University of Applied Sciences Tyrol

Antivirals are life-saving medications. However, pathogens develop resistances, mitigating their effect. Resistance studies (gain-of-function, GOF) are therefore paramount before and while antivirals are used clinically to characterize resistances and ideally study how to counteract them with other antivirals. The ability to switch from one antiviral, against which the virus is resistant, to another, depends on the availability of alternative drugs. Furthermore, targeting different parts of the virus synergistically with multiple drugs decreases the odds of simultaneous resistance. However, studying resistance, cross-resistance and remaining susceptibility requires working with the actual pathogen. Especially when introducing resistances into dangerous viruses, performing GOF studies would raise safety concerns and require firm biological containment. In this study we developed a novel dual-chimeric virus encoding both SARS-CoV-2 spike glycoprotein and main protease (Mpro) based on the model virus, vesicular stomatitis virus (VSV). We applied selection pressure with spike and Mpro inhibitors, generated mutants of these viruses and determined their resistance and cross-resistance profiles by performing dose-response experiments with live and pseudotyped viruses. Additionally, we conducted in silico calculations to determine the impact of spike substitutions to the observed resistance phenotype. With the new technology presented here, we demonstrate that it is possible to carry out GOF studies more safely and highlight their importance in the future challenges of virological research.

ABSTRACT Distributional regression extends generalized additive models by linking all distributional parameters to covariates. Gradient boosting is among the most effective estimation techniques for such models, yet it can suffer from vanishing gradients, resulting in unstable updates and weak variable selection. We introduce stagewise boosting for distributional regression, using sign‐based, semiconstant step updates to stabilize learning. The method includes the best‐subset updating across parameters and a correlation filtering criterion for regularization and early stopping, with batchwise variants for large data. Simulations and a lightning count application with 9.1 million observations and 672 covariates demonstrate improved selection accuracy, predictive calibration and scalability. The approach provides a robust, computationally efficient alternative to gradient‐based boosting in distributional regression.

Digitally delivered physical exercise interventions are becoming increasingly popular in addressing the obesity epidemic. However, there remains uncertainty on their efficacy regarding the reduction of body weight (BW) and body fat, which may, at least partly, be due to variations in study designs and inconsistent adherence to international physical activity (PA) guidelines. This study aimed to evaluate the effectiveness of digital exercise interventions based on PA guidelines in reducing BW and fat in adults with overweight or obesity, as well as their impact on PA-related factors. This review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Comprehensive searches were performed in October 2024 across PubMed, Cochrane Library, Web of Science, and Ovid MEDLINE databases. Eligible studies included adults (aged ≥18 years) with objectively confirmed overweight or obesity who used digital interventions aligned with international PA guidelines. Risk of bias was evaluated using the Cochrane Risk of Bias (version 2) tool for randomized controlled trials and the Risk of Bias in Nonrandomized Studies of Interventions tool for nonrandomized studies. A random-effects meta-analysis with Hartung-Knapp adjustment was performed using R software. Out of 4948 studies identified, 188 (3.8%) were screened in full and 30 (0.6%) met the eligibility criteria. Intervention durations ranged from 8 weeks to 24 months (average 6.4, SD 5.5 months). Meta-analysis showed that guideline-based digital exercise interventions significantly reduced BW compared to controls (mean difference [MD]=-1.17 kg; P=.003; I2=0.0%), with subgroup analysis revealing greater effects in active (nondigital) controls (MD=-1.23 kg; I2=7.5%) compared to passive (waitlist) controls (MD=-0.52 kg; I2=0.0%). A significant reduction in BMI was observed (MD=-0.50 kg/m2; P=.003), although with substantial heterogeneity (I2=70.0%), and subgroup analysis showed greater effects compared to passive controls (MD=-0.70 kg/m2; I2=43.1%) rather than to active controls (MD=-0.45 kg/m2; I2=74.5%). No significant effect was observed for body fat percentage overall (MD=-0.08%; P=.84; I2=7.4%). Qualitative analysis (including findings from noncomparative studies) showed that guideline-based digital exercise interventions led to significant reductions in BW (22/25, 88% studies; range -1.3 to -8.4 kg); BMI (19/23, 83% of studies; range -0.4 to -3.4 kg/m2); waist circumference (15/16, 94% of studies; range -2.1 to -9.2 cm), body fat percentage (9/9, 100% of studies; range -0.3% to -4.1%); and fat mass (7/7, 100% of studies; range -0.4 to -6.5 kg), while findings for waist-to-hip ratio and PA outcomes were inconsistent. Guideline-based digital PA and exercise interventions show potential in reducing excess BW in adults with overweight or obesity, with stronger effects when compared to nondigital interventions. However, their superiority over traditional methods is uncertain for BMI and body composition. Substantial variations in study designs present challenges in drawing definitive conclusions on specific characteristics of effective digital exercise tools. PROSPERO CRD42024620020; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024620020.

Background/Objectives: The implementation of polygenic scores (PGSs) and multifactorial risk assessments (MFRAs) has the potential to enhance breast cancer risk stratification, particularly in carriers of moderate-penetrance pathogenic variants (PVs), whose risk profiles often remain unclear if testing is limited to monogenic risk factors. Methods: To enhance breast cancer risk stratification, we included the BCAC313 polygenic score, together with MFRA, for carriers of moderate-penetrance pathogenic variants (PVs) during routine diagnostics and assessed its effect on the classification of patients' risk categories in a real-world cohort at our center in its first year of implementation. Seventeen carriers with PVs in moderate-risk breast cancer genes were included in this study. Thirteen of them qualified for analysis for a full MFRA, including PGS, according to ancestry estimation and clinical criteria. The MFRA was performed using the CanRisk tool, which incorporates clinical, lifestyle, familial, and genetic data, including the BCAC313 score. Results: PGS z-scores were significantly higher in breast cancer patients compared to the unaffected control cohort (p = 0.016). The MFRA, including PGS, increased risk estimates for contralateral breast cancer in seven of eight patients with breast cancer and for primary breast cancer in three of five healthy carriers, compared to the risk conferred by the MFRA and moderate-penetrance pathogenic variant alone. Risk estimates varied widely, demonstrating the value of MFRA in personalized care. In five cases, one with a CHEK2-PV and four with an ATM-PV, the modified risk assessment contributed to the surgical decision for a prophylactic mastectomy. Conclusions: The MFRA, including PGS, provides the clinically meaningful refinement of breast cancer risk estimates in individuals with moderate-risk PVs. Personalized risk predictions can inform clinical management and support decision-making, which highlights the utility of this approach in clinical practice.

Motor skill development in early childhood is essential for children's overall growth, including social participation and academic readiness. Despite the importance of motor skills, Austria's preventive health program for preschoolers currently lacks standardized motor screenings. This study explores the perceptions of parents and kindergarten educators regarding the potential implementation of regular, standardized motor skill screenings in kindergartens across Tyrol. In April-May 2024, questionnaires were distributed to 25 kindergartens across Tyrol. Parents and educators responded to structured and open-ended questions on the perceived importance, feasibility and potential impact of mobility screenings. Quantitative data were analysed descriptively, whereas qualitative data underwent thematic analysis to identify key themes regarding attitudes and practical considerations for implementing mobility screenings. A total of 892 parents and 19 educator teams responded. Both strongly supported mobility screenings, with 90.6% of the parents viewing them as important as existing health screenings and 100% of educators valuing their importance regarding children's motor development. Qualitative responses from parents emphasized the role of mobility screenings in promoting general development while highlighting the need for a child-friendly, voluntary approach. Educators not only showed strong support, noting the feasibility and benefit of daily routines, but also identified logistical and communication challenges regarding follow-up. Both groups acknowledged the potential of standardized screenings for early identification, allowing timely developmental support. The findings underscore the perceived importance of mobility screening in kindergarten to identify motor skill deficits in early childhood, an insight strongly supported by both educators and parents. Stakeholder support is a critical prerequisite for potential policy adaptations towards offering standardized kindergarten mobility screenings. To ensure effective integration, practical factors such as logistics, tool selection and accessibility must be addressed.

The birth process involves biopsychosocial aspects, the identification of which has been little researched. This systematic review aims to identify biopsychosocial aspects of interventions during physiological birth in first-time mothers and to assess the effectiveness of these interventions on birth outcomes.A systematic guideline search resulted in the definition of a physiological birth of first-time mothers with a singleton from the cephalic position at 37+0 to 42+0 weeks' gestation. A systematic literature search assessed intervention studies for evidence quality using the GRADE methodology. Structured content analysis according to Mayring was used to identify biopsychosocial aspects.18 bio-organic, psychological and sociological aspects were identified from 20 studies. The quality of evidence was mostly low to very low due to inadequate reporting of fetal and maternal outcomes and characteristics. Moderate confidence was shown for midwifery care and aromatherapy in increasing spontaneous labor, and transcutaneous electrical nerve stimulation in improving satisfaction, subjective pain perception and APGAR score. Identified biopsychosocial aspects enable a multidimensional assessment of physiological birth and could lead to a biopsychosocial care model. Insufficient quality of evidence does not allow the derivation of specific interventions. Studies in obstetrics should use defined endpoints and characteristics to improve the quality of evidence.

Environmental physiotherapy is epistemologically anchored in the critical recognition that physiotherapeutic practice is fundamentally embedded within a planetary ecological framework, demanding a holistic, systemically integrated approach to professional practice. This perspective article highlights and underscores the value of risky play for child health and the commonalities with environmental pediatric physiotherapy. The article starts with a discussion of current challenges in child health around the globe, often resulting from a lack of physical activity of children, and claims finding new, promising and sustainable ways that are able to attract children and their parents to playfully increase the time that children are physically active. Followed by an overview of physiotherapists' roles and responsibilities in child public health, the authors point to the need to move beyond an isolated profession-centric approach when tackling the existing, concerning issues in child health worldwide. Foundational information about risky play underpinned with scientific results and its acknowledgment by other health professions is then presented. By including a perspective of what children want, the authors identify a gap between the world's children's actual needs and current societal offers. The benefits of risky play for child health are presented in detail, along with a discussion of various considerations pertaining to child safety. Concluding, this perspective article demonstrates how physiotherapists can contribute to better child health by including risky play in physiotherapy theory and practice.

Due to the rising number of long-term mental health conditions, there has been a shift in therapeutic focus from curing these conditions, to living a meaningful life with them. Self-management is described as the ability to live with the emotional, life role and medical consequences of long-term conditions such as schizophrenia. However, the perspective of people with schizophrenia on self-management in current literature is missing. A lack of understanding of strategies used by people with schizophrenia to self-manage, could adversely affect the use of self-management interventions. Therefore, this study aims to identify how people with schizophrenia manage their daily life. Semi-structured interviews (n = 9) were conducted in a qualitative descriptive design. The study is reported by using the COREQ checklist. All participants, recruited through purposive sampling, have been stabilised after a schizophrenic episode and have been reintegrated into their community. The data were analysed through thematic analysis. Self-management for people with schizophrenia is an individualised process that revolves around performing day-to-day activities according to the participant's wishes. In addition, participants tried to prevent relapse by self-managing daily life. Personal-, social- and schizophrenia-related factors were seen as barriers and/or facilitators in their self-management. These barriers and/or facilitators were self-managed using daily activities. Current self-management interventions for this population often aim at improving medication adherence. Self-management interventions facilitated by health care professionals should (i) focus more on supporting patients in finding their daily structure through meaningful activities and (ii) be mindful of the duality contained within self-management of people with stabilised schizophrenia.

Background: Human albumin, a vital plasma protein with diverse molecular properties, has garnered interest for its therapeutic potential in various diseases, including critical illnesses. However, the efficacy of albumin infusion in critical care and its associated complications remains controversial. To address this, a review of recent meta-analyses was conducted to summarize the evidence pertaining to albumin use in critical illness. Methods: Adhering to the rapid review approach, designed to provide a concise synthesis of existing evidence within a short timeframe, relevant meta-analyses published in the last five years were identified and analyzed. PubMed, Embase, and Cochrane databases of systematic reviews were searched using pre-defined search terms. Eligible studies included meta-analyses examining the association between albumin infusion and outcomes in critically ill and perioperative patients. Results: Twelve meta-analyses were included in the review, covering diverse critical illnesses and perioperative scenarios such as sepsis, cardiothoracic surgery, and acute brain injury. The analyses revealed varying levels of evidence for the effects of albumin use on different outcomes, ranging from no significant associations to suggestive and convincing. Conclusions: Albumin infusion stabilizes hemodynamic resuscitation endpoints, improves diuretic resistance, and has the potential to prevent hypotensive episodes during mechanical ventilation in hypoalbuminemic patients and improve the survival of patients with septic shock. However, caution is warranted due to the methodological limitations of the included studies. Further high-quality research is needed to validate these findings and inform clinical decision-making regarding albumin use in critical care.