Enhancing Dementia Risk Mitigation: Standardized Digital Monitoring in Clinical Trials and Platform Design for At-Risk Elderly Individuals.

BACKGROUND: Dementia is becoming a significant public health concern, affecting approximately 130,000 individuals in Austria, whereby nearly 40% of the cases are attributed to modifiable risk factors. Multidomain lifestyle interventions have thereby demonstrated significant effects in reducing the risk of dementia. OBJECTIVES: The goal was to define an interoperability framework to conduct standardized monitoring in clinical trials for enhancing dementia risk mitigation. In addition, the identified standards should be integrated into the components of the project. METHODS: A step-by-step approach was used, where initially data collection, aggregation and harmonization was carried out with retrospective data from various clinical centers. Afterwards, the interoperability framework was defined including the prospective data that is gathered during a clinical trial. RESULTS: A guideline for integrating healthcare standards was developed and incorporated into the technical components for the clinical trial. CONCLUSION: The interoperability framework was designed in a scalable way and will be regularly updated for future needs.

LETHE: A Digital Intervention for Cognitive Decline.

Dementia is the main cause of disability in elderly populations. It has been shown that the risk factors of dementia are a mixture of pathological, lifestyle and heritable factors, with some of those being provably modifiable. Early diagnosis of dementia and approaches to slow down its evolution are currently the most prominent management methodologies due to lack of a cure. For that reason, a plethora of home-based assistive technologies for dementia management do exist, with most of them focusing on the improvement of memory and thinking. The main objective of LETHE is prevention in the whole spectrum of cognitive decline in the elderly population at risk reaching from asymptomatic to subjective or mild cognitive impairment to prodromal Dementia. LETHE will provide a Big Data collection platform and analysis system, that will allow prevention, personalized risk detection and intervention on cognitive decline. Through the subsequent 2-year clinical trial, the LETHE system, as well as the respective knowledge gained will be evaluated and validated. The scope of the current paper is to introduce the LETHE study and its respective novel platform as a holistic approach to multidomain lifestyle intervention trial studies. The present work depicts the architectural perspective and extends beyond state-of-the-art guidelines and approaches to health management systems and cloud platform development.Clinical Relevance - Patient Management Systems as well as lifestyle management platforms have significant clinical relevance as they allow for remote and continuous monitoring of patients' health status. LETHE aims to improve patient outcomes by providing predictive models for cognitive decline and patient adherence to the multimodal lifestyle intervention, enabling prompt and appropriate medical decisions.

[Overweight and obesity in adults: general principles of treatment and conservative management]. / Übergewicht und Adipositas bei Erwachsenen: allgemeine Behandlungsgrundsätze und konservatives Management.

The prevalence of overweight and obesity is steadily increasing in Austria as well as internationally. Obesity in particular is associated with multiple health risks, comorbidities, functional disability, and social stigma. Obesity is an independent, complex, chronic disease and should be treated as such by a multidisciplinary team of appropriately qualified personnel. In addition to recent international guidelines, this consensus paper outlines the overall principles of the management of overweight and obesity and provides guidance for the diagnosis and conservative treatment, focusing on lifestyle modifications and pharmacotherapy. Using the "5A" framework of behavioral health intervention, guidelines for a structured, pragmatic, and patient-centered medical care of adults with overweight or obesity are presented.

[Prevention and management of postinterventional weight regain]. / Prävention und Management von postinterventioneller Gewichtszunahme.

Decreasing levels of patient motivation or compliance are far from being the only causes of postinterventional weight regain after lifestyle, psychological, pharmacological and surgical interventions. Weight regain originates from a complex and individually varying set of central and peripheral mechanisms, with the overall purpose of increasing food intake by both stimulating hunger and reducing satiety (mediated by gastrointestinal hormones) and decreasing the body's energy demands (via metabolic adaption). These mechanisms counteract any attempts to reduce or maintain body weight in today's increasingly prevalent adipogenic environments. The knowledge about the biological mechanisms of body weight regulation should be taken into consideration when planning treatment programs for long-term weight reduction, including follow-up treatment for the prevention and individualized treatment of postinterventional weight regain. Therapeutic measures as well as the frequency of medical follow-ups should be based on the extent of weight regain.

Development and initial validation of the German version of the Exergame Enjoyment Questionnaire (EEQ-G).

BACKGROUND: Analyzing and adjusting training programs to increase exercise enjoyment is crucial to achieve long-term adherence and thus also maximize health benefits. The Exergame Enjoyment Questionnaire (EEQ) is the first questionnaire specifically developed to monitor exergame enjoyment. To be used in German speaking countries, the EEQ must be translated, cross-culturally adapted, and tested on its psychometric properties. OBJECTIVES: The aim of this study was to develop (i.e., translate and cross-culturally adapt) the German Version of the EEQ (EEQ-G) and investigate its psychometric properties. METHODS: Psychometric properties of the EEQ-G were tested using a cross-sectional study design. Each participant performed two consecutive exergame sessions (i.e., 'preferred' and 'unpreferred' condition) in randomized order and rated the EEQ-G as well as reference questionnaires. Internal consistency of the EEQ-G was assessed by calculating Cronbach's α. Construct validity was assessed by calculating Spearman's rank correlation coefficients (rs) between the scores of the EEQ-G and reference questionnaires. Responsiveness was analyzed by performing a Wilcoxon signed-rank test between the median EEQ-G scores of the two conditions. RESULTS: Fourty-three healthy older adults (HOA; mean age = 69.4 ± 4.9 years; 53.5% females) were included. Cronbach's α of the EEQ-G was 0.80. The rs values between the EEQ-G and reference questionnaire scores for intrinsic motivation, game enjoyment, physical activity enjoyment, and external motivation were 0.198 (p = 0.101), 0.684 (p < 0.001), 0.277 (p = 0.036), and 0.186 (p = 0.233), respectively. The EEQ-G was rated higher in the 'preferred' than the 'unpreferred' condition (p < 0.001, r = 0.756). CONCLUSION: The EEQ-G has high internal consistency and is responsive to changes in exergame enjoyment. The highly skewed data with ceiling effects in some of the reference questionnaires deem the construct validity of the EEQ-G to be inconclusive and thus in need of further evaluation.

Agreement, Reliability, and Concurrent Validity of an Outdoor, Wearable-Based Walk Ratio Assessment in Healthy Adults and Chronic Stroke Survivors.

Purpose: The walk ratio (WR)-the step-length/cadence relation-is a promising measure for gait control. GPS-running watches deliver clinically relevant outcomes including the WR. The aim of this study was to determine test-retest agreement, reliability and concurrent validity of an outdoor WR assessment using a GPS-running watch. Methods: Healthy adults and moderate-high functioning stroke survivors (≥6 months), performed the 1 km-outdoor walk twice using a GPS-running watch (Garmin Forerunner 35, GFR35) and a Step Activity Monitor (SAM 3). Global cognition was assessed using the Montreal Cognitive Assessment. Test-retest agreement and reliability were assessed using Bland-Altman plots, standard error of measurement (SEM), intraclass correlation coefficients (ICCs) and smallest detectable changes (SDCs). Concurrent validity was determined by the mean difference (MD), standard error (SE), mean absolute percentage errors (MAPEs) and Spearman's Rho between GFR35 and SAM3. WR values of the two groups were compared by a Welch's test. A hierarchical multiple regression was performed with the WR as dependent variable and possible predictors as independent variables. Results: Fifty-one healthy adults [median: 60.0 (47.0, 67.0) years) and 20 stroke survivors [mean: 63.1 (12.4) years, median: 76 (30, 146) months post-stroke] were included. Test-retest agreement and reliability were excellent (SEM% ≤ 2.2, ICCs > 0.9, SDC% ≤ 6.1) and concurrent validity was high (MAPE < 5, ρ > 0.7) for those walking ≥ 1 m/s. Walking < 1 m/s impaired accurate step counting and reduced agreement, reliability, and validity. The WR differed between healthy adults and stroke survivors (t = -2.126, p = 0.045). The hierarchical regression model including stroke and global cognition (Montreal Cognitive Assessment, 0-30) explained 25% of the WR variance (ΔR2 = 0.246, p < 0.001). Stroke had no effect (ß = -0.05, p = 0.682), but global cognition was a predictor for an altered WR (ß = 0.44, p = 0.001). Discussion: The outdoor WR assessment using the GFR35 showed excellent test-retest agreement, reliability and concurrent validity in healthy adults and chronic stroke survivors walking at least 1 m/s. As the WR seems relevant in chronic stroke, future studies should further investigate this parameter.

Evidence-Based Mobile Wound Application to Support Professionals in State-of-the-Art Chronic Wound Treatment.

BACKGROUND: One of the most important tasks within wound management and the basis of successful wound care is a clear and accurate nursing documentation which can be created in various ways. However, this documentation is only partially standardized mainly due to the interdisciplinarity of this task. OBJECTIVES: The goal is to overcome interdisciplinary boundaries in home care between health professionals, and to increase the patient's motivation to actively participate in wound healing by providing consistent structure and guidance. In this paper, the development of a mobile wound documentation application is described. METHODS: Comprehensive literature reviews were conducted on state-of-the-art wound documentation as well as on machine learning frameworks, databases and mobile app development technologies. RESULTS: As a result, a mobile wound application with Flutter, SQLite and Tensorflow Lite was developed. During the development process interoperability was considered to enable future extensibility. CONCLUSION: Further development in respect of backend and API is planned, involving user field tests.

Motor-cognitive intervention concepts can improve gait in chronic stroke, but their effect on cognitive functions is unclear: A systematic review with meta-analyses.

Motor-cognitive intervention concepts are promising to counteract residual gait and cognitive impairments in chronic stroke. There is, however, considerable variation in motor-cognitive intervention types, which may lead to different effects. This systematic review strived to summarize and compare the effects of different motor-cognitive intervention concepts on gait and cognitive functions in chronic stroke. The systematic search identified twenty-nine articles, which were allocated to three types of motor-cognitive training concepts; SEQUENTIAL, SIMULTANEOUS-ADDITIONAL, and SIMULTANEOUS-INCORPORATED. Random-effects meta-analyses revealed that motor-cognitive interventions may be better than non-combined training approaches for improving gait function in chronic stroke (e.g. gait speed: g = 0.43, 95 % CI [0.22, 0.64], p < 0.0001). SIMULTANEOUS-INCORPORATED motor-cognitive training seems the most promising concept. As very few articles measured both, spatiotemporal gait parameters and cognitive outcomes, future studies are warranted to investigate the effects of motor-cognitive intervention concepts on gait control and cognitive functions in chronic stroke.

Personalized Motor-Cognitive Exergame Training in Chronic Stroke Patients-A Feasibility Study.

Purpose: Exergame training may be beneficial for improving long-term outcome in stroke patients. Personalized training prescription applying progression rules, is missing. We adapted a theory-based taxonomy for a rehabilitation approach using user-centered exergames. The aims were primarily to investigate the feasibility of this rehabilitation approach, and secondarily to evaluate its performance of personalizing training progression, as well as explore the effects on secondary outcomes. Methods: Chronic stroke patients (≥ 18 years) were included, who were able to walk 10 meters and stand for 3 min. The rehabilitation approach was administered twice per week for 8 weeks. As primary outcome, feasibility was evaluated by comparing achieved rates of inclusion, adherence, compliance, attrition, motivation, and satisfaction to pre-defined thresholds for acceptance. Secondary outcomes were (1) perceived motor and cognitive task difficulty throughout the intervention; (2) measures collected during baseline and post-measurements-a gait analysis, the Timed-up-and-go test (TUG), several cognitive tests assessing attentional, executive, and visuospatial functions. Results: Thirteen patients [median: 68.0 (IQR: 49.5-73.5) years, median: 34.5 (IQR: 12.25-90.75) months post-stroke] were included, of whom ten completed the study. Rates for inclusion (57%), adherence (95%), compliance (99%), motivation (77%), and satisfaction (74%) were acceptable, however, the attrition rate was high (23%). The perceived motor and cognitive task difficulty predominantly moved below the targeted range. We found a significant change in the TUG (p = 0.05, r = 0.46) and medium-to-large effect sizes (p > 0.05) for swing time of the affected leg, the asymmetry index, time needed for the Trail-making test (TMT) A and accuracy for the TMT B and the Mental Rotation Test (MRT; 0.26 ≤ r ≤ 0.46). Discussion: The intervention was feasible with minor modifications necessary, which warrants a larger trial investigating the effects of the rehabilitation approach following the adapted taxonomy on mobility, gait and cognitive functions. Two main limitations of the rehabilitation approach were; (1) the taxonomy decoupled motor and cognitive progression, which may be improper as motor and cognitive learning is coupled; (2) separate subjective ratings were used to guide the progression. Future studies should develop an instrument to objectively assess motor-cognitive task difficulty for monitoring the progression of an exergame-based training.

Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging.

Biological aging research is expected to reveal modifiable molecular mechanisms that can be harnessed to slow or possibly reverse unhealthy trajectories. However, there is first an urgent need to define consensus molecular markers of healthy and unhealthy aging. Established aging hallmarks are all linked to metabolism, and a 'rewired' metabolic circuitry has been shown to accelerate or delay biological aging. To identify metabolic signatures distinguishing healthy from unhealthy aging trajectories, we performed nontargeted metabolomics on skeletal muscles from 2-month-old and 21-month-old mice, and after dietary and lifestyle interventions known to impact biological aging. We hypothesized that common metabolic signatures would highlight specific pathways and processes promoting healthy aging, while revealing the molecular underpinnings of unhealthy aging. Here, we report 50 metabolites that commonly distinguished aging trajectories in all cohorts, including 18 commonly reduced under unhealthy aging and 32 increased. We stratified these metabolites according to known relationships with various aging hallmarks and found the greatest associations with oxidative stress and nutrient sensing. Collectively, our data suggest interventions aimed at maintaining skeletal muscle arginine and lysine may be useful therapeutic strategies to minimize biological aging and maintain skeletal muscle health, function, and regenerative capacity in old age.

Application of the concept of oxime library screening by mass spectrometry (MS) binding assays to pyrrolidine-3-carboxylic acid derivatives as potential inhibitors of γ-aminobutyric acid transporter 1 (GAT1).

In the present study, the concept of oxime library screening by MS Binding Assays was successfully extended to N-substituted lipophilic pyrrolidine-3-carboxylic acid derivatives in the pursuit of varying the amino acid motif in order to identify new inhibitors for GAT1 and to broaden structure-activity-relationships for this target, the most abundant GABA transporter in the central nervous system. For the screening, 28 different oxime sub-libraries were employed that were generated by simple condensation reaction of an excess of pyrrolidine-3-carboxylic acid derivatives carrying a hydroxylamine functionality with various sub-libraries each assembled of eight aldehydes with broadly varying chemical structures and functionalities. The compounds responsible for the activity of an oxime sub-library were identified by deconvolution experiments performed by employing single oximes. Binding affinities of the oxime hits were confirmed in full-scale competitive MS Binding Assays. Thereby, oxime derivatives with a 1,1'-biphenyl moiety were found as the first inhibitors of mGAT1 comprising a pyrrolidine-3-carboxylic acid motif with affinities in the submicromolar range.

Identification of Pyrrolidine-3-acetic Acid Derived Oximes as Potent Inhibitors of γ-Aminobutyric Acid Transporter†1 through Library Screening with MS Binding Assays.

In this study, pyrrolidine-3-acetic acid derived oxime libraries were applied to the concept of library screening by MS Binding Assays, as a powerful technique to reveal new potent murine γ-aminobutyric acid transporter subtype (mGAT1) inhibitors. Library generation was accomplished by condensation of an excess of pyrrolidine-3-acetic acid bearing a hydroxylamine unit with various libraries, each composed of eight different aldehydes. The oxime libraries have been screened by means of competitive MS Binding Assays and, as a consequence, the most active libraries were further investigated through deconvolution experiments to identify single oximes responsible for the observed activity on the target mGAT1. All identified hits were finally resynthesized to characterize them with respect to their binding affinities, and a set of new potent inhibitors with the pyrrolidine-3-acetic acid motif were found, of which the most potent oxime, possessing a 2',4'-dichlorobiphenyl residue, displayed a binding affinity in the low nanomolar range (pKi =7.87±0.01).

Modeling multi-cellular behavior in epidermal tissue homeostasis via finite state machines in multi-agent systems.

MOTIVATION: For the efficient application of multi-agent systems to spatial and functional modeling of tissues flexible and intuitive modeling tools are needed, which allow the graphical specification of cellular behavior in a tissue context without presuming specialized programming skills. RESULTS: We developed a graphical modeling system for multi-agent based simulation of tissue homeostasis. An editor allows the intuitive and hierarchically structured specification of cellular behavior. The models are then automatically compiled into highly efficient source code and dynamically linked to an interactive graphical simulation environment. The system allows the quantitative analysis of the morphological and functional tissue properties emerging from the cell behavioral model. We demonstrate the relevance of the approach using a recently published model of epidermal homeostasis as well as a series of cell-cycle models. AVAILABILITY: The complete software is available in binary executables for MS-Windows and Linux at tiga.uni-hd.de.

Synthesis and anti-CVB 3 evaluation of substituted 5-nitro-2-phenoxybenzonitriles.

The synthesis and SAR of a series of 60 substituted 2-phenoxy-5-nitrobenzonitriles (analogues of MDL-860) as inhibitors of enterovirus replication (in particular of coxsackievirus B3 (CVB 3)) are reported. Several of the analogues inhibited CVB 3 and other enteroviruses at low-micromolar concentrations.

Modelling epidermal homeostasis as an approach for clinical bioinformatics.

Modelling in systems biology currently lacks clinical applications. As a possible approach leading to clinical relevance the modelling of tissue homeostasis is proposed. As an example a model of epidermal homeostasis is presented which reproduces central morphological and kinetic characteristics of epidermal tissue. Each individual cell is modelled as an agent. The tissue arises as an emergent phenomenon from the interactions of agents. Each agent's behaviour is qualitatively modelled by a simple differentiation state-flow program. Epithelialisation under the influence of parameters concerning stem-cell location is briefly demonstrated.