We screened 5314 articles, of which 37 were included in the review. We assessed study quality with the Mixed Methods Appraisal Tool. Results We synthesized the findings in a table and narratively, reporting the main outcomes organized according to mental health constructs. The included studies were mainly cross‐sectional. The results showed that adolescent‐rated PCC quality is negatively associated with mental health constructs, demonstrating small to large effects across different mental health constructs and populations. The associations were found for general mental health and specific domains, including depression, anxiety, psychosis, suicidal ideation, post‐traumatic stress symptoms, and addictive internet use/gaming. Conclusions The findings demonstrate that PCC is a relevant variable to consider in assessing adolescent mental health and preventive efforts. Limitations include the exclusive focus on adolescent‐reported PCC questionnaires since parent‐ and observer‐rated instruments may lead to different results. Also, PCC is related to other constructs, such as dyadic relationships, that were not included in this review. We conclude that PCC is a relevant variable to consider in mental health research. Our findings suggest that PCC may be considered in mental health practice, both in terms of assessing its quality and potentially by tailoring interventions to enhance PCC. These may represent a mean to promote adolescent mental health.

Background: Abdominal tumors rarely occur in childhood but are associated with great psychological stress for patients and their families. Parents playing a central role in their children’s treatment may experience adverse effects on their Health-Related Quality of Life (HRQoL) and mental health due to the children’s illness and required treatment. Given the limited knowledge of the psychosocial burden of parents with children suffering from solid abdominal tumors, this study aims to assess their HRQoL and mental health along with the impact of various psychosocial factors. Methods: A cross-sectional cohort study was carried out involving 54 parents of children with solid abdominal tumors who had surgery at the University Medical Center Hamburg-Eppendorf in Germany. The results were compared with 46 parents of children undergoing routine surgeries without a prior tumor diagnosis, and with normative values. Data were obtained using standardized questionnaires. Results: Parents of the index group showed significantly worse HRQoL and limited mental health. Furthermore, they showed significantly higher parental burden in several subscales and less social support in comparison with the control group. Conclusions: Considering the lower parental HRQoL and the central role parents play in their children’s lives, it is crucial to include prevention and intervention measures for parents as part of a multimodal treatment regime for children with solid pediatric abdominal tumors.

Introduction Incisional hernia (IH) is a prevalent and potentially dangerous complication of abdominal surgery, especially in high-risk groups. Mesh reinforcement of the abdominal wall has been studied as a potential intervention to prevent IHs. Randomised controlled trials (RCTs) have demonstrated that prophylactic mesh reinforcement after abdominal surgery, in general, is effective and safe. In patients with abdominal aortic aneurysm (AAA), prophylactic mesh reinforcement after open repair has not yet been recommended in official guidelines, because of relatively small sample sizes in individual trials. Furthermore, the identification of subgroups that benefit most from prophylactic mesh placement requires larger patient numbers. Our primary aim is to evaluate the efficacy and effectiveness of the use of a prophylactic mesh after open AAA surgery to prevent IH by performing an individual patient data meta-analysis (IPDMA). Secondary aims include the evaluation of postoperative complications, pain and quality of life, and the identification of potential subgroups that benefit most from prophylactic mesh reinforcement.Methods and analysis We will conduct a systematic review to identify RCTs that study prophylactic mesh placement after open AAA surgery. Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase, Web of Science Core Collection and Google Scholar will be searched from the date of inception onwards. RCTs must directly compare primary sutured closure with mesh closure in adult patients who undergo open AAA surgery. Lead authors of eligible studies will be asked to share individual participant data (IPD). The risk of bias (ROB) for each included study will be assessed using the Cochrane ROB tool. An IPDMA will be performed to evaluate the efficacy, with the IH rate as the primary outcome. Any signs of heterogeneity will be evaluated by Forest plots. Time-to-event analyses are performed using Cox regression analysis to evaluate risk factors.Ethics and dissemination No new data will be collected in this study. We will adhere to institutional, national and international regulations regarding the secure and confidential sharing of IPD, addressing ethics as indicated. We will disseminate findings via international conferences, open-source publications in peer-reviewed journals and summaries posted online.PROSPERO registration number CRD42022347881.

Medienkritikfähigkeit ist eine Zentralkategorie des deutschsprachigen medienpädagogischen Diskurses und zählt als grundlegende Dimension von Medienkompetenz. Während die theoretische Diskussion zur Medienkritikfähigkeit rege geführt wird, fristen Fragen ihrer empirischen Erforschung bislang ein Schattendasein. Auf eben diese ein Licht zu werfen, ist Anliegen des Beitrags. Hierzu werden Streifzüge unternommen sowohl durch theoretische Konzeptionierungen von Medienkritikfähigkeit als auch durch empirische Untersuchungen im deutschsprachigen Raum. Identifiziert werden methodische wie methodologische Herausforderungen, die die Grundlage für die Formulierung von Implikationen künftiger Vorhaben zur empirischen Erforschung der Medienkritikfähigkeit von Kindern und Jugendlichen bilden. Darauf aufbauend werden abschliessend zwei prototypische Messmodelle zur Erfassung von Medienkritikfähigkeit ausgearbeitet.

The parametrisation of infectious disease models is often done based on epidemiological studies that use diagnostic and serology tests to establish disease prevalence or seroprevalence in the population being modelled. During outbreaks of an emerging infectious disease, tests are often used, both for disease control and epidemiological studies, before studies evaluating their accuracy in the population have concluded, with assumptions made about accuracy parameters like sensitivity and specificity. In this simulation study, we simulated such an outbreak, based on the case study of COVID-19, and found that inaccurate parametrisation of infectious disease models due to assumptions about antibody test accuracy in a seroprevalence study can cause modelling results that inform public health decisions to be inaccurate; for example, in our simulation setup, assuming that antibody test specificity was 0.99 instead of 0.90 when it was in fact 0.90 led to an average relative difference of 0.78 in model-projected peak hospitalisations, even when test sensitivity and all other parameters were accurately characterised. We therefore suggest that methods to speed up test evaluation studies are vitally important in the public health response to an emerging outbreak.

BackgroundTacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation.Methods/designThe study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs).DiscussionThis study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents.Clinical Trial RegistrationEUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

The accuracy of a diagnostic test is often expressed using a pair of measures: sensitivity (proportion of test positives among all individuals with target condition) and specificity (proportion of test negatives among all individuals without target condition). If the outcome of a diagnostic test is binary, results from different studies can easily be summarized in a meta-analysis. However, if the diagnostic test is based on a discrete or continuous measure (e.g., a biomarker), several cut-offs within one study as well as among different studies are published. Instead of taking all information of the cut-offs into account in the meta-analysis, a single cut-off per study is often selected arbitrarily for the analysis, even though there are statistical methods for the incorporation of several cut-offs. For these methods, distributional assumptions have to be met and/or the models may not converge when specific data structures occur. We propose a semiparametric approach to overcome both problems. Our simulation study shows that the diagnostic accuracy is under-estimated, although this underestimation in sensitivity and specificity is relatively small. The comparative approach of Steinhauser et al. is better in terms of coverage probability, but may lead to convergence problems. In addition to the simulation results, we illustrate the application of the semiparametric approach using a published meta-analysis for a diagnostic test differentiating between bacterial and viral meningitis in children.

Abstract The formation of protein aggregates is a hallmark of many neurodegenerative diseases and systemic amyloidoses. These disorders are associated with the fibrillation of a variety of proteins/peptides, which ultimately leads to cell toxicity and tissue damage. Understanding how amyloid aggregation occurs and developing compounds that impair this process is a major challenge in the health science community. Here, we demonstrate that pathogenic proteins associated with Alzheimer’s disease, diabetes, AL/AA amyloidosis, and amyotrophic lateral sclerosis can aggregate within stress-inducible physiological amyloid-based structures, termed amyloid bodies (A-bodies). Using a limited collection of small molecule inhibitors, we found that diclofenac could repress amyloid aggregation of the β-amyloid (1–42) in a cellular setting, despite having no effect in the classic Thioflavin T (ThT) in vitro fibrillation assay. Mapping the mechanism of the diclofenac-mediated repression indicated that dysregulation of cyclooxygenases and the prostaglandin synthesis pathway was potentially responsible for this effect. Together, this work suggests that the A-body machinery may be linked to a subset of pathological amyloidosis, and highlights the utility of this model system in the identification of new small molecules that could treat these debilitating diseases.

Abstract Whether you are reading, running or sleeping, your brain and its fluid environment continuously interacts to distribute nutrients and clear metabolic waste. Yet, the precise mechanisms for solute transport within the human brain have remained hard to quantify using imaging techniques alone. From multi-modal human brain MRI data sets in sleeping and sleep-deprived subjects, we identify and quantify CSF tracer transport parameters using forward and inverse subject-specific computational modelling. Our findings support the notion that extracellular diffusion alone is not sufficient as a brain-wide tracer transport mechanism. Instead, we show that human MRI observations align well with transport by either by an effective diffusion coefficent 3.5 $$\times $$ × that of extracellular diffusion in combination with local clearance rates corresponding to a tracer half-life of up to 5 h, or by extracellular diffusion augmented by advection with brain-wide average flow speeds on the order of 1–9 $$\mu $$ μ m/min. Reduced advection fully explains reduced tracer clearance after sleep-deprivation, supporting the role of sleep and sleep deprivation on human brain clearance.

Passivated, selective contacts in silicon solar cells consist of a double layer of highly doped polycrystalline silicon (poly Si) and thin interfacial silicon dioxide (SiO2). This design concept allows for the highest efficiencies. Here, we report on a selective laser activation process, resulting in highly doped p++-type poly Si on top of the SiO2. In this double-layer structure, the p++-poly Si layer serves as a layer for transporting the generated holes from the bulk to a metal contact and, therefore, needs to be highly conductive for holes. High boron-doping of the poly Si layers is one approach to establish the desired high conductivity. In a laser activation step, a laser pulse melts the poly Si layer, and subsequent rapid cooling of the Si melt enables electrically active boron concentrations exceeding the solid solubility limit. In addition to the high conductivity, the high active boron concentration in the poly Si layer allows maskless patterning of p++-poly Si/SiO2 layers by providing an etch stop layer in the Si etchant solution, which results in a locally structured p++-poly Si/SiO2 after the etching process. The challenge in the laser activation technique is not to destroy the thin SiO2, which necessitates fine tuning of the laser process. In order to find the optimal processing window, we test laser pulse energy densities (Hp) in a broad range of 0.7 J/cm2 ≤ Hp ≤ 5 J/cm2 on poly Si layers with two different thicknesses dpoly Si,1 = 155 nm and dpoly Si,2 = 264 nm. Finally, the processing window 2.8 J/cm2≤ Hp ≤ 4 J/cm2 leads to the highest sheet conductance (Gsh) without destroying the SiO2 for both poly Si layer thicknesses. For both tested poly Si layers, the majority of the symmetric lifetime samples processed using these Hp achieve a good passivation quality with a high implied open circuit voltage (iVOC) and a low saturation current density (J0). The best sample achieves iVOC = 722 mV and J0 = 6.7 fA/cm2 per side. This low surface recombination current density, together with the accompanying measurements of the doping profiles, suggests that the SiO2 is not damaged during the laser process. We also observe that the passivation quality is independent of the tested poly Si layer thicknesses. The findings of this study show that laser-activated p++-poly Si/SiO2 are not only suitable for integration into advanced passivated contact solar cells, but also offer the possibility of maskless patterning of these stacks, substantially simplifying such solar cell production.

Abstract Background Antidepressants are established as an evidence-based, guideline-recommended treatment for Major Depressive Disorder. Prescriptions have markedly increased in past decades, with a specific surge in maintenance prescribing. Patients often remain on antidepressants longer than clinically necessary. When attempting to stop, many patients experience adverse discontinuation symptoms. Discontinuation symptoms can be debilitating and hinder successful discontinuation. While discontinuation symptoms can result from pharmacological effects, evidence on nocebo-induced side effects of antidepressant use suggests that patients' expectations may also influence occurrence. Methods To disentangle pharmacological and expectation effects in antidepressant discontinuation, patients with fully remitted Major Depressive Disorder who fulfill German guideline recommendations to discontinue will either remain on or discontinue their antidepressant. Participants' expectations will be manipulated by varying verbal instructions using an open-hidden paradigm. Within the open trial arms, participants will receive full information about treatment, i.e., high expectation. Within the hidden trial arms, participants will be informed about a 50% chance of discontinuing versus remaining on their antidepressant, i.e., moderate expectation. A total of N = 196 participants will be randomly assigned to either of the four experimental groups: open discontinuation (OD; n = 49), hidden discontinuation (HD; n = 49), open continuation (OC; n = 49), or hidden continuation (HC; n = 49). Discontinuation symptom load during the 13-week experimental phase will be our primary outcome measure. Secondary outcome measures include discontinuation symptom load during the subsequent 39-week clinical observation phase, recurrence during the 13-week experimental period, recurrence over the course of the complete 52-week trial evaluated in a time-to-event analysis, and stress, anxiety, and participants’ attentional and emotional processing at 13 weeks post-baseline. Blood and saliva samples will be taken as objective markers of antidepressant blood serum level and stress. Optional rsfMRI measurements will be scheduled. Discussion Until today, no study has explored the interplay of pharmacological effects and patients’ expectations during antidepressant discontinuation. Disentangling their effects has important implications for understanding mechanisms underlying adverse discontinuation symptoms. Results can inform strategies to manage discontinuation symptoms and optimize expectations in order to help patients and physicians discontinue antidepressants more safely and effectively. Trial registration ClinicalTrials.gov (NCT05191277), January 13, 2022.

Abstract Since Purcell’s seminal report 75 years ago, electromagnetic resonators have been used to control light-matter interactions to make brighter radiation sources and unleash unprecedented control over quantum states of light and matter. Indeed, optical resonators such as microcavities and plasmonic antennas offer excellent control but only over a limited spectral range. Strategies to mutually tune and match emission and resonator frequency are often required, which is intricate and precludes the possibility of enhancing multiple transitions simultaneously. In this letter, we report a strong radiative emission rate enhancement of Er3+-ions across the telecommunications C-band in a single plasmonic waveguide based on the Purcell effect. Our gap waveguide uses a reverse nanofocusing approach to efficiently enhance, extract and guide emission from the nanoscale to a photonic waveguide while keeping plasmonic losses at a minimum. Remarkably, the large and broadband Purcell enhancement allows us to resolve Stark-split electric dipole transitions, which are typically only observed under cryogenic conditions. Simultaneous radiative emission enhancement of multiple quantum states is of great interest for photonic quantum networks and on-chip data communications.

The snake pipefish, Entelurus aequoreus (Linnaeus, 1758), is a northern Atlantic fish inhabiting open seagrass environments that recently expanded its distribution range. Here, we present a highly contiguous, near chromosome-scale genome of E. aequoreus. The final assembly spans 1.6 Gbp in 7,391 scaffolds, with a scaffold N50 of 62.3 Mbp and L50 of 12. The 28 largest scaffolds (>21 Mbp) span 89.7% of the assembly length. A BUSCO completeness score of 94.1% and a mapping rate above 98% suggest a high assembly completeness. Repetitive elements cover 74.93% of the genome, one of the highest proportions identified in vertebrates. Our demographic modeling identified a peak in population size during the last interglacial period, suggesting the species might benefit from warmer water conditions. Our updated snake pipefish assembly is essential for future analyses of the morphological and molecular changes unique to the Syngnathidae.

BackgroundDigital media-use disorders (DMUD) in adolescents are a rising phenomenon associated with psychological distress, comorbid mental disorders, and high burden on affected families. Since the ICD-11 introduced criteria for gaming disorder, these can now be transferred to describe additional DMUD associated with social media platforms and streaming services. Most evidence for effective treatments comes from cognitive-behavioral therapy (CBT). However, interventions based on theoretical models for adolescents and their parents are widely missing, leading to a significant clinical gap.MethodsRes@t digital (Resource-Strengthening Training for Adolescents with Problematic Digital-Media Use and their Parents) is the app-based translation of the first model-based digital intervention for adolescents with DMUD and their parents based on CBT. It comprises separate but content-related modules for adolescents (Res@t–A) and parents (Res@t–P), applying multimodal techniques. The effectiveness of Res@t will be evaluated within a multicenter cluster-randomized controlled evaluator-blinded pre–post follow-up trial with the waitlist control group (CG). In addition to the Res@t program in the intervention group, both groups will receive treatment as usual within primary child and adolescent psychiatric/psychotherapeutic healthcare. The primary outcome addresses DMUD symptom reduction after 10 weeks. Secondary outcomes are related to a reduction in psychological and family-related problems and an increase in parental self-efficacy. All outcomes will be assessed using standardized self-report measures. A total of 1,334 participating adolescent–parent dyads from a large clinical network throughout Germany are planned to be included in the primary analyses based on an intention-to-treat approach, applying linear mixed models.DiscussionAssuming superiority of Res@t over the control condition, the intervention has the potential to provide evidence-based treatment for a significant number of help-seeking families, supporting local healthcare structures and resources. It is a promising program for practicable implementation and flexible use in different settings.Clinical trial registrationhttps://drks.de, DRKS00031043.

Introduction Intravenous fluid therapy is the most common intervention in critically ill children. There is an increasing body of evidence questioning the safety of high-volume intravenous fluid administration in these patients. To date, the optimal fluid management strategy remains unclear. We aimed to test the feasibility of a pragmatic randomised controlled trial comparing a restrictive with a standard (liberal) fluid management strategy in critically ill children.Methods and analysis Multicentre, binational pilot, randomised, controlled, open-label, pragmatic trial. Patients