Thermotolerance in S. cerevisiae as a model to study extracellular vesicle biology.

The budding yeast Saccharomyces cerevisiae is a proven model organism for elucidating conserved eukaryotic biology, but to date its extracellular vesicle (EV) biology is understudied. Here, we show yeast transmit information through the extracellular medium that increases survival when confronted with heat stress and demonstrate the EV-enriched samples mediate this thermotolerance transfer. These samples contain vesicle-like particles that are exosome-sized and disrupting exosome biogenesis by targeting endosomal sorting complexes required for transport (ESCRT) machinery inhibits thermotolerance transfer. We find that Bro1, the yeast ortholog of the human exosome biomarker ALIX, is present in EV samples, and use Bro1 tagged with green fluorescent protein (GFP) to track EV release and uptake by endocytosis. Proteomics analysis reveals that heat shock protein 70 (HSP70) family proteins are enriched in EV samples that provide thermotolerance. We confirm the presence of the HSP70 ortholog stress-seventy subunit A2 (Ssa2) in EV samples and find that mutant yeast cells lacking SSA2 produce EVs but they fail to transfer thermotolerance. We conclude that Ssa2 within exosomes shared between yeast cells contributes to thermotolerance. Through this work, we advance Saccharomyces cerevisiae as an emerging model organism for elucidating molecular details of eukaryotic EV biology and establish a role for exosomes in heat stress and proteostasis that seems to be evolutionarily conserved.

Cymoxanil disrupts RNA synthesis through inhibiting the activity of dihydrofolate reductase.

The agricultural fungicide cymoxanil (CMX) is commonly used in the treatment of plant pathogens, such as Phytophthora infestans. Although the use of CMX is widespread throughout the agricultural industry and internationally, the exact mechanism of action behind this fungicide remains unclear. Therefore, we sought to elucidate the biocidal mechanism underlying CMX. This was accomplished by first performing a large-scale chemical-genomic screen comprising the 4000 haploid non-essential gene deletion array of the yeast Saccharomyces cerevisiae. We found that gene families related to de novo purine biosynthesis and ribonucleoside synthesis were enriched in the presence of CMX. These results were confirmed through additional spot-test and colony counting assays. We next examined whether CMX affects RNA biosynthesis. Using qRT-PCR and expression assays, we found that CMX appears to target RNA biosynthesis possibly through the yeast dihydrofolate reductase (DHFR) enzyme Dfr1. To determine whether DHFR is a target of CMX, we performed an in-silico molecular docking assay between CMX and yeast, human, and P. infestans DHFR. The results suggest that CMX directly interacts with the active site of all tested forms of DHFR using conserved residues. Using an in vitro DHFR activity assay we observed that CMX inhibits DHFR activity in a dose-dependent relationship.

Interpersonal factors in internet-based cognitive behavioral therapy for depression: Attachment style and alliance with the program and with the therapist.

Objective This open-trial study examined effects of a culturally-adapted Hebrew version of guided internet-based cognitive behavioural therapy (ICBT) for depression. We examined therapeutic alliance with the therapist and with the programme (content) as potential predictors of outcomes. Furthermore, we examined whether anxious and avoidant attachment styles improved, although relationships were not the focus of treatment. Method: We examined alliance with therapist and alliance with programme and their time-lagged (1 week), longitudinal relationship with depression outcomes, and change in anxious and avoidant attachment during treatment. Results: Depression and insomnia improved significantly (Cohen's d: depression = 1.34, insomnia = 0.86), though dropout was relatively high (49%). Alliance with programme and with the therapist predicted adherence and dropout, whereas only alliance with therapist predicted symptom improvement. Avoidant attachment decreased over treatment whereas anxious attachment did not. Conclusion: A culturally-adapted version of ICBT for depression showed that alliance with therapist and alliance with programme both can play an important role in its effectiveness: alliance with programme and the therapist drive adherence and dropout and alliance with therapist is related to symptom improvement. Although the focus of treatment is not interpersonal, avoidant attachment style can improve following ICBT.

Gene-Environment Interactions in Irrational Beliefs: The Roles of Childhood Adversity and Multiple Candidate Genes.

Cognitive behavioral therapy is based on the view that maladaptive thinking is the causal mechanism of mental disorders. While this view is supported by extensive evidence, very limited work has addressed the factors that contribute to the development of maladaptive thinking. The present study aimed to uncover interactions between childhood maltreatment and multiple genetic differences in irrational beliefs. Childhood maltreatment and irrational beliefs were assessed using multiple self-report instruments in a sample of healthy volunteers (N = 452). Eighteen single-nucleotide polymorphisms were genotyped in six candidate genes related to neurotransmitter function (COMT; SLC6A4; OXTR), neurotrophic factors (BDNF), and the hypothalamic-pituitary-adrenal axis (NR3C1; CRHR1). Gene-environment interactions (G×E) were first explored in models that employed one measure of childhood maltreatment and one measure of irrational beliefs. These effects were then followed up in models in which either the childhood maltreatment measure, the irrational belief measure, or both were substituted by parallel measures. Consistent results across models indicated that childhood maltreatment was positively associated with irrational beliefs, and these relations were significantly influenced by COMT rs165774 and OXTR rs53576. These results remain preliminary until independent replication, but they represent the best available evidence to date on G×E in a fundamental mechanism of psychopathology.

Effectiveness of an online recovery training for employees exposed to blurred boundaries between work and non-work: Bayesian analysis of a randomised controlled trial.

BACKGROUND: Blurred work-non-work boundaries can have negative effects on mental health, including sleep. OBJECTIVES: In a randomised control trial, we aimed to assess the effectiveness of an online recovery training programme designed to improve symptoms of insomnia in a working population exposed to blurred boundaries. METHODS: 128 participants with severe insomnia symptoms (Insomnia Severity Index ≥15) and working under blurred work and non-work conditions (segmentation supplies <2.25) were randomly assigned to either the recovery intervention or a waitlist control group (WLC). The primary outcome was insomnia severity, assessed at baseline, after 2 months (T2) and 6 months (T3). FINDINGS: A greater reduction in insomnia was observed in the intervention compared with the WLC group at both T2 (d=1.51; 95% CI=1.12 o 1.91) and T3 (d=1.63; 95% CI=1.23 to 2.03]. This was shown by Bayesian analysis of covariance (ANCOVA), whereby the ANCOVA model yielded the highest Bayes factor (BF 10=3.23×e60] and a 99.99% probability. Likewise, frequentist analysis revealed significantly reduced insomnia at both T2 and T3. Beneficial effects were found for secondary outcomes including depression, work-related rumination, and mental detachment from work. Study attrition was 16% at T2 and 44% at T3. CONCLUSIONS: The recovery training was effective in reducing insomnia symptoms, work related and general indicators of mental health in employees exposed to blurred boundaries, both at T2 and T3. CLINICAL IMPLICATIONS: In addition to demonstrating the intervention's effectiveness, this study exemplifies the utilisation of the Bayesian approach in a clinical context and shows its potential to empower recipients of interventional research by offering insights into result probabilities, enabling them to draw informed conclusions. TRIAL REGISTRATION NUMBER: German Clinical Trial Registration (DRKS): DRKS00006223, https://drks.de/search/de/trial/DRKS00006223.

"WOOP is my safe haven": A qualitative feasibility and acceptability study of the Wish Outcome Obstacle Plan (WOOP) intervention for spouses of people living with early-stage dementia.

OBJECTIVES: As symptoms emerge and worsen in people living with dementia, their spouses can benefit from behavioral interventions to support their adjustment as a care partner. The Wish Outcome Obstacle Plan (WOOP) intervention improves the well-being of spouses of people living with dementia early in the disease course, but intervention mechanisms and opportunities for improvement are unclear. The present study gave voice to spouses who participated in a trial of WOOP, describing how WOOP was incorporated into their lives and how it could be improved for future implementation. METHOD: For this qualitative study, we conducted longitudinal semi-structured interviews among 21 spouses of people living with dementia (three interviews over three months; 63 interviews total). Codebook thematic analysis was performed. RESULTS: Three meta-themes were derived: (1) assessing baseline strengths and limitations of WOOP, (2) learning from experience, and (3) fine-tuning and sustaining WOOP. Participants described how WOOP addressed their interpersonal and emotional stressors, their responses to behaviors of the person living with dementia, and their relationship quality. Considerations for future intervention delivery (e.g., solo vs. in group settings) and instructions (e.g., encouraging writing vs. thinking through the four steps of WOOP) were identified as areas of improvement. CONCLUSIONS: WOOP was described as a practical, feasible, and desirable intervention for spouses at the early stages of their partner's dementia. Participants made WOOP easier to incorporate in their everyday lives by adapting the design into a mental exercise that they used as needed. Suggestions from participants specified how to make the everyday use of WOOP more feasible, sustainable, and applicable in a variety of contexts. TRIAL REGISTRATION: ClinicalTrials.gov HIC 2000021852.

Reciprocal relationships between positive expectancies and positive emotions during the COVID-19 pandemic: a cross-lagged panel study.

INTRODUCTION: Previous research highlighted the importance of investigating distinct protective factors that predict the experience of positive emotions during stressful situations, such as the COVID-19 pandemic. In this longitudinal study, we specifically focused on positive expectancies towards the future (optimism, response expectancy, and response hope) in relation to the experience of positive emotions during the COVID-19 pandemic. Our primary objectives were to identify the best predictors for experiencing short-term and long-term positive emotions and investigate their interrelationships. METHODS: Data from 271 participants (average age = 29.2 years, 84.7% female) were analyzed using four cross-lagged models. RESULTS: Results showed that response expectancy was the best predictor for experiencing positive emotions in the short term, while optimism was the best predictor for experiencing positive emotions in the long term. Additionally, through further exploratory analysis, multiple bidirectional relationships were identified between positive expectancies and positive emotions. DISCUSSION: Our results highlight the significant role played by positive expectancies in predicting the experience of positive emotions. Specifically, dispositional optimism emerged as a stronger predictor of longer-term positive emotions, whereas response expectancy proved to be a better predictor of shorter-term positive emotions. Thus, interventions targeting positive expectancies have the potential to enhance emotional functioning in individuals during challenging situations like the COVID-19 pandemic.

Response expectancy positively predicts positive emotions in the short term.Optimism positively predicts positive emotions in the long term.Response expectancy positively predicts optimism in the short and long term.Response expectancy positively predicts response hope in the short term.Response hope negatively predicts optimism in the short and long term.Positive emotions positively predict positive expectancies (response expectancy, response hope, and optimism) on short term.The discrepancy score negatively predicts positive emotions in the short term.The discrepancy score negatively predicts optimism in the short and long term.

The Involvement of YNR069C in Protein Synthesis in the Baker's Yeast, Saccharomyces cerevisiae.

Maintaining translation fidelity is a critical step within the process of gene expression. It requires the involvement of numerous regulatory elements to ensure the synthesis of functional proteins. The efficient termination of protein synthesis can play a crucial role in preserving this fidelity. Here, we report on investigating a protein of unknown function, YNR069C (also known as BSC5), for its activity in the process of translation. We observed a significant increase in the bypass of premature stop codons upon the deletion of YNR069C. Interestingly, the genomic arrangement of this ORF suggests a compatible mode of expression reliant on translational readthrough, incorporating the neighboring open reading frame. We also showed that the deletion of YNR069C results in an increase in the rate of translation. Based on our results, we propose that YNR069C may play a role in translation fidelity, impacting the overall quantity and quality of translation. Our genetic interaction analysis supports our hypothesis, associating the role of YNR069C to the regulation of protein synthesis.

Death Anxiety in the COVID-19 Pandemic: Testing REBT Models of Psychopathology and Psychological Health of Death Anxiety.

Objective: This paper aimed to examine the validity of the death anxiety psychopathological and psychological health models of Rational-Emotive Behavior Therapy (REBT). We investigated whether irrational and rational beliefs were associated with death anxiety and if there are possible significant positive correlations between death anxiety and depression, anxiety, and stress. Method: A sample of 200 individuals completed online self-report measures and Structural Equation Modelling (SEM) was chosen to assess the validity of the REBT psychopathological model and the REBT psychological health model. Pearson's correlation analysis was utilized to confirm the relationships between death anxiety and depression, anxiety, and stress. Results: REBT's model of psychopathology provide acceptable fit of the data. Results suggest that LFT beliefs mediate the relationship between DEM and death anxiety, while no mediation effect was found for the psychological health model. Additionally, high correlations were obtained between death anxiety and depression, anxiety, and stress. Conclusions: Results provided empirical support for the REBT models of death anxiety and underline the critical importance of cognitive constructs in the prediction of death anxiety. Results are discussed within the framework of REBT theory, which can serve as a foundation for new research directions regarding death anxiety, both theoretical and clinical.

Clinical and cognitive insight in panic disorder: phenomenology and treatment effects in internet cognitive behavior therapy.

Clinical observations suggest that individuals with panic disorder (PD) vary in their beliefs about the causes of their panic attacks. Some attribute these attacks to psychological factors, while others to physiological or medical factors. These beliefs also extend to whether individuals perceive panic attacks as dangerous. In other areas of psychiatric nosology, these phenomena are commonly called clinical insight (recognition of disorder and the need for treatment) and cognitive insight (the ability to reflect on one's beliefs). Despite its importance, limited research exists on insight in PD and its relation to symptoms and treatment outcomes. This study examines clinical and cognitive insight in 83 patients with PD who received internet-based cognitive behavioral therapy, investigating their relationship with symptoms, treatment outcomes, and changes in insight. We assessed patients using interview and self-report measures of insight and symptoms. Clinical and cognitive insight were correlated and both constructs improved significantly during treatment. Good clinical insight pretreatment was positively correlated with more severe pretreatment symptoms. Pretreatment clinical and cognitive insight were not correlated with symptom change or attrition. Greater change in clinical and cognitive insight was related to greater change in symptoms. The findings highlight the significance of clinical and cognitive insight in PD, and the importance of distinguishing between them. This suggests the need to develop interventions according to patients' level of insight, particularly focusing on those lacking insight. Further research is essential to advance our understanding of the relationship between insight and the phenomenology and treatment of PD.

The Evaluation of the GET.ON Nationwide Web-Only Treatment Service for Depression- and Stress-Related Symptoms: Naturalistic Trial.

BACKGROUND: GET.ON (HelloBetter) treatment interventions have been shown to be efficacious in multiple randomized controlled trials. OBJECTIVE: This study evaluated the effectiveness of 2 GET.ON interventions, GET.ON Mood Enhancer and GET.ON Stress, in a national digital mental health service implemented across Germany. METHODS: Following an initial web-based questionnaire, participants were allocated to either intervention based on their baseline symptom severity and personal choice and received a semistandardized guided, feedback-on-demand guided, or self-guided version of the treatment. Uncontrolled routine care data from 851 participants were analyzed using a pretest-posttest design. Half of the participants (461/851, 54.2%) were allocated to the stress intervention (189/461, 41% semistandardized; 240/461, 52% feedback on demand; and 32/461, 6.9% self-guided), and almost all participants in the mood intervention (349/352, 99.2%) received semistandardized guidance. RESULTS: Results on depression-related symptom severity indicated a reduction in reported symptoms, with a large effect size of d=-0.92 (95% CI -1.21 to -0.63). Results on perceived stress and insomnia indicated a reduction in symptom severity, with large effect sizes of d=1.02 (95% CI -1.46 to -0.58) and d=-0.75 (95% CI -1.10 to -0.40), respectively. A small percentage of participants experienced deterioration in depression-related symptoms (11/289, 3.8%), perceived stress (6/296, 2%), and insomnia (5/252, 2%). After completing treatment, 51.9% (150/289) of participants showed a clinically reliable change in depression-related symptoms, whereas 20.4% (59/289) achieved a close to symptom-free status. Similar improvements were observed in perceived stress and insomnia severity. Guidance moderated the effectiveness of and adherence to the interventions in reducing depressive symptom severity. Effect sizes on depression-related symptom severity were d=-1.20 (95% CI -1.45 to -0.93) for the semistandardized group, d=-0.36 (95% CI -0.68 to -0.04) for the feedback-on-demand group, and d=-0.83 (95% CI -1.03 to -0.63) for the self-guided group. Furthermore, 47.6% (405/851) of the participants completed all modules of the intervention. Participant satisfaction was high across all patient groups and both interventions; 89.3% (242/271) of participants would recommend it to a friend in need of similar help. Limitations include the assignment to treatments and guidance formats based on symptom severity. Furthermore, part of the differences in symptom change between groups must be assumed to be due to this baseline difference in the measures. CONCLUSIONS: Future digital health implementation and routine care research should focus on monitoring symptom deterioration and other negative effects, as well as possible predictors of deterioration and the investigation of individual patient trajectories. In conclusion, this study supports the effectiveness of tailored digital mental health services in routine care for depression- and stress-related symptoms in Germany. The results highlight the importance of guidance in delivering internet-based cognitive behavioral therapy interventions and provide further evidence for its potential delivered as web-only solutions for increasing access to and use of psychological treatments.

Hydrogen peroxide sensitivity connects the activity of COX5A and NPR3 to the regulation of YAP1 expression.

Reactive oxygen species (ROS) are among the most severe types of cellular stressors with the ability to damage essential cellular biomolecules. Excess levels of ROS are correlated with multiple pathophysiological conditions including neurodegeneration, diabetes, atherosclerosis, and cancer. Failure to regulate the severely imbalanced levels of ROS can ultimately lead to cell death, highlighting the importance of investigating the molecular mechanisms involved in the detoxification procedures that counteract the effects of these compounds in living organisms. One of the most abundant forms of ROS is H2 O2 , mainly produced by the electron transport chain in the mitochondria. Numerous genes have been identified as essential to the process of cellular detoxification. Yeast YAP1, which is homologous to mammalian AP-1 type transcriptional factors, has a key role in oxidative detoxification by upregulating the expression of antioxidant genes in yeast. The current study reveals novel functions for COX5A and NPR3 in H2 O2 -induced stress by demonstrating that their deletions result in a sensitive phenotype. Our follow-up investigations indicate that COX5A and NPR3 regulate the expression of YAP1 through an alternative mode of translation initiation. These novel gene functions expand our understanding of the regulation of gene expression and defense mechanism of yeast against oxidative stress.

Are web-based stress management interventions effective as an indirect treatment for depression? An individual participant data meta-analysis of six randomised trials.

QUESTION: Depression is highly prevalent and associated with numerous adverse consequences for both individuals and society. Due to low uptake of direct treatment, interventions that target related, but less stigmatising problems, such as perceived stress, have emerged as a new research paradigm.This individual participant data (IPD) meta-analysis examines if a web-based stress management intervention can be used as an 'indirect' treatment of depression. STUDY SELECTION AND ANALYSIS: Bayesian one-stage models were used to estimate pooled effects on depressive symptom severity, minimally important improvement and reliable deterioration. The dose-response relationship was examined using multilevel additive models, and IPD network meta-analysis was employed to estimate the effect of guidance. FINDINGS: In total, N=1235 patients suffering from clinical-level depression from K=6 randomised trials were included. Moderate-to-large effects were found on depressive symptom severity at 7 weeks post-intervention (d=-0.65; 95% credibility interval (CrI): -0.84 to -0.48) as measured with the Center for Epidemiological Studies' Depression Scale. Effects were sustained at 3-month follow-up (d=-0.74; 95% CrI: -1.01 to -0.48). Post-intervention symptom severity was linearly related to the number of completed sessions. The incremental impact of guidance was estimated at d=-0.25 (95% CrI: -1.30 to 0.82), with a 35% posterior probability that guided and unguided formats produce equivalent effects. CONCLUSIONS: Our results indicate that web-based stress management can serve as an indirect treatment, yielding effects comparable with direct interventions for depression. Further research is needed to determine if such formats can indeed increase the utilisation of evidence-based treatment, and to corroborate the favourable effects for human guidance. STUDY REGISTRATION: Open material repository: osf.io/dbjc8, osf.io/3qtbe. TRIAL REGISTRATION NUMBER: German Clinical Trial Registration (DRKS): DRKS00004749, DRKS00005112, DRKS00005384, DRKS00005687, DRKS00005699, DRKS00005990.

Factores que influyen en la supervivencia de pacientes con diálisis en El Salvador / Influencing Factors in the Survival of Dialysis Patients in El Salvador

Introducción. La enfermedad renal crónica es responsable de aproximadamente 2,4 millones de defunciones a nivel mundial. La supervivencia a los cinco años después de iniciar diálisis se encuentra entre un 39 a 60 % dependiendo del país. Objetivo. Describir la situación epidemiológica de los pacientes con diálisis y analizar los factores que influyen en la supervivencia de pacientes a cinco años de iniciar tratamiento sustitutivo renal en El Salvador. Metodología. Estudio de cohorte retrospectivo de los pacientes incluidos en el Registro Nacional de Diálisis y Trasplante Renal desde enero de 2016 hasta febrero de 2023. El seguimiento se comenzó al inicio de la diálisis, el evento de interés fue la muerte del paciente. Se utilizó el método de Kaplan-Meier para determinar la supervivencia al año y a los cinco años y la regresión de Cox con el modelo de Royston-Parmar para analizar los factores que influyen sobre la supervivencia a los cinco años. Resultados. El estudio incluyó 7088 pacientes, la supervivencia a uno y cinco años fue del 79,5 % (IC 95 %: 78,6-80,5) y 50,6 % (IC 95 %: 49,1-52,1) respectivamente. La regresión de Cox para la edad de inicio de tratamiento resultó en un hazard ratio de 1,02 (IC 95 %: 1,01-1,02), mientras que para el oficio de ser agricultor el hazard ratio fue 1,1 (IC 95 %: 1,01-1,18) y para la etiología hipertensiva el hazard ratio fue de 0,7 (IC 95 %: 0,64-0,78). Conclusión. La edad de inicio de tratamiento y el ser agricultor están asociados con una menor supervivencia a cinco años en pacientes con diálisis

Introduction. The chronic kidney disease is responsible for approximately 2.4 million deaths worldwide, in El Salvador during 2019 death rate was 72.9 for 100 000 habitants, five year survival in patients after starting dialysis was between 39 and 60 % depending on the country. Objective. Analyze the factors that influence the five years survival in patients after starting renal replacement therapy in El Salvador. Methodology. It is a retrospective cohort study from patients included in dialysis and renal replacement therapy national registry from January 2016 to February 2023, the start point for the following was the initiation of dialysis, the event of interest was patient ́s death, the Kaplan-Meier method was used to determine one year and five year survival; and Cox regression with Royston-Parmar model was used to analyze the factors that influence survival. Results. The study included 7088 patients, one and five-years survival was 79.5 % (CI 95 %: 78.6-80.5) and 50.6 % (CI 95 %: 49.1-52.1) respectively. The Cox regression for age of treatment initiation resulted in a hazard ratio of 1.02 (CI 95 %: 1.01-1.02), while for farmers, the hazard ratio was 1.09 (CI 95 %: 1.00-1.18), for hypertensive etiology the hazard ratio was 0.7 (CI 95 %: 0.64-0.78). Conclusion. Data suggest that age of treatment initiation, and jobs related to agriculture were associated with less five year survival in dialysis patients.

Predicting effects of a digital stress intervention for patients with depressive symptoms: Development and validation of meta-analytic prognostic models using individual participant data.

OBJECTIVE: Digital stress interventions could be helpful as an "indirect" treatment for depression, but it remains unclear for whom this is a viable option. In this study, we developed models predicting individualized benefits of a digital stress intervention on depressive symptoms at 6-month follow-up. METHOD: Data of N = 1,525 patients with depressive symptoms (Center for Epidemiological Studies' Depression Scale, CES-D ≥ 16) from k = 6 randomized trials (digital stress intervention vs. waitlist) were collected. Prognostic models were developed using multilevel least absolute shrinkage and selection operator and boosting algorithms, and were validated using bootstrap bias correction and internal-external cross-validation. Subsequently, expected effects among those with and without a treatment recommendation were estimated based on clinically derived treatment assignment cut points. RESULTS: Performances ranged from R² = 21.0%-23.4%, decreasing only slightly after model optimism correction (R² = 17.0%-19.6%). Predictions were greatly improved by including an interim assessment of depressive symptoms (optimism-corrected R2 = 32.6%-35.6%). Using a minimally important difference of d = -0.24 as assignment cut point, approximately 84.6%-93.3% of patients are helped by this type of intervention, while the remaining 6.7%-15.4% would experience clinically negligible benefits (δ^ = -0.02 to -0.19). Using reliable change as cut point, a smaller subset (39.3%-46.2%) with substantial expected benefits (δ^ = -0.68) receives a treatment recommendation. CONCLUSIONS: Meta-analytic prognostic models applied to individual participant data can be used to predict differential benefits of a digital stress intervention as an indirect treatment for depression. While most patients seem to benefit, the developed models could be helpful as a screening tool to identify those for whom a more intensive depression treatment is needed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Inferring free-energy barriers and kinetic rates from molecular dynamics via underdamped Langevin models.

Rare events include many of the most interesting transformation processes in condensed matter, from phase transitions to biomolecular conformational changes to chemical reactions. Access to the corresponding mechanisms, free-energy landscapes and kinetic rates can in principle be obtained by different techniques after projecting the high-dimensional atomic dynamics on one (or a few) collective variable. Even though it is well-known that the projected dynamics approximately follows - in a statistical sense - the generalized, underdamped or overdamped Langevin equations (depending on the time resolution), to date it is nontrivial to parameterize such equations starting from a limited, practically accessible amount of non-ergodic trajectories. In this work we focus on Markovian, underdamped Langevin equations, that arise naturally when considering, e.g., numerous water-solution processes at sub-picosecond resolution. After contrasting the advantages and pitfalls of different numerical approaches, we present an efficient parametrization strategy based on a limited set of molecular dynamics data, including equilibrium trajectories confined to minima and few hundreds transition path sampling-like trajectories. Employing velocity autocorrelation or memory kernel information for learning the friction and likelihood maximization for learning the free-energy landscape, we demonstrate the possibility to reconstruct accurate barriers and rates both for a benchmark system and for the interaction of carbon nanoparticles in water.

Elastic Deformation of Optical Coherence Tomography Images of Diabetic Macular Edema for Deep-Learning Models Training: How Far to Go?

- Objective: To explore the clinical validity of elastic deformation of optical coherence tomography (OCT) images for data augmentation in the development of deep-learning model for detection of diabetic macular edema (DME). METHODS: Prospective evaluation of OCT images of DME (n = 320) subject to elastic transformation, with the deformation intensity represented by ([Formula: see text]). Three sets of images, each comprising 100 pairs of scans (100 original & 100 modified), were grouped according to the range of ([Formula: see text]), including low-, medium- and high-degree of augmentation; ([Formula: see text] = 1-6), ([Formula: see text] = 7-12), and ([Formula: see text] = 13-18), respectively. Three retina specialists evaluated all datasets in a blinded manner and designated each image as 'original' versus 'modified'. The rate of assignment of 'original' value to modified images (false-negative) was determined for each grader in each dataset. RESULTS: The false-negative rates ranged between 71-77% for the low-, 63-76% for the medium-, and 50-75% for the high-augmentation categories. The corresponding rates of correct identification of original images ranged between 75-85% ([Formula: see text]0.05) in the low-, 73-85% ([Formula: see text]0.05 for graders 1 & 2, p = 0.01 for grader 3) in the medium-, and 81-91% ([Formula: see text]) in the high-augmentation categories. In the subcategory ([Formula: see text] = 7-9) the false-negative rates were 93-83%, whereas the rates of correctly identifying original images ranged between 89-99% ([Formula: see text]0.05 for all graders). CONCLUSIONS: Deformation of low-medium intensity ([Formula: see text] = 1-9) may be applied without compromising OCT image representativeness in DME. Clinical and Translational Impact Statement-Elastic deformation may efficiently augment the size, robustness, and diversity of training datasets without altering their clinical value, enhancing the development of high-accuracy algorithms for automated interpretation of OCT images.

Validation of the German Normalisation Process Theory Measure G-NoMAD: translation, adaptation, and pilot testing.

BACKGROUND: Implementing evidence-based healthcare practices (EBPs) is a complex endeavour and often lags behind research-informed decision processes. Understanding and systematically improving implementation using implementation theory can help bridge the gap between research findings and practice. This study aims to translate, pilot, and validate a German version of the English NoMAD questionnaire (G-NoMAD), an instrument derived from the Normalisation Process Theory, to explore the implementation of EBPs. METHODS: Survey data has been collected in four German research projects and subsequently combined into a validation data set. Two versions of the G-NoMAD existed, independently translated from the original English version by two research groups. A measurement invariance analysis was conducted, comparing latent scale structures between groups of respondents to both versions. After determining the baseline model, the questionnaire was tested for different degrees of invariance (configural, metric, scalar, and uniqueness) across samples. A confirmatory factor analysis for three models (a four-factor, a unidimensional, and a hierarchical model) was used to examine the theoretical structure of the G-NoMAD. Finally, psychometric results were discussed in a consensus meeting, and the final instructions, items, and scale format were consented to. RESULTS: A total of 539 health care professionals completed the questionnaire. The results of the measurement invariance analysis showed configural, partial metric, and partial scalar invariance indicating that the questionnaire versions are comparable. Internal consistency ranged from acceptable to good (0.79 ≤ α ≤ 0.85) per subscale. Both the four factor and the hierarchical model achieved a better fit than the unidimensional model, with indices from acceptable (SRMR = 0.08) to good (CFI = 0.97; TLI = 0.96). However, the RMSEA values were only close to acceptable (four-factor model: χ2164 = 1029.84, RMSEA = 0.10; hierarchical model: χ2166 = 1073.43, RMSEA = 0.10). CONCLUSIONS: The G-NoMAD provides a reliable and promising tool to measure the degree of normalisation among individuals involved in implementation activities. Since the fit was similar in the four-factor and the hierarchical model, priority should be given to the practical relevance of the hierarchical model, including a total score and four subscale scores. The findings of this study support the further usage of the G-NoMAD in German implementation settings. TRIAL REGISTRATION: Both the AdAM project (No. NCT03430336, 06/02/2018) and the EU-project ImpleMentAll (No. NCT03652883, 29/08/2018) were registered on ClinicalTrials.gov. The ImplementIT study was registered at the German Clinical Trial Registration (No. DRKS00017078, 18/04/2019). The G-NoMAD validation study was registered at the Open Science Framework (No7u9ab, 17/04/2023).

Metallic Nanowires Self-Assembled in Quasi-Circular Nanomolds Templated by DNA Origami.

The self-assembly of conducting nanostructures is currently being investigated intensively in order to evaluate the feasibility of creating novel nanoelectronic devices and circuits using such pathways. In particular, methods based on so-called DNA Origami nanostructures have shown great potential in the formation of metallic nanowires. The main challenge of this method is the reproducible generation of very well-connected metallic nanostructures, which may be used as interconnects in future devices. Here, we use a novel design of nanowires with a quasi-circular cross-section as opposed to rectangular or uncontrolled cross-sections in earlier studies. We find indications that the reliability of the fabrication scheme is enhanced and the overall resistance of the wires is comparable to metallic nanostructures generated by electrochemistry or top-down methods. In addition, we observe that some of the nanowires are annealed when passing a current through them, which leads to a clear enhancement for the conductance. We envision that these nanowires provide further steps towards the successful generation of nanoelectronics using self-assembly.

An Online Mindfulness Intervention for International Students: A Randomized Controlled Feasibility Trial.

Background: Student mobility across borders poses challenges to health systems at the university and country levels. International students suffer from stress more than their local peers, however, do not seek help or underutilize existing help offers. Some barriers to help-seeking among international students are insufficient information regarding the health offers, stigma, and language, which might be overcome via culturally adapted internet and mobile-based interventions (IMI). Method: A randomized controlled feasibility trial with a parallel design assessed the feasibility and potential efficacy of an online mindfulness intervention adapted for international university students. Participants were randomized into either an adapted online mindfulness intervention (StudiCareM-E) (IG, n = 20) or a waitlist control group (WL, n = 20). Participants were assessed at baseline (t0) and eight-week post-randomization (t1). The feasibility of StudiCareM-E was evaluated regarding intervention adherence, client satisfaction, and potential negative effects. The potential efficacy of StudiCareM-E was measured by means of the level of mindfulness, perceived stress, depression, anxiety, presenteeism, and wellbeing. Efficacy outcomes were evaluated with regression models on the intention-to-treat (ITT) sample (n = 40), adjusting for the baseline values. Results: Participants' formative feedback suggested improvements in the content of the IMI. There were no crucial negative effects compared to WL. Assessment dropout was 35% (IG: 50%: WL: 20%), and intervention dropout was 60%. StudiCareM-E yielded significant improvements in mindfulness (ß = .34), well-being (ß = .37), and anxiety (ß = -.42) compared to WL. Conclusion: StudiCareM-E might be used among culturally diverse international student populations to improve their well-being. Future studies might carefully inspect the extent of the adaptation needs of their target group and design their interventions accordingly.